raltegravir-potassium and HIV-Infections

Integrase strand transfer inhibitors (INSTIs), including raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB), are increasingly used, given excellent data on their efficacy, effectiveness, and tolerability profile in adults, while data in children are accumulating. To review the most recent evidence on the efficacy, effectiveness, safety, and resistance of INSTIs in children, a quick narrative review of the available literature data was performed using the MEDLINE/PubMed and Scopus databases, including only English-language studies, published between 2009 and 2022. Six studies (259 children) on RAL use, 17 studies (3,448 children) on DTG, 2 studies (73 children) on EVG, and 1 study (102 children) on BIC were retrieved. Results on efficacy and effectiveness were close to those reported in adult studies, suggesting similarities between children and adult population. Resistance to RAL was detected in four studies, ranging between 5.0% to 35.3% of participants. In four studies resistance to DTG occurred in 12.4% to 22% of children. Adverse events to RAL have been uncommon reported. In studies on EVG, 8% to 74% of children developed uveitis, nausea, or abdominal pain. In DTG studies, the proportion of weight gain ranged from 10% to 87%, and neuropsychiatric effects ranged 1% to 16% of participants. One BIC study reported adverse events >10% of participants. The evidence supports high efficacy and low toxicity of INSTIs in pediatric and adolescent populations.

Topics: Adolescent; Adult; Child; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Integrases; Oxazines; Raltegravir Potassium

The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the pharmacokinetics of drugs and, as a consequence, increase the risk of drug interactions and toxicity that may impact treatment. The aim of this study was to carry out a systematic review of the literature on the effect of aging on ARV pharmacokinetics.. Searches were performed in the BVS, EMBASE and PUBMED databases until November 2022. All studies available in English, Spanish and Portuguese investigating the pharmacokinetics of ARV approved by the US Food and Drug Administration (FDA) from 2005 to 2020 were selected. Peer-reviewed publications were included if they met all criteria: adults (≥ 18 years of age) living with or without HIV; report any pharmacokinetic parameter or plasma concentration of at least one of the following ARVs: tenofovir alafenamide fumarate (TAF); doravirine (DOR), rilpivirine (RIL) and etravirine (ETR); darunavir (DRV), tipranavir (TPV) and fostemsavir (FTR); dolutegravir (DTG), raltegravir (RAL), bictegravir (BIC) and elvitegravir (EVG); maraviroc (MVC); ibalizumab (IBA); cobicistat (COBI). Pharmacokinetic parameters were reported stratified per age group: young adults (aged 18-49 years) or older (age ≥ 50 years) and all studies were evaluated for quality. The review protocol was registered in the PROSPERO database (registration number CRD42021236432).. Among 97 studies included, 20 reported pharmacokinetic evaluation in older individuals (age ≥ 50 years). Twenty five percent of the articles were phase I randomized clinical trials with HIV-negative participants and non-compartmental pharmacokinetic analysis presenting the parameters area under the curve (AUC) and peak drug concentration (C. Exposure to DRV increases modestly with age, while exposure to BIC, DOR and RAL appears to be unaffected by age. As the available evidence to confirm a potential effect of aging on ARV pharmacokinetics is limited, further studies are necessary.

Topics: Adenine; Adolescent; Aged; Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; HIV Infections; Humans; Pharmaceutical Preparations; Raltegravir Potassium; Tenofovir; Young Adult

Global antiretroviral therapy has entered a new era. Integrase strand transfer inhibitor (INSTI) has become the first choice in acquired immunodeficiency syndrome (AIDS) treatment. Because INSTI has high antiviral efficacy, rapid virus inhibition, and good tolerance. However, INSTIs may increase the risk of obesity. Each INSTI has its unique impact on weight gain in patients with human immunodeficiency virus (HIV)/AIDS. This study systematically assessed different INSTIs in causing significant weight gain in HIV/AIDS patients by integrating data from relevant literature.. PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), and Wanfang databases were searched to find studies on the influence of different INSTIs in weight gain. Data on weight change were extracted, and a network meta-analysis was performed.. Eight studies reported weight changes in HIV/AIDS patients were included. Results of the network meta-analysis showed that the weight gain of HIV/AIDS patients treated with Dolutegravir (DTG) was significantly higher than that of Elvitegravir (EVG) [MD = 1.13, (0.18-2.07)]. The consistency test results showed no overall and local inconsistency, and no significant difference in the results of the direct and indirect comparison was detected (p > 0.05). The rank order of probability was DTG (79.2%) > Bictegravir (BIC) (77.9%) > Raltegravir (RAL) (33.2%) > EVG (9.7%), suggesting that DTG may be the INSTI drug that causes the most significant weight gain in HIV/AIDS patients.. According to the data analysis, among the existing INSTIs, DTG may be the drug that causes the most significant weight gain in HIV/AIDS patients, followed by BIC.

Topics: Acquired Immunodeficiency Syndrome; Body Weight; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Network Meta-Analysis; Raltegravir Potassium

Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.

Topics: Adult; Child; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium

Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0-19 years.. Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009-March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted.. In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0-50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug.. These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes.

Topics: Adolescent; Child; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Raltegravir Potassium

Integrase Strand Transfer Inhibitors (INSTIs) are currently used as the most effective therapy in the treatment of human immunodeficiency virus (HIV) infections. Raltegravir (RAL) and Elvitegravir (EVG), the first generation of INSTIs used successfully in clinical treatment, are susceptible to the emergence of viral resistance and have a high rate of cross-resistance. To counteract these resistant mutants, second-generation INSTI drugs have been developed: Dolutegravir (DTG), Cabotegravir (CAB), and Bictegravir (BIC). However, HIV is also able to develop resistance mechanisms against the second-generation of INSTIs. This review describes the mode of action of INSTIs and then summarizes and evaluates some typical resistance mutations, such as substitution and insertion mutations. The role of unintegrated viral DNA is also discussed as a new pathway involved in conferring resistance to INSTIs. This allows us to have a more detailed understanding of HIV resistance to these inhibitors, which may contribute to the development of new INSTIs in the future.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Integrases; Mutation; Raltegravir Potassium

There are approximately 40 million people living with HIV globally, and 21% (7.9 million) are older adults (aged > 50 years) as of 2019. The average age of HIV-positive patients is predicted to increase to 58 by 2035. The favorable clinical efficacy of integrase strand transfer inhibitors has led to high rates of viral suppression and have now become the preferred agents by the AIDS guideline when initiating antiretroviral therapy. There are concerns of increasing adverse effects from HIV medications, such as integrase strand transfer inhibitors, as a result of changes in pharmacodynamic and pharmacokinetic parameters within the older population. The authors aim to describe the safety concerns of the current integrase strand transfer inhibitors based upon a narrative literature review, including recommendations for drug-drug interactions, and relevant comorbidities to consider for selection of the most appropriate integrase strand transfer inhibitor for older people living with HIV. Raltegravir is a well-tolerated option with minor adverse events; however, adherence to a twice-daily regimen may be difficult in older patients who are also taking many other medications for various comorbidities. Elvitegravir is also well tolerated with limited adverse effects, but has many drug-drug interactions that may pose problems for older patients with polypharmacy. Dolutegravir has been associated with more frequent adverse events, such as neuropsychiatric disorders.

Topics: Aged; Drug Interactions; HIV Infections; HIV Integrase Inhibitors; Humans; Integrases; Pyridones; Raltegravir Potassium

There is still no consensus on the optimal management of COVID-19 within the general population due to the emerging evidence base. High-risk groups, including kidney transplant recipients living with HIV present unique additional challenges. Here we discuss two kidney transplant recipients living with HIV with SARS-CoV-2 infection and their clinical course, and review the existing literature for this subset of challenging patients.

Topics: Adult; Anti-Bacterial Agents; Anti-HIV Agents; Atovaquone; CD4 Lymphocyte Count; CD4-CD8 Ratio; COVID-19; Dideoxynucleosides; Female; Glucocorticoids; Graft Rejection; HIV Infections; HIV-1; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Lamivudine; Male; Middle Aged; Mycophenolic Acid; Pneumonia, Pneumocystis; Prednisolone; Raltegravir Potassium; RNA, Viral; SARS-CoV-2; Tacrolimus; Trimethoprim, Sulfamethoxazole Drug Combination

Many innovations, such as long-acting agents, new delivery modalities (injectable and nanoparticles), and novel paradigms (immunotherapy or dual therapy), have been introduced to facilitate the administration of antiretroviral treatment (ART) to patients infected with HIV and improve their adherence and quality of life without altering the drugs' effectiveness. Studies have investigated the use of intermittent treatment, especially weekends-off ART in HIV-suppressed patients. In this review, we analyzed data concerning intermittent ART to help determine if this strategy is reasonable for the management of patients living with HIV. The results of early studies, in 2007-2015, were encouraging, but the studies were flawed because of the small number of patients included, the absence of a control arm, and random designs with variable patterns of ART administration. From 2016, studies have included more patients, and some are prospective, randomized controlled studies. While non-nucleoside reverse transcriptase inhibitors have been most studied, treatment with integrase inhibitors also has been reported, with the findings that viral resistance did not appear when treatment failed with dolutegravir but not with raltegravir. The most recent study, QUATUOR, found that a 4-day on, 3-day off pattern was non-inferior to the continuous pattern (7 days on). Better-quality studies with long-term follow-up (96 weeks or more) are needed to determine the validity of intermittent treatment and the optimal regimens and monitoring to be used in the management of viro-logically suppressed patients living with HIV.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; HIV Infections; Humans; Prospective Studies; Quality of Life; Raltegravir Potassium; Viral Load

Antiretroviral therapy has been imperative in controlling the human immunodeficiency virus (HIV) epidemic. Most low- and middle-income countries have used nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors extensively in the treatment of HIV. However, integrase strand transfer inhibitors (INSTIs) are becoming more common. Since their identification as a promising therapeutic drug, significant progress has been made that has led to the approval of five INSTIs by the US Food and Drug Administration (FDA), i.e. dolutegravir (DTG), raltegravir (RAL), elvitegravir (EVG), bictegravir (BIC) and cabotegravir (CAB). INSTIs have been shown to effectively halt HIV-1 replication and are commended for having a higher genetic barrier to resistance compared with NRTIs and NNRTIs. More interestingly, DTG has shown a higher genetic barrier to resistance compared with RAL and EVG, and CAB is being used as the first long-acting agent in HIV-1 treatment. Considering the increasing interest in INSTIs for HIV-1 treatment, we focus our review on the retroviral integrase, development of INSTIs and their mode of action. We also discuss each of the INSTI drugs, including potential drug resistance and known side effects.

Topics: Amides; Anti-Retroviral Agents; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25-200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis.Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25-200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.

Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Child, Preschool; Female; HIV Infections; Humans; Lamivudine; Myositis; Raltegravir Potassium; Viral Load

Topics: Adolescent; Adult; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Pregnancy; Pyridones; Raltegravir Potassium

Integrase strand transfer inhibitors (INSTIs) are the most recent class of antiretroviral drugs with potent and durable antiviral activity used to treat human immunodeficiency virus type 1 (HIV-1) infection. However, development of drug resistance increases the risk of treatment failure, disease progression and mortality. A better understanding of drug efficacy and resistance against INSTIs is crucial for their efficient use and the development of new antiretrovirals. A meta-analysis of studies reporting efficacy and resistance data on INSTI use in HIV-infected patients was performed. Odds ratios (ORs) of efficacy outcome data favouring INSTI use in different clinical settings demonstrated that INSTIs have higher efficacy compared with drugs of other classes. For combination antiretroviral therapy-naïve patients and virologically-suppressed patients who switched to INSTI-based therapy, the OR was 1.484 (95% CI 1.229-1.790) and 1.341 (95% CI 0.913-1.971), respectively. ORs of resistance data indicated decreased treatment-emergent resistance development to dolutegravir (DTG) upon virological failure than to non-INSTIs (OR = 0.081, 95% CI 0.004-1.849), whereas the opposite was observed for raltegravir (RAL) (OR = 3.137, 95% CI 1.827-5.385) and elvitegravir (EVG) (OR = 1.886, 95% CI 0.569-6.252). Pooled analysis of resistance data indicated that development of resistance to DTG and bictegravir was rare, whereas EVG and RAL had low genetic barriers to resistance and the intensive cross-resistance between them limits INSTI efficiency. Efficient means of monitoring the emergence of resistance to INSTIs and the development of drugs with high genetic barriers are clear paths for future research.

Topics: Amides; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

Prevention of mother-to-child transmission of HIV and optimal maternal treatment are the most important goals of antiretroviral therapy in pregnant women with HIV. These goals may be at risk due to possible reduced exposure during pregnancy caused by physiological changes. Limited information is available on the impact of these physiological changes. This is especially true for HIV-integrase inhibitors, a relatively new class of drugs, recommended first-line agents and hence used by a large proportion of HIV-infected patients. Therefore, the objective of this review is to provide a detailed overview of the pharmacokinetics of HIV-integrase inhibitors in pregnancy. Second, this review defines potential causes for the change in pharmacokinetics of HIV-integrase inhibitors during pregnancy. Despite increased clearance, for raltegravir 400 mg twice daily and dolutegravir 50 mg once daily, exposure during pregnancy seems adequate; however, for elvitegravir, the proposed minimal effective concentration is not reached during pregnancy. Lower exposure to these drugs may be caused by increased hormone levels and, subsequently, enhanced drug metabolism during pregnancy. The pharmacokinetics of bictegravir and cabotegravir, which are under development, have not yet been evaluated in pregnant women. New studies need to prospectively assess whether adequate exposure is reached in pregnant women using these new HIV-integrase inhibitors. To further optimize antiretroviral treatment in pregnant women, studies need to unravel the underlying mechanisms behind the changes in the pharmacokinetics of HIV-integrase inhibitors during pregnancy. More knowledge on altered pharmacokinetics during pregnancy and the underlying mechanisms contribute to the development of effective and safe antiretroviral therapy for HIV-infected pregnant women.

Topics: Amides; Anti-Retroviral Agents; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Knowledge; Oxazines; Piperazines; Pregnancy; Pyridones; Quinolones; Raltegravir Potassium

Clinicians sometimes use switching strategies based on regimens such as RAL + ABC/3TC or RPV + ABC/3TC in order to resolve tolerability or safety issues associated with conventional recommended first-line strategies. Despite the low genetic barrier of these regimens, high safety and efficacy rates have been reported in retrospective studies.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Combinations; Drug Resistance, Viral; Drug Substitution; HIV Infections; HIV-1; Humans; Lamivudine; Raltegravir Potassium; Rilpivirine; Treatment Outcome; Viral Load

Treatment of neurological, neurocognitive, and neuropsychiatric impairment in the setting of human immunodeficiency virus (HIV) infection remains a complex problem, given several possible mechanisms of pathogenesis. The etiology must be determined based on clinical judgment and objective evidence, including cerebrospinal fluid (CSF) data from lumbar puncture and neuroimaging information from magnetic resonance imaging, when available and indicated. Other neuroinfectious etiologies must be ruled out, including central nervous system (CNS) opportunistic infections. HIV replication in the CNS (including CSF escape) should be evaluated for and excluded. If CSF HIV is detected, we recommend a treatment switch to antiretrovirals (ARVs) targeted to address any CSF HIV resistance mutations identified, or empiric treatment intensification using ARVs with high CNS penetration. If CSF HIV is not detected, treatment intensification with CCR5 inhibitors may be considered as an adjunct to reduce neuroinflammation. Finally, the current ARV regimen must be examined for possible neurotoxicity. Efavirenz has been well-recognized for its neuropsychiatric adverse effects and potential for causing sleep disturbances. Similar concerns have recently been raised with integrase inhibitors, especially dolutegravir and raltegravir, although further studies are needed to determine the risks for clinically relevant neuropsychiatric side effects from these medications, given their overall high potency and proven success in treating systemic HIV.

Topics: Alkynes; Anti-Retroviral Agents; Benzoxazines; Central Nervous System Infections; Cyclopropanes; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Oxazines; Piperazines; Pyridones; Raltegravir Potassium

Raltegravir (RAL) was the first commercialized agent from a new drug class with an innovative target, the integrase. Since its introduction in clinical practice RAL has become widely used for the treatment of HIV-1 infected patients. A decade after its approval, this article reviews key evidence from RAL with a special interest on safety outcomes. Areas covered: Pharmacologic, safety and efficacy data of RAL from clinical trials and post-commercialization published reports are hereby summarized after a literature review including PubMed search, relating proceedings and abstracts from relevant international HIV conferences, assessment reports from European and United States regulatory agencies and treatment guidelines (World Health Organization, United States Department of Health and Human Services and European AIDS Clinical Society), up to October 2017. Most frequent search terms were 'raltegravir', 'safety', 'adverse events', 'efficacy' and 'integrase-inhibitors'. Expert opinion: Despite the arrival of new integrase strand transfer inhibitors (INSTIs) with advantages in terms of dosing convenience (elvitegravir, ELV) and higher genetic barrier (dolutegravir, DTG), RAL has stood the test of time and its overall favourable safety profile, without significant appearance of unexpected adverse events, vouch for its relevance in the antiretroviral armamentarium.

Topics: HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Raltegravir Potassium

Integrase strand transfer inhibitors (INSTIs) belong to a novel class of antiretroviral agents that have emerged as the new first-line treatments. Three such compounds are currently available, raltegravir, elvitegravir, dolutegravir and two more under development, bictegravir and cabotegravir. These compounds share the same mode of action but exhibit different pharmacokinetic/ pharmacodynamic properties, and drug-drug interactions. A series of studies in the past decade have established their efficacy compared to previous regimens, both in treatment- naïve and experienced patients. INSTIs have demonstrated a favorable safety profile with fewer adverse events and low rates of virological failure. Emergence of resistance to these agents, however, is a worrying concern, particularly for elvitegravir and raltegravir that display a lower genetic barrier than dolutegravir. On-going trials aim at establishing INSTIs as part of dual-drug HIV treatments or even monotherapy. New long-acting, injectable formulations are under investigation for treatment or prevention.

Topics: Anti-Retroviral Agents; Delayed-Action Preparations; Drug Compounding; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium

The World Health Organization identified a need for evidence to inform revision of second- and third-line antiretroviral therapy (ART) options in children failing ART. We performed an in-depth scoping review of all available literature on second-line and subsequent ART regimens in children younger than 18 years.. We comprehensively searched, without language or date limitations, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov.. The search retrieved 1982 records. Eighteen studies provided efficacy data: 1 randomized controlled trial, 7 phase II trials, 5 prospective and 5 retrospective cohorts. Five studies evaluated regimens in children failing first-line ART, 4 in children with multidrug resistance and 9 in children with variable treatment experience. Only 10/18 studies reported week 48 or month 12 outcomes. The overall proportion of children with virologic suppression defined by study at week 48 was 61.8%. Although the randomized controlled trial had low risk of bias, outcomes were similar between groups because of highly active optimized background regimens. All phase II and prospective studies were judged to have moderate to high risk of bias. No study compared currently recommended lopinavir-based second-line regimens for nonnucleoside reverse transcriptase inhibitor failures to other non-nonnucleoside reverse transcriptase inhibitor regimens head-to-head.. We found no evidence comparing current World Health Organization-recommended second- and third-line ART regimens with regimens including drugs of interest: raltegravir, darunavir, etravirine and atazanavir. Randomized controlled trials or prospective cohort studies with comparator arms, and bridging studies, ideally conducted in resource-limited settings, are required to guide future recommendations.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Child; Child, Preschool; Clinical Trials, Phase II as Topic; Cohort Studies; Darunavir; Drug Administration Schedule; Female; HIV Infections; Humans; Male; Nitriles; Practice Guidelines as Topic; Pyridazines; Pyrimidines; Raltegravir Potassium; Viral Load

Selection of optimal second-line antiretroviral therapy (ART) has important clinical and programmatic implications. To inform the 2016 revision of the WHO ART guidelines, we assessed the comparative effectiveness and safety of available second-line ART regimens for adults and adolescents in whom first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens have failed.. In this systematic review and network meta-analysis, we searched for randomised controlled trials and prospective and retrospective cohort studies that evaluated outcomes in treatment-experienced adults living with HIV who switched ART regimen after failure of a WHO-recommended first-line NNRTI-based regimen. We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials for reports published from Jan 1, 1996, to Aug 8, 2016, and searched conference abstracts published from Jan 1, 2014, to Aug 8, 2016. Outcomes of interest were viral suppression, mortality, AIDS-defining illnesses or WHO stage 3-4 disease, discontinuations, discontinuations due to adverse events, and serious adverse events. We assessed comparative efficacy and safety in a network meta-analysis, using Bayesian hierarchical models.. We identified 12 papers pertaining to eight studies, including 4778 participants. The network was centred on ritonavir-boosted lopinavir plus two nucleoside or nucleotide reverse transcriptase inhibitors. Ritonavir-boosted lopinavir monotherapy was the only regimen inferior to others. With the lower estimate of the 95% credible interval (CrI) not exceeding the predefined threshold of 15%, evidence at 48 weeks supported the non-inferiority of ritonavir-boosted lopinavir plus raltegravir to regimens including ritonavir-boosted protease inhibitor plus two NRTIs with respect to viral suppression (odds ratio 1·09, 95% CrI 0·88-1·35). Estimated efficacy of ritonavir-boosted darunavir (800 mg once daily) was too imprecise to determine non-inferiority. Overall, regimens did not differ significantly with respect to continuations, AIDS-defining illnesses or WHO stage 3-4 disease, or mortality.. With the exception of ritonavir-boosted lopinavir plus raltegravir, the evidence base is unable to provide strong support to alternative second-line options to ritonavir-boosted protease inhibitor plus two NRTIs, and thus more trials are warranted.. WHO.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Network Meta-Analysis; Prospective Studies; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir

Integrase strand transfer inhibitors (INSTIs) are the preferred third agent in first-line antiretroviral therapies. Raltegravir (RAL) was the first INSTI to be approved and used in naïve and experienced patients. Due to its good tolerability and low side effects, RAL has been largely used also in hepatitis coinfected patients. Many years of experience in RAL use now allow literature evidence to be gathered on its safety in HIV/HCV-co-infected patients pre, during and post direct acting agents (DAA) treatment, at all possible stages. In both clinical trials and published case series, RAL has been well tolerated in patients harboring HCV co-infection and also in cirrhotic patients with mild hepatic impairment. Literature data show no major interactions or the need for dose adjustments with any of the DAA currently in use for HCV treatment, or with ribavirine. Hence, RAL can be safely administered during HCV treatment with DAA and may be used as a "temporary" regimen in patients who do not present major integrase-inhibitor mutations. Moreover, its characteristics are also favorable in case of orthotropic liver transplantation, both for the evidence of hepatic safety and for possible co-administration with immunosuppressant agents.

Topics: Coinfection; Hepacivirus; Hepatitis C; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium; Time; Treatment Outcome

Topics: Adult; Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Raltegravir Potassium; Tablets; Tenofovir

Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV, with an estimated prevalence between 2.4 and 17%. Such patients are increasingly affected by diseases associated with ageing, including cardiovascular disease and CKD, and the prevalence of risk factors such as smoking and dyslipidaemia is increased in this population. Proteinuria is also now recognized as a common finding in individuals living with HIV. While combination antiretroviral (ARV) treatments reduce CKD in the HIV-infected population overall, some ARV drugs have been shown to be nephrotoxic and associated with worsening renal function. Over the last few years, several highly efficacious new ARV agents have been introduced. This brief review will look at the novel agents dolutegravir, raltegravir, elvitegravir, cobicistat, tenofovir alafenamide fumarate and atazanavir, all of which have been licensed relatively recently, and describe issues relevant to renal function, creatinine handling and potential nephrotoxicity. Given the prevalence of CKD, the wide range of possible interactions between HIV, ARV therapy, CKD and its treatments, nephrologists need to be aware of these newer agents and their possible effect on kidneys.

Topics: Adenine; Alanine; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Creatinine; Disease Progression; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Oxazines; Piperazines; Proteinuria; Pyridones; Quinolones; Raltegravir Potassium; Renal Insufficiency, Chronic; Tenofovir

Topics: Anti-Retroviral Agents; Area Under Curve; Coinfection; Cytochrome P-450 CYP3A; Drug Combinations; Drug Interactions; Female; Half-Life; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Liver Failure; Metabolic Clearance Rate; Oxazines; Piperazines; Pregnancy; Protein Binding; Pyridones; Quinolones; Raltegravir Potassium; Renal Insufficiency

This review of recent published literature and data presented at scientific meetings on integrase stand transfer inhibitors (InSTIs) examines how these findings may impact on their future clinical use.. Elvitegravir (EVG), raltegravir (RAL) and dolutegravir (DTG) are InSTIs recommended as first-line options for treatment naive patients by the European AIDS Clinical Society, British HIV Association, International AIDS Society-USA and DHHS. InSTIs have gained a leading role in the management of HIV-1 because of increased viral suppression and maintaining undetectability with fewer side-effects.RAL 1200 mg once-daily (QD) has been shown to be noninferior to 400 mg BD, and the European Medicines Agency has approved QD RAL for review. RAL and DTG are not metabolized via cytochrome P450 (CYP) resulting in fewer drug interactions and less toxicity risk in patients receiving direct-acting antivirals and other coadministered medications.EVG is currently available as a single tablet regimen and requires cobisistat, a pharmacokinetic booster and CYP3A inhibitor to allow QD dosing. EVG will soon be available in combination with tenofovir alfenamide, which is as efficacious as tenofovir disoproxil fumarate, but offers better renal and bone outcomes.DTG has a high genetic barrier to resistance and has been the subject of a number of simplification and treatment failure trials and shown promise. There are some emerging reports of neuropsychiatric and gastrointestinal side-effects associated with DTG, which were not reported in clinical trials emphasizing the importance of real-life data.Carbotegravir, a long-acting InSTI, is currently in the pipeline of development.. All three InSTIs have impressive data on efficacy, tolerability and safety. The unique differences of each InSTI's pharmacokinetics and pharmacodynamics lend themselves to various clinical scenarios, enabling us as clinicians to provide better patient-centred care.

Topics: Cobicistat; Drug Interactions; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Viral Load

The risk of mother to child transmission (MTCT) of HIV increases in pregnant women diagnosed late in pregnancy. Some experts suggest that the use of raltegravir (RAL), as part of the antiretroviral treatment in these pregnant women, could reduce the risk of MTCT, since RAL can quickly decrease the viral load.. To evaluate the available scientific information on the efficacy and safety of RAL, during the third trimester of pregnancy, in reducing MTCT of HIV.. We conducted a systematic review of the literature. The following databases were consulted: MEDLINE, Tripdatabase, Cochrane, Lilacs and Web of Science. We included systematic reviews, clinical trials, observational studies or case reports. The search was not filtered by language.. Fourteen studies met the inclusion criteria. Selected studies were case reports or case series. We included, in total, 44 pregnancies (with 45 live births). A case of TMI of HIV was reported. Eight studies reported adverse events, of which four cases can be attributed to the use of RAL.. There is insufficient evidence on the efficacy and safety of RAL to decrease the risk of MTCT in HIV pregnant women who present in the last trimester of pregnancy.

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Raltegravir Potassium; Risk Factors; Treatment Outcome

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral agents used to treat HIV. These drugs--raltegravir, elvitegravir, and dolutegravir--are preferred options for treatment-naïve patients when used in combination with two nucleoside reverse transcriptase inhibitors. Based on clinical trials, INSTIs have been proven to be effective with minimal safety concerns. This article reviews the pharmacologic profile, role in therapy, and safety and efficacy of each agent.

Topics: Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Randomized Controlled Trials as Topic

Raltegravir was previously considered an alternative antiretroviral in pregnancy because of limited data, but recent pregnancy guidelines recommend raltegravir as a preferred integrase treatment option. Data from published articles and preliminary meeting reports between 2001 and July 2015 are reviewed. The literature includes a total of 278 maternal-infant pairs who received raltegravir during pregnancy. The standard raltegravir dose seems safe and effective in preventing mother-to-child transmission in late pregnancy presenters with unknown or unsuppressed viral load, or in multidrug resistance. Viral decay was rapid allowing most women to deliver at undetectable viral levels. Raltegravir was well tolerated, with the exception of a few cases of transient increases in maternal transaminases. No infant adverse effect was consistently reported. Existing data support the use of raltegravir in antiretroviral-naive and experienced pregnant women.

Topics: Anti-HIV Agents; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Treatment Outcome; Viral Load

Three integrase strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), have been approved by the FDA. Resistance against these three INSTIs have been reported and cross-resistance among them has been documented. Due to extensive and dynamic genetic diversity in different HIV-1 variants, significant differences in susceptibility to the INSTIs have been observed among HIV subtypes. This review summarizes what is known about this topic and discusses possible clinical implications.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Integrase strand transfer inhibitors (INSTIs) are a novel class of anti-HIV agents that show high activity in inhibiting HIV-1 replication. Currently, licensed INSTIs include raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG); these drugs have played a critical role in AIDS therapy, serving as additional weapons in the arsenal for treating patients infected with HIV-1. To date, long-term data regarding clinical experience with INSTI use and the emergence of resistance remain scarce. However, the literature is likely now sufficiently comprehensive to warrant a meta-analysis of resistance to INSTIs.. Our team implemented a manuscript retrieval protocol using Medical Subject Headings (MeSH) via the Web of Science, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases. We screened the literature based on inclusion and exclusion criteria and then performed a quality analysis and evaluation using RevMan software, Stata software, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). We also performed a subgroup analysis. Finally, we calculated resistance rates and risk ratios (RRs) for the three types of drugs.. We identified 26 references via the database search. A meta-analysis of the RAL data revealed that the resistance rate was 3.9% (95% CI = 2.9%-4.9%) for the selected randomized controlled trials (RCTs). However, the RAL resistance rate reached 40.9% (95% CI = 8.8%-72.9%) for the selected observational studies (OBSs). The rates of resistance to RAL that were associated with HIV subtypes A, B, and C as well as with more complex subtypes were 0.1% (95% CI = -0.7%-0.9%), 2.5% (95% CI = 0.5%-4.5%), 4.6% (95% CI = 2.7%-6.6%) and 2.2% (95% CI = 0.7%-3.7%), respectively. The rates of resistance to EVG and DTG were 1.2% (95% CI = 0.2%-2.2%) and 0.1% (95% CI = -0.2%-0.5%), respectively. Furthermore, we found that the RRs for antiviral resistance were 0.414 (95% CI = 0.210-0.816) between DTG and RAL and 0.499 (95% CI = 0.255-0.977) between EVG and RAL. When RAL was separately co-administered with nuclear nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs), the rates of resistance to RAL were 0.2% (95% CI = -0.1%-0.5%) and 0.2% (95% CI = -0.2%-0.6%), respectively. The ten major integrase mutations (including N155H, Y143C/R, Q148H/R, Y143Y/H, L74L/M, E92Q, E138E/A, Y143C, Q148Q and Y143S) can reduce the sensitivity of RAL and EVG. The resistance of DTG is mainly shown in 13 integrase mutations (including T97T/A, E138E/D, V151V/I, N155H, Q148, Y143C/H/R, T66A and E92Q).. Our results reveal that the DTG resistance rate was lower than the RAL resistance rate in a head-to-head comparison. Moreover, we confirmed that the EVG resistance rate was lower than the RAL resistance rate. In addition, our results revealed that the resistance rate of RAL was lower than that of efavirenz. The rates of resistance to RAL, EVG and DTG were specifically 3.9%, 1.2% and 0.1%, respectively. Compared with other types of antiviral drugs, the rates of resistance to INSTIs are generally lower. Unfortunately, the EVG and DTG resistance rates could not be compared because of a lack of data.

Topics: Clinical Trials as Topic; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

The first-generation integrase inhibitors (INIs) raltegravir (RAL) and elvitegravir (EVG) have shown efficacy against HIV infection, but they have the limitations of once-more daily dosing and extensive cross-resistance. Dolutegravir (DTG, S/GSK1349572), a second-generation drug that overcomes such shortcomings, is under spotlight. The purpose of this study is to review the evidence for DTG use in clinical settings, including its efficacy and safety.. PubMed, EMbase, Ovid, Web of Science, Science Direct, and related websites were screened from establishment until July 2013, and scientific meeting proceedings were manually searched. Two reviewers independently screened 118 citations repeatedly to identify randomized controlled trials comparing the efficacy and safety of DTG-based regimen with those of RAL- or elvitegravir-based regimens. Using the selected studies with comparable outcome measures and indications, we performed a meta-analysis based on modified intention-to-treat (mITT), on-treatment (OT), and as-treated (AT) virological outcome data. Independent data extraction and quality assessment were conducted.. Four unique studies were included with the use of DTG in antiretroviral therapy-naive patients. In therapy-naive patients, DTG combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) resulted in a significantly better virological outcome with a mITT relative risk (RR)of 1.07 (95 % confidence interval (95 % CI 1.03-1.12). Evidence further supported use of DTG had a better virological suppression in the 50 mg once daily group (mITT RR 1.07; 95 % CI 1.03-1.12) as well as in the sub-analysis in dolutegravir/efavirenz(DTG/EFV) and dolutegravir/raltegravir (DTG/RAL) groups (RR 1.09, 95 % CI 1.03-1.15; RR 1.06, 95 % CI 0.98-1.15, respectively). In the matter of safety of DTG-based regimen, the risk of any event was RR 0.98 (95 % CI 0.94-1.01), the risk of serious adverse events (AEs) was RR 0.84 (95 % CI 0.62-1.15), and the risk of drug-related serious AEs was RR 0.33 (95 % CI 0.13-0.79).. In general, DTG 50 mg given once daily combined with an active background drug is a better choice in terms of both efficacy and safety.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Tenofovir; Treatment Outcome

The aim of this study was to compare an in-person, group-based behavioral weight loss intervention to technology-based interventions in adults with obesity.. Adults (. Findings provide initial information on the use of technology-based interventions that include wearable devices combined with brief monthly telephone calls for weight loss in adults with obesity.. A highly stable amino-coordinated metal-organic framework ZJU-198 has been synthesized and structurally characterized, exhibiting high CO. The use of statins in SLE reduced the serum lipid and high-sensitivity C-reactive protein levels, which suggests a role for the primary prevention of cardiovascular disease. Statins did not affect the SLEDAI score, and therefore their use for modifying SLE disease activity levels is not presently supported.

Topics: Absorptiometry, Photon; Adult; Air Pollutants; Alkynes; Alleles; Animals; Anthracenes; Anthraquinones; Anti-HIV Agents; Benzoxazines; Black or African American; Bone Density; Bone Density Conservation Agents; C-Reactive Protein; Calcium, Dietary; Capsid Proteins; Cardiomyopathy, Dilated; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Collagen Type I; Cyclopropanes; Darunavir; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Emtricitabine; Epitopes; Female; Femur Neck; Gene Expression Profiling; Genetic Predisposition to Disease; Hepatitis, Viral, Animal; Hip Joint; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunization; Inflammation Mediators; Lipoproteins, LDL; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred BALB C; Nitrates; Osteocalcin; Oxidation-Reduction; Parathyroid Hormone; Parvovirus B19, Human; Peptides; Phenotype; Pilot Projects; Polymorphism, Single Nucleotide; Raltegravir Potassium; Ritonavir; RNA, Viral; Sodium Chloride; Tenofovir; Transcriptome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaccines; Vascular Endothelial Growth Factor A; Vitamin D; Young Adult

Long-term use of antiretroviral therapy (ART) to treat HIV infection has been associated with dyslipidemia and metabolic and cardiovascular complications. Available options for patients at risk of cardiovascular disease include antiretroviral drugs with improved lipid profiles. Dolutegravir is one of a new generation of HIV integrase inhibitors recently incorporated into the US Department of Health and Human Services, German, Spanish, and Italian HIV treatment guidelines as a preferred first-line third agent in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) backbone therapies. To understand the lipid profile of dolutegravir in the context of combination ART, we analyzed the lipid outcomes at 48 weeks in ART-naive participants in four phase IIb-IIIb clinical trials.. Variables included in this analysis were total cholesterol (TC), low-density lipoprotein (LDL) cholesterol (LDL-C), high-density lipoprotein (HDL) cholesterol (HDL-C), TC/HDL ratio, and triglycerides at baseline and week 48.. In a comparative analysis, dolutegravir demonstrated a broadly neutral effect on lipids versus efavirenz or ritonavir-boosted darunavir; in both comparisons, patients taking dolutegravir exhibited smaller increases in TC, LDL-C, and triglyceride levels. In comparison with raltegravir, dolutegravir exhibited a similar lipid profile, including small increases in TC, LDL-C, and triglyceride levels for both agents. In the pooled dolutegravir analysis, minimal increases in LDL-C and triglycerides were observed but mean values at 48 weeks remained below National Cholesterol Education Program target levels. HDL-C levels increased at 48 weeks, and the mean TC/HDL-C ratio was 0.6 at 48 weeks; these values are associated with a lower risk of cardiovascular disease.. Together, these data show that dolutegravir has a safer lipid profile in combination ART and provides an important treatment option for older patients who may have other risk factors for metabolic syndrome or cardiovascular disease.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Darunavir; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lipids; Male; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Ritonavir; Time Factors; Treatment Outcome

The resistance profile of dolutegravir differs significantly from those of earlier integrase inhibitors (INI). Dolutegravir displays in vitro activity against mutant HIV-1 harboring any isolated resistance mutations selected during failures to raltegravir or elvitegravir (Y143C/H/, N155H, Q148H/K/R, E92G/Q, T66A/I/K, T97A, E138A/K, G140A/S). Its activity is only compromised by Q148X mutations combined with other mutations, particularly > 1 mutation. The drug has pharmacokinetic/pharmacodynamic properties (plasmatic t1/2 15.3 h, inhibitory quotient 19, dissociative t1/2 from the IN-DNA complex 71 h) that favor a high genetic barrier to resistance. In vitro the selection of HIV-1 resistance to dolutegravir is extremely difficult to achieve. The mutations eventually selected (R263K, H51Y and E138K) do not confer significant resistance, and induce a fitness cost that prevents HIV-1 from evading drug pressure. Suprisingly, HIV-1 is not able to compensate, leading the virus to a previously unnoticed evolutionary pathway with very low chances of developing resistance to INI or the backbone. No treatment-naïve patients starting dolutegravir therapy (+TDF/FTC o ABC/3TC) have selected resistance in IN or against the backbone. No INI- naïve patients with prior virologic failure selected phenotypic dolutegravir resistance. Only 4 out of 354 patients selected resistance mutations in IN, and rates of selection of mutations in IN or against the backbone were significantly lower than with raltegravir. In multitreated patients with widespread resistance including IN resistance, the high efficacy of dolutegravir was confirmed, irrespective of the previous pattern of IN mutations, provided that Q148X associated with other mutations was absent.

Topics: Amino Acid Substitution; Clinical Trials as Topic; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mutation, Missense; Oxazines; Piperazines; Point Mutation; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

Integrase inhibitors (INIs) are the latest class of antiretroviral drugs approved for the treatment of HIV infection and are becoming 'standard' drugs in the treatment of both naïve as well as heavily pretreated individuals with HIV.. Data on efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and resistance are reviewed from the pivotal Phase III clinical trials published in PubMed high-impact medical journals or presented at international meetings.. Due to their outstanding data of efficacy, tolerability, safety--shared by all three drugs (raltegravir, elvitegravir, dolutegravir) currently belonging to this new family of antiretrovirals--INIs have become part of the recommended initial antiretroviral therapy options. Some differences in dosing, drug-drug interactions and robustness/genetic barrier among the three drugs will provide the physician the characteristics to make the best choice.

Topics: Clinical Trials as Topic; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium

Raltegravir was the first available integrase inhibitor for treating HIV-positive patients. This review aims to provide an overview of its role in the management of HIV-1 infection, highlighting its key pharmacokinetic and pharmacodynamic properties.. This review covers material searched and obtained through Medline and PubMed up to April 2015.. Raltegravir for its tolerability, efficacy, few drug-to-drug interactions and for the amount of available data in difficult subgroups of patients is a key drug in the antiretroviral armamentarium. For its weak genetic barrier to resistance and erratic pharmacokinetic profile, it should be administered twice daily and with fully active companion antiretrovirals.

Topics: Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium

Resistance to antiretroviral drugs is an increasingly prevalent challenge affecting both the adult and pediatric HIV-infected populations. Though data on the safety, pharmacokinetics, and efficacy of newer antiretroviral agents in children typically lags behind adult data, newer agents are becoming available for use in HIV-infected children who are failing to respond to or are experiencing toxicities with traditional antiretroviral regimens. Integrase strand transfer inhibitors are one such new class of antiretrovirals. Raltegravir has been US Food and Drug Administration (FDA) approved for use in patients over the age of 4 weeks. Elvitegravir is a second member of this class, and has the potential for use in children but does not yet have a Pediatric FDA indication. Dolutegravir, a second-generation integrase inhibitor, is approved for those older than 12 years. This review summarizes the use of integrase inhibitors in children and adolescents, and highlights the results of recent clinical trials.

Topics: Adolescent; Adult; Age Factors; Child; Drug Approval; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Raltegravir and lamivudine have been part of highly active therapy regimens throughout the past years of antiretroviral therapy. A fixed-dose, single-tablet regimen comprising a non-poloxamer formulation of the integrase inhibitor raltegravir and the transcriptase inhibitor lamivudine (raltegravir/lamivudine; Dutrebis(®)) has been recently licensed for the treatment of HIV-1 infection. In several Phase I pharmacokinetic studies, one Dutrebis (150 mg lamivudine/300 mg raltegravir) fixed-dose combination tablet showed a higher bioavailability but comparable lamivudine and 400 mg raltegravir poloxamer exposures. Thus, the co-administration of raltegravir together with lamivudine created a potent, effective, well-tolerated antiretroviral combination, which could be more convenient for the patient. However, the disadvantage of twice a day administration, and the existence of other fixed-dose combinations limit its widespread clinical use. This article reviews pharmacokinetics data and appraises their potential use in current and future HIV therapy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biological Availability; Drug Combinations; HIV Infections; HIV-1; Humans; Lamivudine; Raltegravir Potassium; Tablets

To review the pharmacology, safety, and efficacy of dolutegravir, an integrase strand-transfer inhibitor (INSTI), and to discuss its role in the treatment of HIV-1-infected patients.. PubMed articles indexed through August 2013 were identified using the search terms S/GSK1349572, dolutegravir, and integrase inhibitor. Information was also identified from the package insert, cited publication references, professional meeting abstracts, and the ClinicalTrials.gov registry.. English language articleswere selected for evaluation, with preference given to safety, efficacy, and pharmacokinetic studies conducted in HIV-1-infected patients.. Dolutegravir is a new INSTI approved for combination treatment in HIV-1-infected adults and adolescent children. Four phase 3 studies provide the basis for current labeling in antiretroviral-naïve and antiretroviral-experienced adults. Results from these studies demonstrate that dolutegravir is noninferior in efficacy to raltegravir in antiretroviral-naïve patients and superior in antiretroviral-experienced patients. Superiority to efavirenz and darunavir/ritonavir was also demonstrated in antiretroviral-naïve patients. Dolutegravir is well tolerated, exhibits low potential for drug-drug interactions, and has a long serum half-life, allowing it to be administered once-daily in patients without preexisting INSTI resistance. Twice-daily administration is recommended in patients with known or suspected resistance mutations to first-generation INSTIs. Mild elevations in serum creatinine occur following dolutegravir initiation from inhibition of renal organic cation transporter 2 but do not reflect changes in glomerular filtration.. Dolutegravir is the first second-generation INSTI and exhibits several advantages over current integrase inhibitors and other preferred antiretrovirals. Long-term efficacy and safety are needed to define dolutegravir's role in treatment.

Topics: Alkynes; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Drug Interactions; Half-Life; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir

Raltegravir (ISENTRESS(®)) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults with HIV-1 infection, and has recently been approved for the treatment of HIV-1-infected children and adolescents aged 2-18 years. A new chewable formulation has been introduced and results of a pharmacokinetic study have led to the establishment of dosages for this formulation for children. In a phase I/II, open-label, multicentre, clinical trial, raltegravir (administered as the chewable or the film-coated tablet) in combination with optimized background antiretroviral therapy was an effective treatment for treatment-experienced children and adolescents with HIV-1 infection, in terms of virologic measures of efficacy (i.e. a decrease of in HIV-1 RNA levels of ≥1 log(10), or an HIV-1 RNA level of <400 copies/mL at the 24-week primary efficacy assessment), with virologic efficacy sustained at the 48-week assessment. Immunologic improvements (increases from baseline in CD4+ cell counts) were also observed. As a component of combination therapy, raltegravir was generally well tolerated over a period of up to 48 weeks. Raltegravir is an important new option for the treatment of children and adolescents with HIV-1 infection, and the introduction of a new chewable formulation (allowing dosage flexibility) extends its benefits to the treatment of younger children.

Topics: Adolescent; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

HIV, a major cause of morbidity and mortality worldwide has been transformed by antiretroviral (ARV) therapy into a manageable condition. Drug resistance, tolerability and drug interactions remain major concerns when choosing ARV therapy. Raltegravir , the first integrase inhibitor in the armamentarium against HIV, has been shown to be efficacious in both treatment-naïve and treatment-experienced patients when used in combination as part of nucleoside-reverse transcriptase inhibitor-containing regimens. Its key advantages include safety, tolerability and fewer drug interactions but it has some important limitations such as a lower barrier to resistance and a twice-daily dosing schedule. Its role in nucleoside-sparing regimens is under investigation.. PubMed was searched for publications in English from 2004 to September 2013 using the terms 'raltegravir', 'integrase inhibitor' and 'MK-0518'. Relevant publications were reviewed and reference lists were examined for further publications. Conference abstracts from the Conference on Retroviruses and Opportunistic Infections, Interscience Conference on Antimicrobial Agents and Chemotherapy, and International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention for 2013 were also reviewed.. Raltegravir is an important agent for both naïve and experienced HIV patients. Its key features include its tolerability, efficacy and lack of significant drug interactions.

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Adult; Anti-HIV Agents; Drug Hypersensitivity Syndrome; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium

Dolutegravir, is a second generation integrase inhibitor that had recently received United States Food and Drug Administration and European Commission approval for the treatment of adult patients with HIV-1 infection. Dolutegravir provides distinct advantages compared with first generation integrase inhibitors. Unlike raltegravir, dolutegravir can be given once daily for patients who are antiretroviral treatment naïve. Once-a-day dolutegravir dosing also does not require a pharmacokinetic booster like elvitegravir which minimizes the drug-drug interaction potential of dolutegravir. In Phase III clinical trials, dolutegravir-containing regimens have demonstrated either non-inferiority or superiority to current first line agents such as raltegravir, darunavir/ritonavir, and efavirenz containing regimens. Moreover, dolutegravir may be effective for patients with a history of raltegravir and/or elvitegravir resistance. Dolutegravir will likely play a major role in the management of patients with HIV-1 infection, and will be aided when coformulation with abacavir/lamivudine as a single pill, once-daily regimen is available.

Topics: Adult; Clinical Trials as Topic; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium

The integrase (IN) strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens has attained remarkably high levels, reaching undetectable viral loads in 90% of patients by Week 48; however, there remain patients who require a change in regimen due to adverse events, virologic failure with emergent resistance or other issues of patient management. Large, randomized clinical trials conducted in antiretroviral treatment-naive individuals are required for drug approval in this population in the US, EU and other countries, with the primary endpoint for virologic success at Week 48. However, there are differences in the definition of virologic failure and the evaluation of drug resistance among the trials. This review focuses on the methodology and tabulation of resistance to INSTIs in phase 3 clinical trials of first-line regimens and discusses case studies of resistance.

Topics: Clinical Trials, Phase III as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Endpoint Determination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; Treatment Outcome; Viral Load

A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1-infected patients.. A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed.. Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions.. Three clinical trials of DTG have demonstrated comparable or superior efficacy and safety to DRV, RAL, and EFV in HIV-1-infected treatment-naive patients. This network meta-analysis suggests DTG is also favorable or comparable to other commonly used third agents (ATV/r, LPV/r, RPV, and EVG/c).

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Lipids; Lopinavir; Nitriles; Organophosphonates; Oxazines; Piperazines; Pyridones; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Rilpivirine; Ritonavir; Tenofovir; Time Factors; Treatment Outcome; Viral Load

Maternal-to-fetal transfer of antiretroviral drugs contributes to prevention of vertical transmission of HIV.. This systematic review discusses published studies containing data pertaining to the pharmacokinetics of placental transfer of antiretrovirals in humans, including paired cord and maternal plasma samples collected at the time of delivery as well as ex vivo placental perfusion models.. Articles pertaining to placental transfer of antiretrovirals were identified from PubMed, from references of included articles, and from US Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission guidelines. Articles from non-human animal models or that had no original maternal-to-fetal transfer data were excluded. PRISMA guidelines were followed.. A total of 103 published studies were identified. Data across studies appeared relatively consistent for the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleotide reverse transcriptase inhibitors (NNRTIs), with cord to maternal ratios approaching 1 for many of these agents. The protease inhibitors atazanavir and lopinavir exhibited consistent maternal-to-fetal transfer across studies, although the transfer may be influenced by variations in drug-binding proteins. The protease inhibitors indinavir, nelfinavir, and saquinavir exhibited unreliable placental transport, with cord blood concentrations that were frequently undetectable. Limited data, primarily from case reports, indicate that darunavir and raltegravir provide detectable placental transfer.. These findings appear consistent with current guidelines of using two NRTIs plus an NNRTI, atazanavir/ritonavir, or lopinavir/ritonavir to maximize placental transfer as well as to optimally suppress maternal viral load. Darunavir/ritonavir and raltegravir may reasonably serve as second-line agents.

Topics: Animals; Anti-HIV Agents; Female; Fetus; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Infectious Disease Transmission, Vertical; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; United States

This review discusses recent changes in HIV treatment guidelines, focussing on the optimal time for starting antiretroviral therapy (ART) in chronic asymptomatic infection, and treatment options for ART-naïve patients.. Understanding of HIV pathogenesis has progressed significantly, with a growing appreciation of the role of HIV replication in causing inflammation and promoting both AIDS and non-AIDS diseases. Early suppression of HIV replication with ART benefits the individual, and by reducing transmission and promoting engagement with care also brings public health benefits. For years, efavirenz-based ART was favoured by treatment guidelines, reflecting unsurpassed performance in clinical trials. New treatment options show high efficacy and safety and include single-tablet coformulations for once-daily dosing to improve convenience. Recent data have demonstrated superiority over efavirenz of regimens based on rilpivirine in patients with low pre-ART HIV-1 RNA load and raltegravir or dolutegravir regardless of the viral load.. Some guidelines now recommend starting ART regardless of CD4 cell counts, whereas others take a more cautious approach pending results from studies that are testing the clinical benefit of early therapy. New treatment options allow therapy to be tailored to the patient's circumstances and are suitable for early ART initiation.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Comorbidity; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Nitriles; Observational Studies as Topic; Oxazines; Piperazines; Practice Guidelines as Topic; Pyridones; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Rilpivirine; Viral Load

The integrase enzyme facilitates the incorporation of HIV-1 proviral DNA into the host cell genome and catalyses a function vital to viral replication. Inhibitors of this enzyme represent the newest class of antiretroviral drugs in our armamentarium to treat HIV-1 infection. Raltegravir, an integrase strand transfer inhibitor, was the first drug of this class approved by the US FDA; it is a potent and well tolerated antiviral agent. However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance. These qualities have prompted the search for agents with once-daily dosing, a more robust barrier to resistance, and a resistance profile of limited overlap with that of raltegravir. We review a series of integrase inhibitors that are in clinical or advanced pre-clinical studies. Elvitegravir, recently approved by the FDA as part of the elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir. Dolutegravir is the most advanced second-generation integrase inhibitor, and it boasts good tolerability, once-daily dosing with no need for a pharmacological enhancer, and relatively little cross-resistance with raltegravir. S/GSK1265744 has been developed into a long-acting parenteral agent that shows a high barrier to resistance in vitro and the potential for an infrequent dosing schedule. BI 224436 is in early clinical trials, but is unlikely to demonstrate cross-resistance with other integrase inhibitors. The inhibitors of the lens epithelium-derived growth factor (LEDGF)/p75 binding site of integrase (LEDGINs) are extremely early in development. Each of these contributes a new benefit to the class and will extend the treatment options for patients with HIV-1 infection.

Topics: Clinical Trials as Topic; Drug Discovery; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium

In the late 1990s, reports of unusual changes in body fat distribution named 'lipodystrophy' (LD) began to appear in HIV patients mitigating the enormous enthusiasm about improvement of survival and quality of life provided by the combinations of antiretroviral (ARV) drug classes, the so-called highly active antiretroviral therapy (HAART), which had just become available at that time. The objective of this paper is to critically review the literature on LD and to discuss the impact of newer ARV agents, namely atazanavir, darunavir and raltegravir, as well as strategies of the late HAART era, including single-tablet regimens and nucleoside-sparing regimens. Studies in which LD was measured by dual-energy x-ray absorptiometry or by abdominal computed tomography or magnetic resonance imaging scan only, were included. We were unable to identify studies depicting a negative impact of drugs or ARV regimens on limb fat loss. On the contrary, a few studies identified a negative impact of atazanavir/ritonavir or darunavir/ritonavir on trunk fat increase. It should be noted that this anthropometric measure is a poor instrument since it cannot distinguish between subcutaneous and visceral fat. We conclude that presumably the body fat changes currently observed in HIV-infected patients is the net result of competing phenomena: on one side the natural history of lipohypertrophy as a result of HIV and HAART impact, and on the other side the physiological body fat changes observed in the aging population.

Topics: Adiposity; Aging; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Darunavir; Drug Combinations; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Nucleosides; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Sulfonamides

Integrase inhibitors are a promising new group of antiretroviral drugs that suppress the integrase yielded by human immunodeficiency viruses (HIV) via inhibiting the ,,integration" of the viral deoxyribonucleic acid (DNA) into the hosts' DNA genome. In 2007, raltegravir was the first integrase inhibitor that has been approved for the treatment of HIV-1 infections in antiretroviral-pretreated (-experienced) and antiretroviral-naive patients. Recently, elvitegravir, as a fixed coformulation with cobicistat, tenofovir und emtricitabine, has been approved for the treatment of HIV-1-infected antiretroviral-naive patients. InAugust of 2013, dolutegravir, a third integrase inhibitor, has been approved by the US Food and Drug Adiministation (FDA) for the treatment of HIV-1 infections in adults and children aged 12 years and older. Raltegravir has to be applied twice daily without a boosting agent. Elvitegravir and dolutegravir are applied once daily in the presence of a booster (elvitegravir) or unboosted (dolutegravir). In contrast to raltegravir and elvitegravir, dolutegravir shows a high genetic barrier to resistance, and is also applicable for the treatment of several HIV-1 infections with raltegravir and elvitegravir-resistant HIV variants. During the last years, raltegravir, elvitegravir and dolutegravir have been proven and established in the antiretroviral treatment of HIV-1 infections as effective, safe and well-tolerated agents. However, reliable statement forecasts of long-term toxicity of these substances can not yet be made.

Topics: Anti-HIV Agents; Contraindications; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Integrase Inhibitors; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; United States

To review the literature concerning the role of raltegravir in the treatment of HIV-1 in antiretroviral (ARV)-experienced and ARV-naïve patients.. A PubMed search was conducted for published data through March 2012 using the search terms raltegravir, MK-0518, and integrase strand transfer inhibitor. An additional search of International Pharmaceutical Abstracts for unpublished data, including data from the Infectious Diseases Society of America, the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society, and the Interscience Conference on Antimicrobial Agents and Chemotherapy, was conducted using similar search terms.. In vitro and in vivo Phase 2, Phase 3, and postmarketing studies available in English, evaluating antiretroviral regimens that contain raltegravir for the treatment of HIV-1 infection in both ARV-naïve and ARV-experienced patients, were evaluated. Studies assessing raltegravir pharmacokinetics and pharmacodynamics were included for review.. The nucleoside-based regimen of raltegravir with tenofovir/emtricitabine provides an effective first-line treatment option. However, nucleoside-sparing regimens appear unfavorable in ARV-naïve subjects and should be reserved for patients with limited treatment options. Raltegravir used with optimized background therapy provides an alternative regimen for ARV-experienced patients. This review describes the available in vitro and in vivo data on raltegravir potency, defined as the ability to achieve undetectable viral load, and safety profile, as well as comparison to standard HIV-1 therapies.. Raltegravir has demonstrated potent antiretroviral activity against HIV-1 in both ARV-naïve and ARV-experienced subjects, with the benefits of a favorable adverse effect profile and minimal drug interactions. Raltegravir must be dosed twice daily, as once daily raltegravir displays decreased virologic efficacy compared to twice daily dosing. However, the ongoing development of new integrase strand transfer inhibitors may provide potent once daily regimens.

Topics: Adenine; Animals; Anti-HIV Agents; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Tenofovir

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Coinfection; Deoxycytidine; Dideoxynucleosides; Disease Progression; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Emtricitabine; Hepatitis C, Chronic; HIV Infections; Homosexuality, Male; Humans; Interferon-alpha; Lamivudine; Liver Cirrhosis; Liver Diseases; Male; Oligopeptides; Organophosphonates; Polyethylene Glycols; Proline; Pyrrolidinones; Raltegravir Potassium; Recombinant Proteins; Ribavirin; Serine Proteinase Inhibitors; Substance Abuse, Intravenous; Tenofovir; Treatment Outcome

Raltegravir (RAL) is the first antiretroviral in the integrase strand transfer inhibitors (INSTI) class. The use of RAL has expanded since its approval in October 2007 for multidrug-resistant human immunodeficiency virus type 1 infection in adults. RAL is now a guideline-preferred treatment option for antiretroviral-naïve patients, indicated for treatment in adolescents, and is being studied as an integral part of nucleoside sparing regimens. The development of resistance and the need for a once-daily dosing option has led to the development of new INSTIs, including elvitegravir and dolutegravir. Elvitegravir is being studied in a promising once-daily single-tablet regimen with tenofovir, emtricitabine, and the investigational pharmacoenhancer cobicistat. The development of cobicistat and the new once-daily INSTIs may revolutionize the treatment of human immunodeficiency virus type 1 infection. This article reviews the current literature on raltegravir and new developments in the INSTI class.

Topics: Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium

In this review we will discuss recent findings on the use of inhibitors of the HIV-1 integrase enzyme for the treatment of antiretroviral naive patients. We will also discuss differences between integrase inhibitors, and comment on the use of this class of drugs in the future.. Raltegravir when taken twice daily is as effective and well tolerated as efavirenz. Once daily dosing of raltegravir is virologically inferior to raltegravir taken twice daily. A novel nucleoside-free regimen of raltegravir in combination with a once daily ritonavir-boosted protease inhibitor did not produce adequate viral suppression, although raltegravir with a twice daily protease inhibitor yielded better results. Subset analyses have demonstrated a favorable impact of raltegravir on lipid levels and body fat composition. Two once daily integrase inhibitors not yet Food and Drug Administration-approved, elvitegravir and dolutegravir, have completed phase-2 testing and are also virologically noninferior to efavirenz.. Integrase inhibitors provide potent antiretroviral activity, little short-term toxicity and excellent tolerability. For patients with preexisting atherosclerosis or cardiac risk factors this class of therapy is a logical preferred treatment choice. Raltegravir is a preferred option for those in whom therapy for hepatitis C virus infection is anticipated.

Topics: Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Coinfection; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; Treatment Outcome

The purpose of this study is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir, and elvitegravir (both in phase III drug development).. Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens, and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter-patient and intra-patient pharmacokinetic variability is high. Twice-daily 400  mg dosing has been shown to be clinically superior to 800  mg once-daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was US Food and Drug Administration (US FDA)-approved in December 2011. Cobicistat-boosted elvitegravir, and the second-generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, whereas boosted elvitegravir participates in additional CYP3A-mediated interactions.. Raltegravir's potent antiretroviral activity has resulted in widespread use in both treatment-naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.

Topics: Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; United States

We review the most recent clinical trials of integrase inhibitors (INIs) in antiretroviral therapy (ART)-experienced patients, including trails of new strategies such as intensification and simplification therapy with this new class of compounds.. After the excellent results of the first-generation INIs [raltegravir (RAL) and elvitegravir] in the treatment of ART-experienced patients, dolutegravir--a new second-generation compound in this drug class--adds the possibility of rescuing ART-experienced patients after virologic failure to first-generation INIs like RAL. RAL may have a role in an intensification strategy--adding RAL to a suppressive ART therapy--that could have an effect in avoiding new cycles of infection and cellular activation. On the contrary, RAL has clearly shown efficacy in switching away from boosted protease inhibitors (PI/r). This simplification strategy may be an interesting option in patients suffering from side effects of boosted protease inhibitors. In simplification, the length of time of HIV suppression before the switch may be used as a marker of probable success.. In ART-experienced patients INIs are a new and exciting part of the armamentarium for the control of HIV replication. INIs could play an interesting role in strategies such as intensification or simplification.

Topics: Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; Salvage Therapy; Treatment Outcome

This review discusses the available safety data for three integrase strand transfer inhibitors (INSTIs)--raltegravir, elvitegravir and dolutegravir--derived from studies in both HIV-infected and HIV-uninfected cohorts.. Phase 2 and 3 clinical trials show that all three INSTIs are well tolerated in treatment-naive and treatment-experienced patients with headache and gastrointestinal effects being the most commonly reported adverse events. Other nervous system (including neuropsychiatric) effects are often reported with INSTIs but are milder and less frequent than with efavirenz. Limited data suggest that effects upon lipid metabolism with raltegravir and dolutegravir are favourable compared with efavirenz and protease inhibitors, with more variable findings for elvitegravir because of coadministration with the boosting agent cobicistat. Cobicistat and dolutegravir have effects upon proximal renal tubular function causing mild-to-moderate creatinine elevation. Rare and severe events possibly related to INSTIs include systemic hypersensitivity reactions and rhabdomyolysis.. INSTIs are an important recent addition to the antiretroviral armamentarium, with good short-term and medium-term safety. Long-term data from ongoing clinical studies are needed for a definitive assessment of their safety profile.

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Kidney; Lipid Metabolism; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium

In the last decade, some evidence has arisen supporting the usefulness of Asian ginseng (Panax ginseng, fam. Araliaceae) as a complementary remedy in patients receiving antiretroviral therapy. However, its role in current therapeutics remains unclear.. The patient was admitted for an acute elevation of liver enzymes, marked jaundice, and significant weight loss after taking ginseng-based tablets starting approximately 39 days prior. His past medical history (PMH) was also significant for HIV+, long-term hepatitis C, an episode of mitochondrial toxicity, and several comorbidities. His outpatient medications included raltegravir 400 mg plus lopinavir/ritonavir 400/100 mg twice daily, aspirin 100 mg daily, and esomeprazole 40 mg daily as needed.. The cessation of the ginseng lozenges led to a progressive improvement in the performance status and laboratory values. Both the Hansten and Horn nomogram and the Roussel Uclaf Causality Assessment Method indicated that the association between the ginseng medicine and the liver injury was probable (six points).. We suggest that ginseng is involved in the episode through an interaction resulting in elevated plasma concentrations of raltegravir. As a consequence, clinicians should be alert when managing patients on other CYP3A4-metabolized drugs or previous liver-damaging conditions. However, larger studies are required to explicitly clarify these statements.

Topics: Chemical and Drug Induced Liver Injury; Complementary Therapies; Cytochrome P-450 CYP3A; Herb-Drug Interactions; HIV Infections; HIV Integrase Inhibitors; Humans; Liver; Male; Middle Aged; Panax; Pyrrolidinones; Raltegravir Potassium

Raltegravir has demonstrated potent and durable efficacy and a favorable safety profile in 3 phase III studies in treatment-naïve and treatment-experienced patients with HIV-1 infection. This manuscript provides a review of the raltegravir safety profile using data from these and other studies in the clinical development program.. Comprehensive 96-week safety data from STARTMRK (raltegravir versus efavirenz, each with tenofovir/emtricitabine) and BENCHMRK (raltegravir versus placebo, each with optimized background therapy) are summarized. A cumulative meta-analysis of raltegravir 400 mg bid was conducted across the entire development program.. In STARTMRK, drug-related adverse events (AEs) occurred less frequently with raltegravir than efavirenz. In BENCHMRK, the most common drug-related AEs occurred at generally similar frequencies in both groups. Drug-related serious AEs were uncommon. Rash was observed in raltegravir-treated patients at a higher frequency than placebo but a lower frequency than efavirenz. Depression and immune reconstitution inflammatory syndrome occurred at similar rates for raltegravir and comparators. Isolated elevations of creatine kinase were more common with raltegravir than placebo but occurred without clinical manifestations. The frequency of aminotransferase elevations was greater in patients with viral hepatitis co-infection, but similar in the raltegravir and comparator groups. The relative risk (95% CI) of cancer was 0.75 (0.30, 1.91) indicating no difference between raltegravir and comparator. Overall trends in the cumulative meta-analysis were similar to those observed in the phase III studies.. Long-term data from the phase III clinical trials demonstrate that raltegravir was generally well-tolerated in both treatment-naïve and treatment-experienced patients with HIV infection.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Clinical Trials, Phase III as Topic; Female; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Young Adult

Raltegravir is an HIV-1 integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. Data from healthy volunteers demonstrate that raltegravir is rapidly absorbed with a mean half-life of approximately 7 to 12 hours, with steady state achieved in approximately 2 days. Raltegravir is characterized by both high intra- and interindividual variabilities, although neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency has a clinically meaningful effect on raltegravir pharmacokinetics. Raltegravir lacks activity as a perpetrator of drug-drug interactions and demonstrates a low propensity to be subject to drug-drug interactions. Raltegravir is metabolized primarily by UGT1A1 and is not affected by P450 inhibitors or inducers. Inhibitors of UGT1A1 (eg, atazanavir) can increase plasma concentrations of raltegravir, although this increase has not been found to be clinically meaningful. Likewise, inducers of UGT1A1 (eg, rifampin) can reduce plasma concentrations of raltegravir, and the clinical significance of this reduction is being investigated in ongoing clinical studies. Raltegravir demonstrates favorable clinical pharmacology and a drug interaction profile that permits administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment.

Topics: Anti-HIV Agents; Area Under Curve; HIV Infections; HIV Integrase; Humans; Pyrrolidinones; Raltegravir Potassium

Raltegravir is the first integrase strand transfer inhibitor approved for the treatment of HIV-1 infection. As the first agent in this new class of antiretroviral therapies, raltegravir has demonstrated safety and efficacy in treatment-naive as well as heavily pretreated HIV-infected patients failing therapy with multidrug-resistant virus. Raltegravir has a favorable drug interaction profile that permits both administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment. Data through 96 weeks of follow-up in three phase III studies, protocol 021 (STARTMRK) in treatment-naive patients, and protocols 018 (BENCHMRK-1) and 019 (BENCHMRK-2) in treatment-experienced patients, demonstrated the potent and durable antiretroviral and immunologic effects and the favorable long-term safety profile of raltegravir in both treatment-naive and treatment-experienced patients. Raltegravir represents an important addition to the current armamentarium for the treatment of HIV infection.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Clinical Trials, Phase III as Topic; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

With the approval in 2007 of the first integrase inhibitor (INI), raltegravir, clinicians became better able to suppress virus replication in patients infected with human immunodeficiency virus type 1 (HIV-1) who were harboring many of the most highly drug-resistant viruses. Raltegravir also provided clinicians with additional options for first-line therapy and for the simplification of regimens in patients with stable virological suppression. Two additional INIs in advanced clinical development-elvitegravir and S/GSK1349572-may prove equally versatile. However, the INIs have a relatively low genetic barrier to resistance in that 1 or 2 mutations are capable of causing marked reductions in susceptibility to raltegravir and elvitegravir, the most well-studied INIs. This perspective reviews the genetic mechanisms of INI resistance and their implications for initial INI therapy, the treatment of antiretroviral-experienced patients, and regimen simplification.

Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV-1; Humans; Mutant Proteins; Pyrrolidinones; Raltegravir Potassium

Raltegravir is a first-in-class HIV-1 integrase inhibitor with established antiviral efficacy in treatment-naive and treatment-experienced patients with multidrug-resistant HIV-1 infection. In this article, we summarize pharmacoeconomic evaluations of raltegravir-based treatment regimens, compared with alternative therapies, in the treatment of patients with HIV infection and/or AIDS. Cost-effectiveness evaluations of raltegravir in treatment-experienced patients conducted using a continuous-time, state-transition Markov cohort model suggest that raltegravir, combined with optimized background therapy, falls within the range that would generally be considered cost effective compared with optimized therapy alone in Spanish, Swiss and UK health systems. In treatment-naive populations, raltegravir was evaluated using a three-stage continuous-time state-transition cohort model. Raltegravir-based initiation treatment strategies (first-line raltegravir) were compared with protease inhibitor and non-nucleoside reverse-transcriptase inhibitor initiation strategies, in which raltegravir was retained for salvage therapy. First-line raltegravir was cost-effective versus retaining raltegravir for salvage therapy in several European populations. A separate economic model was used to evaluate first-line raltegravir against two alternative initiation regimens representing standard clinical practice in Australia; raltegravir proved to be cost effective in both scenarios. In all studies examined, results were sensitive to factors including treatment duration, mortality rate, analytic time horizon, health utility weights, cost of raltegravir and optimized therapy, incidence of opportunistic infection and discount rates. Nonetheless, raltegravir remained cost effective under most scenarios.

Topics: Australia; Cost-Benefit Analysis; Drug Costs; Drug Resistance, Viral; Europe; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Markov Chains; Models, Economic; Pyrrolidinones; Quality-Adjusted Life Years; Raltegravir Potassium; Salvage Therapy; Time Factors; Treatment Outcome

HIV resides within anatomical 'sanctuary sites' where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Widespread implementation of antiretroviral therapy has seen a significant decline in the incidence of mother-to-child transmission (MTCT) of HIV. In addition to suppression of maternal plasma/genital viral loads, antiretroviral agents that cross the placenta and achieve adequate concentrations in the fetal compartment may exert a greater prophylactic effect. Penetration of antiretrovirals in the fetal compartment is expressed by accumulation ratios derived from the measurement of drug concentrations in paired maternal plasma and umbilical cord samples. The nucleoside analogues and nevirapine accumulate extensively in cord blood and in the surrounding amniotic fluid, whereas the protease inhibitors (PIs) exhibit low-to-moderate placental accumulation. Early data suggest that high placental/neonatal concentrations are achieved with raltegravir, but to a lesser extent with etravirine and maraviroc (rank order of accumulation: raltegravir/nucleoside reverse transcriptase inhibitor [tenofovir > zidovudine/lamivudine/emtricitabine/stavudine/abacavir] > non-nucleoside reverse transcriptase inhibitor [nevirapine > etravirine] > PI > maraviroc/enfuvirtide). More comprehensive in vivo pharmacokinetic data are required to justify the potential use of these agents as safe and effective options during pregnancy.

Topics: Adenine; Adult; Amniotic Fluid; Anti-HIV Agents; Cyclohexanes; Enfuvirtide; Female; Fetal Blood; Fetus; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Maraviroc; Nevirapine; Organophosphonates; Peptide Fragments; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tenofovir; Triazoles; Viral Load; Zidovudine

HIV-1 integrase (IN) is one of three essential enzymes (along with reverse transcriptase and protease) encoded by the viral pol gene. IN mediates two critical reactions during viral replication; firstly 3'-end processing (3'EP) of the double-stranded viral DNA ends and then strand transfer (STF) which joins the viral DNA to the host chromosomal DNA forming a functional integrated proviral DNA. IN is a 288 amino acid protein containing three functional domains, the N-terminal domain (NTD), catalytic core domain (CCD) and the C-terminal domain (CTD). The CCD contains three conserved catalytic residues, Asp64, Asp116 and Glu152, which coordinate divalent metal ions essential for the STF reaction. Intensive research over the last two decades has led to the discovery and development of small molecule inhibitors of the IN STF reaction (INSTIs). INSTIs are catalytic inhibitors of IN, and act to chelate the divalent metal ions in the CCD. One INSTI, raltegravir (RAL, Merck Inc.) was approved in late 2007 for the treatment of HIV-1 infection in patients with prior antiretroviral (ARV) treatment experience and was recently approved also for first line therapy. A second INSTI, elvitegravir (EVG, Gilead Sciences, Inc.) is currently undergoing phase 3 studies in ARV treatment-experienced patients and phase 2 studies in ARV naïve patients as part of a novel fixed dose combination. Several additional INSTIs are in early stage clinical development. This review will discuss the discovery and development of this novel class of antiretrovirals. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Enzyme Inhibitors; History, 20th Century; History, 21st Century; HIV Infections; HIV Integrase; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

Raltegravir (Isentress) is the first approved HIV integrase inhibitor. Agents in this class target a different viral enzyme compared with agents inhibiting reverse transcriptase and protease. A wide number of patients are currently susceptible to integrase inhibitors, including heavily antiretroviral-experienced patients harbouring drug-resistant viruses. The good tolerability and convenience of raltegravir have recently begun to be appreciated, leading to the consideration of other indications for the drug. Data recently released using the drug as first-line therapy or in switch strategies are very promising and the role of raltegravir in intensification therapy is currently under investigation. Altogether, the current information supports a broad use of raltegravir beyond its initial approval for antiretroviral-experienced HIV-infected patients.

Topics: Anti-HIV Agents; Clinical Trials as Topic; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium

To review the pharmacology, efficacy, safety, and resistance profiles of the integrase inhibitors raltegravir and elvitegravir.. A search of PubMed was conducted (2000-August 2009) using the following key words: raltegravir, MK-0518, elvitegravir, and GS-9137. Articles were evaluated for content and bibliographies were reviewed. Data available exclusively in abstracts from major infectious diseases and HIV conferences were also evaluated for inclusion.. Studies included were in vitro investigations; Phase 1, 2, and 3 clinical trials; retrospective analyses including case reports; and pharmacokinetic and pharmacodynamic evaluations.. Raltegravir is currently approved by the Food and Drug Administration for the management of HIV-1 infection in treatment-naïve or-experienced adults as part of an optimized combination regimen. When combined with other active agents, it has demonstrated similar virologic efficacy after 96 weeks to the combination of efavirenz, tenofovir, and emtricitabine in treatment-naïve patients. Unlike many antiretrovirals, raltegravir does not enter cytochrome P450 metabolism and instead undergoes glucuronidation. Elvitegravir is in the late stages of clinical development. A Phase 2 study has demonstrated virologic efficacy in treatment-experienced patients comparable to protease inhibitor-based regimens after 24 weeks. Boosting of elvitegravir through inhibition of CYP3A4 metabolism has been investigated and suggests a pharmacokinetic profile conducive to once-daily-dosing. Phase 2 and 3 clinical trials evaluating boosted elvitegravir are in process. The Phase 2 trial combines elvitegravir with a non-ritonavir boosting agent plus tenofovir/emtricitabine given once daily as a "quad-pill" formulation. The Phase 3 trial compares once-daily ritonavir-boosted elvitegravir with twice-daily raltegravir, each given with an optimized background regimen. Both integrase inhibitors are well tolerated and raltegravir has few drug-drug interactions. Resistance mutations have been identified in patients experiencing virologic failure and cross resistance between raltegravir and elvitegravir has been confirmed.. The integrase inhibitors provide a novel target for antiretroviral therapy and provide an option for patients harboring resistance to other antiretrovirals.

Topics: Anti-HIV Agents; HIV Infections; Humans; Integrase Inhibitors; Pyrrolidinones; Quinolones; Raltegravir Potassium

More than 25 years have passed since HIV was identified as a causative agent of AIDS. In the monotherapy era, the efficacy of antiretroviral therapy was limited due to emergence of drug resistance. In late 1990s when the highly active antiretroviral therapy (HAART) was started to apply, the mortality of HIV infected people dramatically declined. Nowadays, more than 20 drugs are applicable and treatment regimen has become more potent and more convenient. However, emergence of multi-drug resistant HIV and long-term toxicity of antiretroviral is still remarkable concern. Raltegravir, the first approved integrase inhibitor (INI), shows preferable safety profile. When long-term reliability of INI is proven, antiretroviral combination will be individualized by choosing the optimal drug from 4 classes.

Topics: Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; HIV Infections; Humans; Integrase Inhibitors; Pyrrolidinones; Raltegravir Potassium

Raltegravir, a first-in-class, oral HIV type-1 (HIV-1) integrase inhibitor, blocks the covalent integration of HIV-1 complementary DNA into the host genome. In a large, randomized, double-blind, multinational, ongoing trial in treatment-naive patients with HIV-1 infection, raltegravir 400 mg twice daily was noninferior to efavirenz 600 mg once daily in achieving plasma HIV-1 RNA viral levels of <50 copies/mL after 48 weeks' treatment (primary endpoint), when used as part of an antiretroviral therapy (ART) combination regimen. The time to achieve a virological response was significantly shorter in the raltegravir group than in the efavirenz group. Furthermore, significantly more raltegravir than efavirenz recipients achieved HIV-1 RNA viral levels of <50 copies/mL at weeks 2-16. The efficacy of raltegravir in achieving HIV-1 RNA levels of <50 copies/mL was also demonstrated in subgroups of patients separated according to baseline viral levels, CD4+ cell counts and viral subtypes. Preliminary evidence suggests that both virological and CD4+ cell count improvements were maintained at 96 weeks for treatment-naive recipients of raltegravir 400 mg twice daily. As part of an ART combination regimen, raltegravir treatment was generally well tolerated and was associated with significantly fewer drug-related adverse events than efavirenz treatment. Moreover, after 96 weeks, raltegravir treatment was associated with a significantly lower impact on serum lipid levels than efavirenz treatment.

Topics: Administration, Oral; CD4 Lymphocyte Count; Drug Therapy, Combination; Evidence-Based Medicine; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

Raltegravir is the first HIV-integrase inhibitor licensed by the FDA.. A PubMed search was conducted for all published reports up to 1 May 2010 related to raltegravir pharmacokinetics, pharmacology, drug-drug interactions and clinical studies in HIV-infected patients. Also included in this review are the updated European and US Prescriber's Information (European Medicines Agency and the FDA) and abstracts from recent international scientific meetings.. After reading the review, a thorough insight in raltegravir pharmacokinetics and pharmacology will be obtained, as well as an up-to-date overview of all published drug-drug interaction studies. Furthermore, one should be able to make an evidence-based opinion on the drug's clinical efficacy and tolerability.. Raltegravir is a welcome addition to the antiretroviral drug armamentarium due to its good tolerability, low potential for drug-drug interactions and good clinical efficacy in both treatment-naive and -experienced patients.

Topics: Cell Line; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

Integrase inhibitors are the newest class of antiretroviral agents developed to treat HIV-1 infection. Raltegravir (RAL), the only integrase inhibitor (INI) currently approved for the treatment of HIV-infected patients, has proven to be a potent and well-tolerated antiretroviral (ARV) agent. It is currently approved and used for the treatment of both ARV-experienced and ARV-naive patients. Nevertheless, the relatively low genetic barrier for resistance of RAL encourages the search for new INIs with different mechanisms of actions and resistance profiles.. Here we review the data available about INI that are currently being tested in clinical trials or are in preclinical development: elvitegravir (EVG), S/GSK1349572, S/GSK1265744 and LEDGINs. We focus on their clinical efficacy, pharmacokinetic, safety and resistance profiles.. Up-to-date overview on the currently available, clinically relevant INIs and promising preclinical inhibitors at all phases of development.. Integrase inhibitors represent the newest therapeutic class available to treat HIV-1 infection. There are a variety of compounds either available in the clinic (RAL), advancing to Phase III trials (EVG), or in earlier phases of development. Taken together, this class offers new treatment options for the HIV-infected individual.

Topics: Cell Line; Clinical Trials as Topic; Drug Design; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium

The genetic barrier for the antiretroviral describes the ability to select resistant viruses to this antiretroviral when the viral replication is not controlled. This includes combining several concepts: (1) the number of nucleotide changes required for a resistance mutation, (2) the impact of this mutation on the level of susceptibility to antiretroviral (3) the impact of this mutation on viral replication capacity; all theses conditions influencing the level of resistant variants. The antiretroviral concentration impact also the emergence of resistance. Finally, combine with other molecules, the selection of resistance mutations ton an antiretroviral may differ from one treatment to another. It is recognized that the genetic barrier to lamivudine/emtricitabine, efavirenz and nevirapine is low, and is intermediate for nucleoside such as zidovudine and tenofovir. However, ritonavir boosted protease inhibitor with high plasma concentration have a high genetic barrier. For integrase inhibitors such as raltegravir, the emergence of resistance is certainly faster than the ritonavir boosted protease inhibitors, but seems slower and less systematic than for efavirenz or lamivudine. Many factors could influence the raltegravir resistance such as the level of viral load and replication duration, genetic polymorphism of HIV (integrase gene and other, viral subtype) and the plasma and/or intra- cellular raltegravir concentration.

Topics: Amino Acid Substitution; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Genes, pol; Genetic Variation; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Mutation; Point Mutation; Pyrrolidinones; Raltegravir Potassium; Selection, Genetic; Virulence; Virus Replication

Agents active against HIV type 1 (HIV-1) that target the viral integrase by inhibiting the strand transfer step of integration have now entered the clinical arena. Raltegravir is the first in this new class. Clinical trials in treatment-experienced and in treatment-naive patients have shown that raltegravir-containing regimens have potent antiretroviral activity and are well tolerated. Drug resistance emerges relatively frequently in patients who fail therapy and is associated with mutations in the gene encoding the integrase enzyme. Although such mutations often confer cross-resistance to other integrase inhibitors, newer agents in development, such as S/GSK1349572, show promise as potential second-generation integrase inhibitors. Given their potency, safety and novel mechanism of action, integrase inhibitors represent an important advance in HIV-1 therapy.

Topics: Clinical Trials as Topic; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

First-line treatment for HIV infection consists of a combination of antiretroviral drugs, specifically including a non-nucleoside reverse transcriptase inhibitor or an HIV protease inhibitor, usually boosted with ritonavir. Raltegravir, the only commercially available HIV integrase inhibitor, marketed since 2007 in the European Union, was initially reserved for patients with multiple treatment failure. It is now authorised for first-line use. Clinical evaluation of first-line raltegravir therapy is based on a comparative double-blind "non-inferiority" trial comparing raltegravir + tenofovir + emtricitabine versus efavirenz + tenofovir + emtricitabine in 566 patients. After 48 weeks, about 84% of the patients in the two arms had undetectable viral load. There are no trials versus other first-line combinations. The adverse effect profile of raltegravir is poorly documented. In the trial comparing raltegravir + tenofovir + emtricitabine with efavirenz + tenofovir+ emtricitabine, adverse effects of the two regimens were generally comparable. In practice, given the lack of firm evidence that raltegravir is a therapeutic improvement over existing first-line regimens, it is better to continue to reserve its use for patients with multiple treatment failure. Many satisfactory first-line combinations have been in use for several years.

Topics: Antiretroviral Therapy, Highly Active; Comparative Effectiveness Research; HIV Infections; HIV Integrase Inhibitors; Humans; Lipid Metabolism; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic

In the two decades since AZT was first approved for clinical use in 1987, 24 additional antiretroviral agents have been approved. They include 7 nucleoside analogs, a nucleotide analog and 4 non-nucleoside reverse transcriptase inhibitors, 10 protease inhibitors, 2 entry inhibitors and an integrase inhibitor. More than 20 investigational agents are currently being studied in clinical trials. Highly active antiretroviral therapy (HAART), which involves a combination of anti-HIV-1 drugs, is extremely effective in suppressing HIV-1 replication and increasing CD4+ number and results in substantial reductions in HIV-1-related morbidity and mortality. In last 20 years, much has been learned about resistance to antiretroviral drugs, drug interactions and metabolic complications of antiviral drug use. Drugs are now selected on the basis of resistance tests and on the risk of specific drug complications in individual patients. As a result, decisions about the therapy of HIV/AIDS have become personalized and are made on a patient-by-patient basis. With appropriate medical management, a person with HIV-1 now has the possibility of a nearly normal life expectancy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cyclohexanes; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Maraviroc; Molecular Structure; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Saquinavir; Triazoles; Virus Replication; Zidovudine

The paper gives the results of the largest international studies demonstrating the efficacy and safety of Raltegravir as part of antiretroviral treatment (ARVT) regimens in both patients starting therapy (STARTMRK study) and those pretreated with antiretroviral drugs (BENCHMRK study). The advantage of Raltegravir over Efavirens is the lower incidence of adverse central nervous system reactions. Based on the results of published investigations, specialists from the USA and European Union have incorporated the first HIV integrase inhibitor Raltegravir into a first-line ARTV regimen. Raltegravir is the drug of choice and should be used in special categories of patients, such as those with chronic hepatitis C or fat metabolic disturbances.

Topics: Antiretroviral Therapy, Highly Active; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load

Raltegravir is the first approved human immunodeficiency virus type 1 (HIV-1) integrase inhibitor; it targets the strand transfer step of HIV-1 integration. Clinical trials have demonstrated that raltegravir-containing regimens have potent antiretroviral activity and are well tolerated in HIV-1-infected individuals. In antiretroviral treatment-experienced persons with drug-resistant HIV infection, raltegravir-containing treatment with an optimized background regimen was superior to an optimized background regimen alone. In treatment-naive persons, raltegravir was not inferior to efavirenz when the drugs were administered with tenofovir and lamivudine or emtricitabine. Raltegravir is metabolized by glucuronidation, not hepatically; thus, the potential for drug-drug interactions is decreased. Drug resistance, conferred by substitutions in the gene coding for the HIV-1 integrase enzyme, develops relatively frequently after virologic failure. As an antiretroviral drug with a novel mechanism of action, raltegravir is an important advancement in HIV-1 treatment options.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Integrase Inhibitors; Pyrrolidinones; Raltegravir Potassium

Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.

Topics: Antiviral Agents; Drug Discovery; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Quinolones; Raltegravir Potassium

Raltegravir, an inhibitor of the HIV-1 integrase enzyme, is now available for the treatment of drug-resistant virus.. To establish raltegravir as an effective addition to the existing antiretroviral armamentarium by reviewing pharmacokinetics, efficacy, safety and tolerability.. Data from pharmacokinetic, Phase II and III clinical trials were reviewed.. Results from clinical trials indicate that raltegravir is safe and highly effective in the treatment of both antiretroviral-naïve and -experienced patients.

Topics: Clinical Trials as Topic; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Raltegravir (Isentress), an integrase inhibitor, inhibits the insertion of HIV-1 complementary DNA into the host genome. It is indicated in combination with other antiretroviral therapy (ART) agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple ART agents. It is the first of a new class of ART agents to be approved that, as a result of a different mechanism of action to other ART agents, has good activity against multidrug-resistant HIV-1 strains. In clinical trials in treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of oral raltegravir to an optimized background therapy (OBT) regimen improved virological and immunological responses at 16 and 48 weeks to a greater extent than placebo plus OBT. Raltegravir therapy was generally well tolerated, with a similar incidence of mild to moderate adverse events in the treatment and placebo arms. The introduction of integrase inhibitors extends the options available for managing treatment-experienced patients with multiple-drug-resistant HIV-1 infection. Results to date suggest that the combination of raltegravir and OBT will be a valuable treatment option for this difficult-to-treat patient group.

Topics: Adult; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Topics: Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Sleep Initiation and Maintenance Disorders; Treatment Outcome

To review all currently published drug-drug interaction studies with the HIV-integrase inhibitor raltegravir.. A PubMed search was conducted for all published reports up to August 1, 2009 as well as a review of updated European and US Prescriber's Information (EMEA and FDA) and abstracts from recent international scientific meetings.. A total of 14 drug-drug interaction studies were found. Due to the relatively broad therapeutic range of raltegravir almost all co-administered agents can safely be combined with raltegravir, with the exception of rifampin in which a doubling of the raltegravir dose to 800 mg BD is currently recommended.. Raltegravir is not without drug-drug interactions but due to the lack of an effect on CYP450 or UGT by raltegravir and the broad therapeutic range of raltegravir itself, this agent can safely combined with almost all tested agents.

Topics: Antibiotics, Antitubercular; Antiviral Agents; Drug Interactions; Enzyme Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Omeprazole; Pyrrolidinones; Raltegravir Potassium; Rifampin

Integration of the HIV-1 viral DNA generated by reverse transcription of the RNA genome into the host cell chromosomes is a key step of viral replication, catalyzed by the viral integrase. In October 2007, the first integrase inhibitor, raltegravir, was approved for clinical use under the name of Isentress superset. The results of the various clinical trials that have evaluated raltegravir have been very encouraging with regard to the immunological and virological efficacy and tolerance. However, as observed for other anti-retrovirals, specific resistance mutations have been identified in patients failing to respond to treatment with raltegravir. Although knowledge of the integrase structural biology remains fragmentary, the structures and modeling data available might provide relevant clues on the origin of the emergence of these resistance mutations. In this review, we describe the mechanism of action of this drug and the main data relating to its use in vivo, together with recent structural data important to our understanding of the origin of viral resistance.

Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; Humans; Models, Chemical; Pyrrolidinones; Raltegravir Potassium; Virus Integration

Raltegravir is the first integrase inhibitor approved for the treatment of HIV infection based on the superior efficacy it showed compared to optimized backbone therapy alone in patients harboring multidrug resistant viruses. Studies on naive patients showed comparable efficacy of raltegravir and efavirenz and just recently the US Food and Drug Administration (FDA) approved raltegravir for the use in naive patients based on the favorable results of the international double-blind phase III STARTMRK trial. Additional interesting findings were the faster, and not yet explained, decay of HIV-1 RNA and the higher CD4+ cells increase in the raltegravir group as compared to the efavirenz group. Raltegravir is generally well tolerated and adverse events were generally similar in raltegravir and comparator arms throughout all studies. When compared to efavirenz, patients on raltegravir showed less incidence of central nervous system-related adverse events. In studies on experienced patients higher incidence of cancers was found in the raltegravir arm: a relationship with the drug was, however not confirmed in a recent review considering all raltegravir studies. Raltegravir also showed a safe lipid profile especially in naive patients, finding that renders the drug attractive for patients with other cardiovascular risk factors. All this characteristics in association with its specific mechanism of action, make raltegravir an interesting drug for naive patients and a large use in this type of patients is predictable. Only time and experience, however, will tell us whether raltegravir will maintain its promises in the long run.

Topics: HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; RNA, Viral

Raltegravir, the first approved integrase inhibitor, has been shown to be virologically effective in Phase II and Phase III clinical trials in both treatment naive and triple class resistant patients. It also has an excellent tolerability profile and lacks significant drug-drug interactions making it an important drug in the treatment of a number of special patient populations. In this review its use in patients undergoing solid organ and bone marrow transplantation and patients receiving cancer chemotherapy, will be discussed. In addition other indications including patients with metabolic complications of existing antiretroviral drugs as well as patients with side effects on current HAART regimens. Other groups of patients where raltegravir may play an important role are patients with renal disease and tuberculosis. Finally, although not licensed for use in pregnancy, raltegravir may need to be considered in some pregnant women with antiretroviral resistance or tolerability issues with current HAART regimens.

Topics: Female; HIV Infections; HIV Integrase Inhibitors; Humans; Neoplasms; Organ Transplantation; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; Tuberculosis

Similar to all antiretroviral drugs, failure of raltegravir-based treatment regimens to fully supress HIV replication almost invariably results in emergence of HIV resistance to this new drug. HIV resistance to raltegravir is the consequence of mutations located close to the integrase active site, which can be divided into three main evolutionary pathways: the N155H, the Q148R/H/K and the Y143R/C pathways. Each of these primary mutations can be accompanied by a variety of secondary mutations that both increase resistance and compensate for the variable loss of viral replicative capacity that is often associated with primary resistance mutations. One unique property of HIV resistance to raltegravir is that each of these different resistance pathways are mutually exclusive and appear to evolve separately on distinct viral genomes. Resistance is frequently initiated by viruses carrying mutations of the N155H pathway, followed by emergence and further dominance of viral genomes carrying mutations of the Q148R/H/K or of the Y143R/C pathways, which express higher levels of resistance. Even if some natural integrase polymorphisms can be part of this evolution process, these polymorphisms do not affect HIV susceptibility in the absence of primary mutations. Therefore, all HIV-1 subtypes and groups, together with HIV-2, are naturally susceptible to raltegravir. Finally, because interaction of integrase strand transfer inhibitors with the HIV integrase active site is comparable from one compound to another, raltegravir-resistant viruses express significant cross resistance to most other compounds of this new class of antiretroviral drugs.

Topics: Drug Resistance, Viral; Genome, Viral; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Since 1996, the prognosis of those living with HIV and AIDS has improved significantly due to highly active antiretroviral therapy (HAART). Treatment failure can occur clinically, immunologically or virologically. Until recently, treatment options for those individuals harboring resistance to the three initial licensed classes of drug have been limited. These three classes are the nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). New drugs are now available in these classes (second generation NNRTIs and novel PIs) as well as new classes of drugs, integrase inhibitors, CCR5 antagonists and fusion inhibitors. If these new drugs are used appropriately with other active antiretroviral agents, it is probable that antiretroviral therapy can achieve the optimum outcome of HIV therapy - durable suppression of HIV viraemia. This article is a review of currently available antiretroviral agents including the new classes and second generation drugs, resistance pathways and treatment options for salvage therapy.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Darunavir; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Maraviroc; Nitriles; Pyridazines; Pyridines; Pyrimidines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Salvage Therapy; Sulfonamides; Treatment Outcome; Triazoles

HIV-1 integrase catalyzes the insertion of HIV-1 DNA into the genome of the host cell and, therefore, represents a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. Raltegravir, marketed as Isentress, is the first integrase inhibitor to be approved by the FDA for the treatment of HIV AIDS infection. This review briefly describes the successful medicinal chemistry efforts that culminated in the discovery of raltegravir, and highlights more recent progress that has been made in the field of HIV-1 integrase inhibition.

Topics: Animals; Drug Design; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Structure; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Raltegravir (formerly known as MK-0518; Isentress) is the first in a new class of integrase inhibitors approved for the use in treatment-experienced adult patients who have evidence of viral replication and HIV strains resistant to multiple antiretroviral agents. It is dosed twice daily with or without food. Raltegravir is a novel antiretroviral that has been shown to be well tolerated. It has demonstrated potent efficacy in the virologic suppression of HIV-1 RNA levels up to 48 weeks in two controlled studies that were conducted in clinically advanced, three-class antiretroviral, treatment-experienced adults.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium

Merck & Co has developed and launched raltegravir, an HIV-1 integrase inhibitor for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. This drug is the lead from a series of integrase strand transfer inhibitors and, by April 2008, it had been launched in Canada, the US, the UK, France, Germany and Spain, and had been filed for approval in Japan.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Interactions; Drug Resistance, Multiple, Viral; HIV Infections; HIV Integrase Inhibitors; Humans; Patents as Topic; Pyrrolidinones; Raltegravir Potassium

New drug therapies to treat hepatitis C (HCV) and HIV infection are being developed with improved understanding of the molecular structures of the viruses themselves, the pathogenesis of infection and the specific immune responses needed to eradicate or control these infections. Interferon and ribavirin based therapies will continue to be a component of HCV therapy for the near future combined with other novel compounds directed at targets of viral replication, immunomodulation or cell entry. The goals of anti-HCV therapy are viral eradication for differing genotypes and prevention of hepatic morbidity such as hepatocellular carcinoma and cirrhosis. Future antiretroviral therapies for HIV will include agents that focus on new classes of inhibitors of viral replication and cell binding. The new treatment choices in HIV will need to ensure effective and durable viral suppression especially against highly resistant virus strains, regimen tolerability and improved toxicity.

Topics: Anti-Retroviral Agents; Antiviral Agents; Comorbidity; Hepatitis C, Chronic; HIV Infections; Humans; Pyrimidine Nucleosides; Pyrrolidinones; Quinolones; Raltegravir Potassium; Substance Abuse, Intravenous

Topics: Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; HIV; HIV Infections; HIV Integrase; HIV Protease Inhibitors; Humans; Pyrrolidinones; Quinolones; Raltegravir Potassium

Topics: Alkaline Phosphatase; Atazanavir Sulfate; CD4 Lymphocyte Count; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium

The availability of new classes of antiretroviral drugs has made it possible for HIV-infected individuals who are highly treatment experienced to achieve the goals of immunologic recovery and virologic suppression. Raltegravir is the first integrase inhibitor to be approved by the US Food and Drug Administration for use in antiretroviral treatment- experienced adult patients with viral resistance.. This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, tolerability, resistance profile, drug interactions, and dosing and administration of raltegravir.. Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to July 2008 were conducted using the terms integrase, raltegravir, and MK-0518. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (1998-2008); Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2007); International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (2001-2007); and European AIDS Conference (2001-2007) were also searched.. Raltegravir blocks HIV replication by inhibiting essential strand-transfer activities of integrase. Raltegravir is rapidly absorbed, with a median T(max) of approximately 4 hours in the fasting state. No dose adjustment is recommended in patients with moderate renal or hepatic insufficiency, and raltegravir may be taken without regard to meals. In Phase II studies in treatment-naive patients, raltegravir had efficacy similar to that of standard initial therapies. In 2 interrelated Phase III clinical studies in treatment-experienced patients with drug-resistant disease, the addition of raltegravir to an optimized background regimen significantly lowered HIV RNA compared with optimized background treatment alone (62.1% vs 32.9%, respectively; P < 0.001). Raltegravir was generally well tolerated. The most common adverse effects reported in Phase II/III trials in treatment-experienced patients were diarrhea (16.6%), nausea (9.9%), and headache (9.7%). Cytochrome P450-related drug interactions are not expected, as raltegravir is not a CYP substrate, inducer, or inhibitor. However, to prevent failure of raltegravir, the drug should not be coadministered with rifampin.. Raltegravir is a potent and generally well tolerated antiretroviral agent that may play an important role in the treatment of patients harboring resistance to other antiretrovirals.

Topics: Area Under Curve; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Half-Life; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Darunavir is a new protease inhibitor. This drug is highly active against wild-type and multiresistant HIV strains, binds strongly to the HIV-1 protease, has extremely high affinity for the protease and, when enhanced by subtherapeutic doses of ritonavir, has a favorable resistance profile differing from that of current protease inhibitors (PIs). After determining the optimal dose, phase IIb clinical trials (POWER studies 1 and 2) observed much higher virological and immunological efficacy with darunavir than with the comparator PIs. The results of a phase III clinical trial (POWER 3) provide further support for the safety and efficacy of darunavir, and the three POWER studies demonstrate the high genetic barrier of this drug against mutations conferring resistance to other PIs, although the baseline sensitivity of darunavir and the specific mutations to this PI influence the virological response. Better therapeutic responses have been obtained when there are two or more antiretroviral drugs active against multiresistant HIV strains. The phase III trials (DUET 1 and 2), in which darunavir was administered with the new nonnucleoside reverse transcriptase inhibitor, etravirine, found that if these two drugs were administered in highly treatment-experienced patients, a large percentage showed suppression of plasma viremia and immunological recovery. These data have been supported by the results of the BENCHMARK studies, in which darunavir was included in an optimized regimen in a substantial number of patients. In these trials, when darunavir was administered with the integrase inhibitor, raltegravir, undetectable viral loads both in the raltegravir arm and in the control group were substantially improved with respect to the overall results obtained in the control group.

Topics: Adult; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Darunavir; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Multicenter Studies as Topic; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viremia

Topics: HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Quinolones; Raltegravir Potassium; Virus Integration

The early establishment of an HIV-1 reservoir with integrated provirus in the DNA of cells with latent infection hampers viral eradication, despite maintenance of viral loads lower than 50 copies/mL for years. By early initiation of highly suppressive antiretroviral therapy (ART), the half-life of this reservoir could be as short as 4.6 months and require only 7.7 years for complete elimination. The constant presence of low-grade viral replication probably indefinitely replenishes this resting CD4+ T cell reservoir. This reservoir probably results from both the release of virus stored in latently-infected cells that have become activated and from residual replication of some still-activated cells. This also allows new resistant mutants selected after therapeutic failure to be incorporated into the reservoir. Raltegravir has been demonstrated to significantly reduce elimination times in the first two viral decay phases after initiation of ART. On starting the second phase, the viral load was 70% lower in patients treated with raltegravir than in those treated with efavirenz. Through its late mechanism of action in the HIV-1 cell cycle, this drug could induce greater decreases in proviral DNA than other antiretroviral agents. The presence of unintegrated HIV DNA under prolonged effective ART indicates that either there is continual low-level viral replication or that this unintegrated DNA can persist for prolonged periods. In both cases, intensification of ART with raltegravir could provide beneficial effects on the speed of elimination of the HIV-1 reservoir.

Topics: CD4-Positive T-Lymphocytes; DNA, Viral; Half-Life; HIV; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Models, Biological; Organ Specificity; Pyrrolidinones; Raltegravir Potassium; Tissue Distribution; Viral Load; Virus Integration; Virus Latency; Virus Replication

The HIV replication cycle passes through a stage of integrating proviral DNA into the cell's DNA. In this process, the viral enzyme, integrase, catalyses two reactions. The first reaction, which seems to occur in the cytoplasm, involves 3'-end processing, in which two nucleotides are removed from the 3' ends of the viral DNA by integrase. The second reaction, which occurs in the nucleus, involves the strand transfer reaction, catalyzed by integrase, in which the recessed 3' ends of the viral DNA are joined to the protruding 5' ends in the target DNA. Although this activity has not yet been completely defined and the structure of the active form of integrase, probably a tetramer, has not been resolved, drugs of the diketoacid (DKA) family have been found. These drugs are highly potent inhibitors of the second phase, the strand transfer reaction. Through a series of optimizations, a highly effective molecule for clinical use, raltegravir, has been achieved. The present article provides a summary of basic knowledge on integrase, as well as the activity and the modes of inhibition of this enzyme. Also discussed is the reduced, but nevertheless real, development of resistance to raltegravir, requiring second-generation integrase inhibitors to be designed.

Topics: Anti-HIV Agents; Catalytic Domain; DNA, Viral; Drug Delivery Systems; Drug Design; Drug Resistance, Viral; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Magnesium; Protein Structure, Tertiary; Proviruses; Pyrrolidinones; Raltegravir Potassium; Virus Integration

Raltegravir is the first integrase inhibitor approved for the treatment of HIV-1 infection in pretreated adults with evidence of viral replication despite receiving antiretroviral therapy. Raltegravir is administered orally at a dose of 400 mg every 12 hours, with or without food. This drug is mainly eliminated through UGT1A1-mediated glucuronidation and is not an inhibitor or inducer of the main liver cytochrome P450 isoenzymes; consequently there is virtually no risk of pharmacological interactions with most commonly used drugs such as methadone, azole antifungal agents or drugs used to treat erectile dysfunction. Studies of interaction with other antiretroviral agents show that raltegravir can be used in combination with tenofovir, efavirenz, atazanavir, ritonavir or tipranavir/ritonavir without the need for dose adjustments. When combined with rifampicin, the dose of raltegravir should be increased to 800 mg/12 h. Proton pump inhibitors increase plasma levels of raltegravir (a 3-fold increase in exposure or AUC levels), and consequently their combined use should be avoided as far as posible. Raltegravir is well tolerated and does not require dose adjustments in patients with severe renal impairment or mild-to-moderate liver impairment. There are no studies in patients with severe liver impairment.

Topics: Adult; Aged; Anti-HIV Agents; Child; Clinical Trials as Topic; Cytochrome P-450 Enzyme System; Drug Interactions; Fasting; Female; Food-Drug Interactions; Glucuronosyltransferase; HIV Infections; HIV Integrase Inhibitors; Humans; Inactivation, Metabolic; Intestinal Absorption; Male; Microsomes, Liver; Polypharmacy; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium

Raltegravir is the first in a new class of antiretroviral treatments called integrase inhibitors, which work by preventing HIV from inserting its genetic material into the DNA of the human chromosome. Phase I-III studies have shown this drug to have potent antiretroviral action, which is more rapid than that of protease inhibitors. The dose selected in efficacy studies is 400 mg every 12 h. However, due to the favorable pharmacokinetic profile of raltegravir, the possibility of administration of 600 to 800 mg once daily is under study. Given that this drug is not metabolized by the cytochrome P450 system, the potential for pharmacological interactions is low. Moreover, because humans lack a cellular homologue for HIV integrase, raltegravir has a low potential for toxicity. Raltegravir has an intermediate genetic barrier and consequently there may be cross-resistance across the integrase inhibitor class. For all these reasons, raltegravir is an attractive option in treatment-naive and pretreated patients and in those receiving simplification regimens.

Topics: Animals; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Viral; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Multicenter Studies as Topic; Pilot Projects; Pyrrolidinones; Rabbits; Raltegravir Potassium; Randomized Controlled Trials as Topic; Rats; Salvage Therapy; Viral Load; Virus Integration

Integrase inhibitors are a new therapeutic modality against HIV. Raltegravir is the first integrase inhibitor to have been approved by the health authorities for human use. This drug acts by inhibiting the HIV enzyme that catalyzes integration of the virus inside the genome of the host cell. In the host cell, there is no homologue to viral integrase and consequently the potential toxicity of this drug is probably low. The results of safety studies in animal models have shown that the recommended dose in humans is lower than the dose below which no secondary effects are observed. Studies of genotoxicity and carcinogenicity, as well as of fertility and embryo development, have been negative to date. During clinical trials, raltegravir has been shown to have a very good safety profile, with few adverse effects, which were mild-to-moderate and similar to those of the comparator. The most notable were diarrhea, nausea and headache. The lipid profile of raltegravir was better than that of efavirenz. In view of the above, the risk-benefit ratio for raltegravir is positive.

Topics: Abnormalities, Drug-Induced; Animals; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Embryonic Development; Female; Gastrointestinal Diseases; Headache; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Male; Mice; Mutagenicity Tests; Pain; Pregnancy; Pyrrolidinones; Rabbits; Raltegravir Potassium; Rats

Integrase inhibitors are the most recently approved family of antiretroviral agents for the treatment of HIV infection. As with other antiretroviral agents, under pharmacological pressure, the virus selects resistance mutations if viral suppression is incomplete. Mutations are selected in the integrase gene, specifically in positions proximal to the catalytic center. Because clinical experience with these drugs is scarce, information on resistance is limited. Virologic failure with raltegravir is associated with selection of primary mutations such as N155H (40%) and distinct changes in position Q148 (28%). Less frequently, Y143R (6.6%) and E92Q are selected. The most frequently observed mutations in failure with elvitegravir are E92Q, E138K, Q148R/K/H and N155H, and less frequently S147G and T66A/I/K. The most common resistance pattern seems to be E138K + E147G + Q148R. There is a high grade of cross resistance between raltegravir and elvitegravir, making sequencing between these two drugs impossible.

Topics: Amino Acid Substitution; Clinical Trials as Topic; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Genetic Variation; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Models, Molecular; Mutation, Missense; Point Mutation; Protein Conformation; Pyrrolidinones; Quinolones; Raltegravir Potassium

Antiretroviral rescue therapy has been revolutionized by the development of new drugs in the last few years: enfuvirtide (a fusion inhibitor), tipranavir/ritonavir (a high genetic barrier protease inhibitor), darunavir/ritonavir (a high genetic barrier protease inhibitor), etravirine (a non-nucleoside reverse transcriptase inhibitor active against nevirapine- and efavirenz- resistant HIV), maraviroc (a CCR5 coreceptor inhibitor) and raltegravir (an integrase inhibitor). The use of these drugs in rescue regimens has allowed the goal of antiretroviral rescue therapy to be the same as that in treatment naive-patients: to achieve a viral load lower than 50 copies of RNA of HIV/ml. Raltegravir is the first integrase inhibitor available for clinical use in Spain. This drug is primarily metabolized through UGT1A1-mediated glucuronidation and consequently has a low potential for interactions with drugs metabolized by the cytochrome P450 pathway. Raltegravir has been demonstrated to have high efficacy in two large clinical trials of rescue therapy, especially when combined with darunavir/ritonavir and enfuvirtide. Preliminary data suggest that raltegravir could also be an effective drug in treatment-naive patients and as substitution therapy in patients with toxicity due to boosted protease inhibitor therapy. The drug's unusual mechanism of action has reopened the possibility of a positive effect on latent HIV reservoirs.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Enfuvirtide; Forecasting; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Maraviroc; Nitriles; Peptide Fragments; Pyridazines; Pyridines; Pyrimidines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Sulfonamides; Triazoles

Integrase is essential for HIV-1 replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity in a manner consistent with inhibition of integration. Raltegravir is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against wild-type and multi-class resistant HIV-1 virus (in vitro IC(95) for HIV-1 in 50% normal human serum = 33 nM). Inhibition of integrase prevents insertion of HIV DNA into the human DNA genome, thus blocking the ability of HIV to replicate. Raltegravir is administered orally every 12 h and does not require boosting with low-dose ritonavir (RTV) to achieve therapeutic concentrations. Raltegravir is not a potent inhibitor or inducer of cytochrome P450 3A4, and it is predominantly metabolized by glucuronidation, specifically by the enzyme UDP-glucuronosyltransferase 1A1.

Topics: Clinical Trials as Topic; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Structure; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Virus Replication

The emergence of antiretroviral drug resistance in patients infected by the human immunodeficiency virus (HIV) has prompted efforts to develop new antiretrovirals that differ from existing agents with regard to mechanism of action and resistance profiles. We evaluated the literature regarding a new class of antiretrovirals, the integrase inhibitors. A MEDLINE search (January 1996-May 2007) was performed to identify relevant clinical trials and review articles; abstracts from HIV conferences were also searched. Raltegravir (MK-0518) and elvitegravir (GS-9137) are the two integrase inhibitors in late-phase development. These agents prevent viral DNA integration into the CD4(+) cell chromosome. Both drugs showed potent antiviral activity in large clinical trials that were performed in treatment-experienced, multidrug-resistant patients. Promising results have also been seen in an initial dose-ranging study with raltegravir in treatment-naïve patients. Preliminary data describe integrase inhibitor resistance profiles, but more data are needed in this area. Both agents were well tolerated in clinical trials, with favorable pharmaco-kinetic profiles for once- or twice-daily dosing. Raltegravir and elvitegravir differ in their metabolism, resulting in distinct drug-interaction profiles for each agent. Based on available data, this new class of antiretrovirals will soon be widely used in antiretroviral-experienced patients infected with HIV. In the future, this class of drugs may become a reasonable treatment option for antiretroviral-naïve patients, but more data are needed in that patient population.

Topics: Dose-Response Relationship, Drug; HIV Infections; HIV Integrase Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Quinolones; Raltegravir Potassium; Randomized Controlled Trials as Topic

Once patients have a triple class virological failure, their treatment options are limited and there is an increased risk of death. In order to construct active treatment regimens, new potent antiretroviral agents are available for these patients. The virological target in patients with treatment failure is now plasma HIV RNA level below 50 copies/ml when 2 or more potent drugs are identified. If at least two active drugs cannot be identified, the current regimen should be maintained until new drugs become available, assuming that there is an immunological and clinical stability, in order to avoid the use of a single-active drug that usually leads to rapid development of resistance, further limiting the future treatment options. In this article, the current state of knowledge about these new agents available and the guidelines of main societies are reviewed.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; HIV; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Organic Chemicals; Peptide Fragments; Practice Guidelines as Topic; Pyridines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; RNA, Viral; Sulfonamides

The need to develop antiretroviral agents with novel mechanisms of action persists for the treatment of both antiretroviral- experienced and antiretroviral-naive patients with HIV/AIDS. This is mandated, in part, by the perpetual advent of antiretroviral-resistant HIV-1 strains. Raltegravir has been shown to specifically inhibit the essential, HIV-1-encoded, integrase enzyme. As a result, this agent represents a promising chemotherapeutic agent for the treatment of HIV/AIDS.. To form an evidence-based determination of the clinical efficacy, pharmacokinetics and safety profile of raltegravir.. We discuss available peer-reviewed publications, preliminary data presented in abstract from relevant scientific meetings and data available from the US Food and Drug Administration (FDA).. Current evidence strongly supports raltegravir use in highly active antiretroviral therapy (HAART) regimens constructed to treat patients failing current therapies with multi-drug-resistant HIV-1. Additional data are needed to determine its role in the treatment of less advanced patients. Issue surrounding long-term adverse effects and genetic barriers to raltegravir resistance will be critical in determining the potential of this agent.

Topics: Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; RNA, Viral

Topics: Drug Discovery; HIV Infections; HIV Integrase Inhibitors; Humans; Protein Binding; Pyrrolidinones; Raltegravir Potassium; Structure-Activity Relationship

In the developed world, access to highly active antiretroviral therapy (HAART) has led to significant reductions in the morbidity and mortality attributed to HIV/AIDS. However, the continual emergence of HIV-1 strains resistant to currently available classes of antiretrovirals highlights the need to develop agents with novel mechanisms of action. Successful completion of the HIV-1 viral life cycle depends in part on the integration of complementary DNA mediated by the enzyme HIV-1 integrase, one of three essential enzymes encoded in the viral genome. The integrase inhibitors have demonstrated the ability to act specifically at the strand transfer step during integration, making HIV-1 integrase a valid and attractive chemotherapeutic target for the treatment of HIV/AIDS. In clinical trials, raltegravir has been shown to be a potent drug with a pharmacokinetic profile that supports a twice-daily dosing schedule. In addition, it has demonstrated a favorable side-effect profile in treatment-naive and -experienced patients and a subset of heavy treatment-experienced patients have been able a achieve virologic suppression with raltegravir as part of combination therapy despite limited treatment options. In October 2007, raltegravir was approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 as part of combination antiretroviral therapy in treatment-experienced patients-providing an additional option for the management of the HIV-1 infected individual.

Topics: Animals; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Drugs in development for the management of HIV type 1 (HIV-1) infection include agents in existing classes and agents of novel classes. Of existing classes, new protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors are in development. Novel therapeutic approaches include the development of chemokine receptor (CCR)5 antagonists, integrase inhibitors and maturation inhibitors. CCR5 antagonists are thought to inhibit HIV-1 entry into host cells by occupying a specific site on the CCR5 receptor, preventing attachment of the HIV-1 envelope protein gp120. Integrase inhibitors are small synthetically prepared molecules that block RNA/DNA interactions and modify protein or enzyme synthesis. Data on the pharmacokinetics and pharmacodynamics of these new antiretroviral agents continue to generate interest. This review reports the known data on the pharmacokinetics of experimental antiretrovirals, and describe the main drug-drug interactions studied so far.

Topics: Animals; Anti-Retroviral Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drug Evaluation, Preclinical; Drug Interactions; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Maraviroc; Nitriles; Organic Chemicals; Protease Inhibitors; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Reverse Transcriptase Inhibitors; Sulfonamides; Triazoles

To study gut microbiota before and 24 weeks after a single antiretroviral agent switch.. HIV-positive patients with efavirenz (EFV) or a protease inhibitor (PI)-based antiretroviral therapy (ART) were randomized to switch EFV or PI to raltegravir (RAL group, n = 19) or to continue unchanged ART (EFV/PI group, n = 22). Age and weight-matched HIV-negative participants (n = 10) were included for comparison.. Microbiota was analyzed using 16S rRNA sequencing. Serum intestinal fatty acid-binding protein (I-FABP) and serum lipopolysaccharide-binding protein (LBP) were measured as gut permeability markers. Three-day food diaries were collected.. At week 24, microbiota diversity (Chao1 index) was higher in RAL than the EFV/PI group (P = 0.014), and RAL group did not differ from HIV-negative participants. In subgroup analysis switching from EFV (P = 0.043), but not from a PI to RAL increased Chao1. At week 24, RAL and EFV/PI group differed in the relative abundance of Prevotella 9 (higher in RAL, P = 0.01), Phascolarctobacterium and Bacteroides (lower in RAL, P = 0.01 and P = 0.03). Dietary intakes did not change during the study and do not explain microbiota differences. Also, I-FABP and LBP remained unchanged.. Here we demonstrate that a single ART agent switch caused microbiota alterations, most importantly, an increase in diversity with EFV to RAL switch. Previously, we reported weight gain, yet reduced inflammation in this cohort. The observed microbiota differences between RAL and EFV/PI groups may be associated with reduced inflammation and/or increase in weight. Further studies are needed to evaluate inflammatory and metabolic capacity of microbiota with ART switches.

Topics: Anti-HIV Agents; Benzoxazines; Gastrointestinal Microbiome; HIV Infections; Humans; Inflammation; Protease Inhibitors; Raltegravir Potassium; RNA, Ribosomal, 16S

We sought to compare virologic outcomes on antiretroviral therapy (ART) between people with HIV (PWH) also treated for tuberculosis in the different countries who participated to two randomized trials.. Pooled analysis of two randomized clinical trials.. In the phase II Reflate TB and phase III Reflate TB2 trials conducted in Brazil, Côte d'Ivoire, Mozambique and Vietnam, ART-naïve PWH treated for tuberculosis were randomized to receive raltegravir or efavirenz. We assessed country differences in baseline characteristic using Wilcoxon tests and chi-square, or Fisher's exact test. We used logistic regression to analyze determinants of virologic success, defined as week-48 plasma HIV-1 RNA <50 copies/ml.. Of 550 participants (140 from Brazil, 170 from Côte d'Ivoire, 129 from Mozambique and 111 from Vietnam) with median baseline HIV-1 RNA of 5.4 log 10  copies/ml, 362 (65.8%) achieved virologic success at week 48. Virologic success rates were: 105/140 (75.0%) in Brazil, 99/170 (58.2%) in Côte d'Ivoire, 84/129 (65.1%) in Mozambique and 74/111 (66.7%) in Vietnam ( P  = 0.0233). Baseline HIV-1 RNA, but not the country, was independently associated with virologic success: baseline HIV-1 RNA ≥500 000 copies/ml (reference), HIV RNA <100 000 copies/ml odds ratio 3.12 [95% confidence interval (CI) 1.94; 5.01] and HIV-1 RNA 100 000-499 999 copies/ml odds ratio: 1.80 (95% CI 1.19; 2.73). Overall, 177/277 (63.9%) patients treated with raltegravir and 185/273 (67.9%) patients treated with efavirenz had a plasma HIV-1 RNA <50 copies/ml at week 48.. Virologic response to antiretroviral therapy in PWH with TB varied across countries but was mainly driven by levels of pretreatment HIV-1 RNA.

Topics: Anti-HIV Agents; HIV Infections; Humans; Raltegravir Potassium; RNA, Viral; Tuberculosis; Viral Load

Topics: Alkynes; Benzoxazines; Coinfection; Cyclopropanes; Hepacivirus; Hepatitis C; HIV Infections; HLA-DR Antigens; Humans; Lipopolysaccharide Receptors; Neopterin; Raltegravir Potassium; Vietnam

Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs.. NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States.. Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal-Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs.. Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m 2 /wk versus 0.11 kg/m 2 /wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) ( P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs.. A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.

Topics: Female; HIV Infections; Humans; Integrase Inhibitors; National Institute of Child Health and Human Development (U.S.); Pregnancy; Raltegravir Potassium; United States; Weight Gain

To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual's viral quasispecies) affects antiretroviral treatment (ART)-suppression at term.. A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls.. HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing. Resistance mutations were assessed using the HIV Stanford Database, and the proportion of cases versus controls with PDR to their ART regimens was compared.. PDR was observed in 7 participants (11.3%; 95% CI 4.7, 21.9) and did not differ between 21 cases and 41 controls (4.8% vs 14.6%, p = 0.4061). PDR detected only as minority variants was less common (3.2%; 95% CI 0.2, 11.7) and also did not differ between groups (0% vs. 4.9%; p = 0.5447). Cases' median plasma HIV RNA at delivery was 347c/mL, with most (n = 19/22) showing progressive diminution of viral load but not ≤200c/mL. Among cases with viral rebound (n = 3/22), none had PDR detected. Virologic non-suppression at term was associated with higher plasma HIV RNA at study entry (p<0.0001), a shorter duration of ART prior to delivery (p<0.0001), and randomization to efavirenz- (versus raltegravir-) based ART (p = 0.0085).. We observed a moderate frequency of PDR that did not significantly contribute to virologic non-suppression at term. Rather, higher pretreatment plasma HIV RNA, randomization to efavirenz-based ART, and shorter duration of ART were associated with non-suppression. These findings support early prenatal care engagement of pregnant women and initiation of integrase inhibitor-based ART due to its association with more rapid suppression of plasma RNA levels. Furthermore, because minority variants appeared infrequent in ART-naïve pregnant women and inconsequential to ART-suppression, testing for minority variants may be unwarranted.

Topics: Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Benzoxazines; Case-Control Studies; Cyclopropanes; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pharmaceutical Preparations; Pregnancy; Pregnant Women; Raltegravir Potassium; RNA; Viral Load

The adipokines leptin and adiponectin, produced primarily by adipose tissue, have diverse endocrine and immunologic effects, and circulating levels reflect adipocyte lipid content, local inflammation, and tissue composition. We assessed relationships between changes in regional fat depots, leptin and adiponectin levels, and metabolic and inflammatory markers over 96 weeks in the AIDS Clinical Trials Group (ACTG) A5260s metabolic substudy of the A5257 randomized trial of tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir among treatment-naive persons with human immunodeficiency virus (PWH).. Fat depots were measured using dual-energy absorptiometry and abdominal computed tomographic imaging at treatment initiation and 96 weeks later. Serum leptin and adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP) were measured at the same timepoints. Multivariable regression models assessed relationships between fat depots, adipokines, HOMA-IR, and hsCRP at week 96.. Two hundred thirty-four participants maintained viral suppression through 96 weeks (90% male, 29% black, median age 36 years). Serum leptin increased over 96 weeks (mean change 22%) while adiponectin did not (mean change 1%), which did not differ by study arm. Greater trunk, limb, and abdominal subcutaneous and visceral fat were associated with higher HOMA-IR and hsCRP at 96 weeks, but serum leptin level was a stronger determinant of these endpoints using a mediation model approach. A similar mediating effect was not observed for adiponectin.. Higher circulating leptin is associated with greater HOMA-IR and hsCRP independent of fat depot size, suggesting that greater adipocyte lipid content may contribute to impaired glucose tolerance and systemic inflammation among PWH starting antiretroviral therapy.

Topics: Acquired Immunodeficiency Syndrome; Adipokines; Adult; Female; HIV Infections; Humans; Insulin Resistance; Male; Raltegravir Potassium; Weight Gain

Pharmacological interactions limit treatment options for children living with human immunodeficiency virus (HIV) and tuberculosis (TB). We found that 12 mg/kg twice daily raltegravir chewable tablets (administered after crushing) safely achieved pharmacokinetic targets in children living with HIV aged 4 weeks to <2 years receiving concurrent rifampin to treat TB.. NCT01751568.

Topics: Anti-HIV Agents; Child; HIV; HIV Infections; Humans; Raltegravir Potassium; Rifampin; Tuberculosis

Etravirine/raltegravir dual therapy has been shown to be highly effective as a twice-daily (q12h) regimen in suppressed HIV-infected patients enrolled in the ANRS-163 study.. As a once-daily (q24h) regimen is easier for daily life, we aimed to evaluate the capacity of etravirine/raltegravir (400/800 mg) q24h to maintain viral suppression in patients on etravirine/raltegravir q12h.. Patients on a suppressive etravirine/raltegravir q12h regimen for at least 96 weeks were switched to etravirine/raltegravir q24h in this prospective, multicentre, open-label, single-arm study. Primary outcome was the rate of virological failure (VF: confirmed pVL >50 copies/mL, single pVL >400 copies/mL or single pVL >50 copies/mL with ART change) at Week 48 (W48). Secondary outcomes included treatment strategy success rate (no VF and no treatment discontinuation), regimen tolerability, plasma drug concentrations and resistance profile in the case of VF.. A total of 111 patients were enrolled, with a median (IQR) age of 57 years (52-62), CD4 count of 710 cells/mm3 (501-919) and viral suppression for 7.9 years (5.9-10.7). Two patients experienced viral rebound at W24 and W48, leading to a VF rate of 2.0% (95% CI 0.5-7.8) at W48, associated with INSTI resistance in one case. Both had past NNRTI mutations. Ten patients discontinued treatment for adverse events (n = 2), investigator or patient decisions (n = 3), lost to follow-up (n = 3), death (n = 1) or pregnancy (n = 1). Overall, the strategy success rate was 89% (95% CI 81.5-93.6) at W48. In a subgroup of 64 patients, median (IQR) plasma C24h concentrations were 401 ng/mL (280-603) for etravirine and 62 ng/mL (31-140) for raltegravir.. Switching patients virally suppressed on etravirine/raltegravir q12h to the same regimen but given q24h was highly effective in maintaining virological suppression in HIV-infected patients.

Topics: Anti-HIV Agents; HIV Infections; HIV-1; Humans; Middle Aged; Nitriles; Prospective Studies; Pyrimidines; Raltegravir Potassium; Treatment Outcome; Viral Load

In patients co-infected with HIV and tuberculosis, antiretroviral therapy options are limited due to drug-drug interactions with rifampicin. A previous phase 2 trial indicated that raltegravir 400 mg twice a day or efavirenz 600 mg once a day might have similar virological efficacy in patients given rifampicin. In this phase 3 trial, we assessed the non-inferiority of raltegravir to efavirenz.. We did a multicentre, open-label, non-inferiority, randomised, phase 3 trial at six sites in Côte d'Ivoire, Brazil, France, Mozambique, and Vietnam. We included antiretroviral therapy (ART)-naive adults (aged ≥18 years) with confirmed HIV-1 infection and bacteriologically confirmed or clinically diagnosed tuberculosis who had initiated rifampicin-containing tuberculosis treatment within the past 8 weeks. Using computerised random numbers, we randomly assigned participants (1:1; stratified by country) to receive raltegravir 400 mg twice daily or efavirenz 600 mg once daily, both in combination with tenofovir and lamivudine. The primary outcome was the proportion of patients with virological suppression at week 48 (defined as plasma HIV RNA concentration <50 copies per mL). The prespecified non-inferiority margin was 12%. The primary outcome was assessed in the intention-to-treat population, which included all randomly assigned patients (excluding two patients with HIV-2 infection and one patient with HIV-1 RNA concentration of <50 copies per mL at inclusion), and the on-treatment population, which included all patients in the intention-to-treat population who initiated treatment and were continuing allocated treatment at week 48, and patients who had discontinued allocated treatment due to death or virological failure. Safety was assessed in all patients who received at least one dose of the assigned treatment regimen. This study is registered with ClinicalTrials.gov, NCT02273765.. Between Sept 28, 2015, and Jan 5, 2018, 460 participants were randomly assigned to raltegravir (n=230) or efavirenz (n=230), of whom 457 patients (230 patients in the raltegravir group; 227 patients in the efavirenz group) were included in the intention-to-treat analysis and 410 (206 patients in the raltegravir group; 204 patients in the efavirenz group) in the on-treatment analysis. At baseline, the median CD4 count was 103 cells per μL and median plasma HIV RNA concentration was 5·5 log. In patients with HIV given tuberculosis treatment, non-inferiority of raltegravir compared with efavirenz was not shown. Raltegravir was well tolerated and could be considered as an option, but only in selected patients.. National French Agency for AIDS Research, Ministry of Health in Brazil, Merck.. For the Portuguese and French translations of the abstract see Supplementary Materials section.

Topics: Adult; Aged; Aged, 80 and over; Alkynes; Anti-HIV Agents; Benzoxazines; Brazil; Coinfection; Cote d'Ivoire; Cyclopropanes; Drug Dosage Calculations; Female; France; HIV Infections; Humans; Male; Middle Aged; Mozambique; Raltegravir Potassium; Treatment Outcome; Tuberculosis; Vietnam; Young Adult

To characterize their potential use in pre-exposure prophylaxis (PrEP) we compared the pharmacokinetics of raltegravir and lamivudine in genital tissue against ex vivo tissue infection with HIV-1.. Open-label trial of 36 HIV-negative females and males randomized to 7 days raltegravir 400 mg twice daily and 7 days raltegravir 400 mg+lamivudine 150 mg twice daily (after washout), or vice versa. Blood, saliva, rectal fluid, rectal tissue, vaginal fluid and vaginal tissue were sampled at baseline and on and off PrEP during a total of 12 days, for pharmacokinetics and antiviral activity via ex vivo HIV-1BaL challenge. Ex vivo infectivity was compared with baseline. The trial has been registered in https://clinicaltrials.gov/ with the identifier NCT03205566.. Steady state for both drugs was reached by day 4. Dosing with raltegravir alone provided modest ex vivo HIV protection with higher drug levels in rectal tissue and vaginal tissue than in plasma on and off PrEP. Off PrEP, plasma and vaginal concentrations declined rapidly, while persisting in the rectum. On PrEP, the highest lamivudine concentrations were in the rectum, followed by vaginal tissue then plasma. Lamivudine washout was rapid in plasma, while persisting in the rectum and vagina. Raltegravir/lamivudine increased ex vivo protection on and off PrEP compared with raltegravir alone, reaching maximum protection at day 2 in rectal tissue and at day 8 in vaginal tissue.. Raltegravir 400 mg+lamivudine 150 mg showed high levels of ex vivo HIV protection, associated with high drug concentrations persisting after discontinuation in vaginal and rectal compartments, supporting further investigation of these agents for PrEP.

Topics: Anti-HIV Agents; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Pre-Exposure Prophylaxis; Raltegravir Potassium

Persistent inflammation and immune activation are associated with lymph node fibrosis and end-organ diseases in treatment-suppressed people living with HIV (PLWH). We investigated the effect of switching to raltegravir and/or adding losartan on lymphoid tissue fibrosis and on the inflammatory/immune-activation mediators in treated HIV patients.. Chronic HIV-infected patients treated with two nucleoside reverse transcriptase inhibitors (2NRTI) and one non-NRTI (NNRTI) or protease inhibitor (PI) during at least 48 weeks were randomized to four groups (n = 48): 2NRTI + efavirenz (EFV), 2NRTI + EFV + losartan, 2NRTI + raltegravir and 2NRTI + raltegravir + losartan for 48 weeks. Tonsillar biopsy and peripheral blood markers of CD4 and CD8 T-lymphocyte activation and senescence, monocyte activation and soluble markers of inflammation were determined at baseline and at week 48 and compared between groups.. No changes in lymphoid tissue architecture were observed. Adding losartan had no impact on lymphocyte subsets. Conversely, patients who switched to raltegravir showed a higher decrease in all activated [CD4+CD38+HLA-DR+, -0.3 vs. 0.48 (P = 0.033); CD8+CD38+ HLA-DR+, -1.6 vs. 1.3 (P = 0.02)] and senescent [CD4+CD28-CD57+, -0.3 vs. 0.26 (P = 0.04); CD8+CD28-CD57+, -6.1 vs. 3.8 (P = 0.002)] T lymphocytes. In addition, the median CD4/CD8 ratio increased by 0.35 in patients in the raltegravir group vs. 0.03 in the other arms (P = 0.002). Differences between groups in monocyte subpopulations or soluble inflammation markers were not observed.. Losartan had no effect on lymphoid fibrosis or immune activation/inflammation. Conversely, switching to a regimen with raltegravir significantly decreased activated and senescent T-lymphocyte subpopulations and increased CD4/CD8 ratio in successfully treated PLWH.

Topics: Anti-HIV Agents; Fibrosis; HIV Infections; Humans; Inflammation; Losartan; Lymphoid Tissue; Raltegravir Potassium; Viral Load

Pregnant women using antiretrovirals (ARVs) may have persistent vaginal viral shedding, which could be associated with sexual and perinatal HIV transmission. However, there are scant data on vaginal viral load (VVL) in pregnant women with undetectable plasma viral load (PVL).. This study was a post hoc analysis of an open-label randomized trial to evaluate the virologic response of 2 ART regimens. The participants were ART-naive women living with HIV initiating ART regimens between 20 and 36 weeks of pregnancy recruited at 19 clinical sites in 6 countries. Participants were randomized to receive 400 mg of raltegravir 2 times a day or 600 mg of efavirenz 4 times a day in addition to 150 mg of lamivudine and 300 mg of zidovudine 2 times a day. VVL and PVL tests were performed at every study visit. The primary outcome measures were HIV-1 PVL and VVL at maternal study week 4 and rates of perinatal HIV transmission.. A total of 408 were enrolled, of whom 323 had VVL samples 4 weeks after enrollment and were included in this analysis. Among women with undetectable/nonquantifiable PVL during ART, the overall rate of quantifiable VVL at week 4 was 2.54% (7/275). Of the 275 with nonquantifiable PVL, 99.1% (115/116) and 96.2% (153/159) had nonquantifiable VVL in the efavirenz and raltegravir arms, respectively. None of the 7 women with quantifiable VVL at the week 4 study visit transmitted HIV to their infants.. Detectable VVL in pregnant women with undetectable/nonquantifiable PVL while receiving ART was rare and not associated with perinatal HIV transmission.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Female; HIV Infections; Humans; Infant; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Pregnant Women; Raltegravir Potassium; Vigna; Viral Load; Virus Shedding; Zidovudine

NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure.. Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression.. Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively].. Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

Topics: Adult; Anti-HIV Agents; Constitutive Androstane Receptor; Darunavir; Emtricitabine; Female; HIV Infections; Humans; Liver-Specific Organic Anion Transporter 1; Male; Multidrug Resistance-Associated Protein 2; Pharmacogenetics; Raltegravir Potassium; Ritonavir; Tenofovir; Viral Load

Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection.. IMPAACT P1110 is a phase 1, multicenter, noncomparative dose-finding study of raltegravir in infants exposed to HIV-1 infection. A 2-cohort adaptive design was utilized where pharmacokinetic data from infants in cohort 1 who received 2 single doses of raltegravir 3 mg/kg were included in population modeling and simulations to guide selection of a daily dose for infants in cohort 2.. A total of 52 infants enrolled in IMPAACT 1110: cohort 1 (N = 16) and cohort 2 (N = 36). Using simulations based on population PK modeling incorporating cohort 1 data, the following daily dosing regimen was selected for study: 1.5 mg/kg daily from birth through day 7; 3 mg/kg twice daily from days 8-28 of life; and 6 mg/kg twice daily after 4 weeks of age through 6 weeks of age. The geometric mean protocol exposure targets for AUC, Ctrough, and Cmax were met or slightly exceeded in all infants. The chosen neonatal raltegravir dosing regimen was safe and well tolerated in full-term neonates during treatment over the first 6 weeks of life and follow-up to age 24 weeks.. Raltegravir can be safely administered to full-term infants using the daily dosing regimen studied. This regimen is not recommended for use in premature infants in a new version of P1110.

Topics: Area Under Curve; Cohort Studies; Dose-Response Relationship, Drug; Female; Half-Life; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infant, Newborn; Infant, Newborn, Diseases; Male; Raltegravir Potassium

Multiple T-cell marker recovery (MTMR: CD4+ T-cells >500 cel/mm3 plus CD4+% >29% plus CD4+/CD8+ ratio >1) has been proposed as the most complete level of immune reconstitution. In this study we quantified differences in the CD4+/CD8+ ratio, CD4+% recovery and MTMR after starting HIV-1 treatment with dolutegravir (DTG) vs. raltegravir (RAL) plus a NRTI backbone.. Exploratory post-hoc analysis of the SPRING-2 study, a randomized double-blind clinical trial comparing DTG and RAL as third agents in naive HIV-infected patients at 100 sites in Canada, USA, Australia, and Europe. Percentage differences and corresponding precision based on 95% confidence intervals (CI) and p-values were calculated for i) CD4+/CD8+ ratio normalization, ii) CD4+% normalization, and iii) the achievement of MTMR.. A total of 822 participants were analyzed (411 in each group). No statistically significant differences in the proportion of patients who reached a CD4+/CD8+ ratio ≥0.5 & ≥1 at w48 & w96 were observed. At w96, the proportion of patients with a CD4+/CD8+ ratio ≥1 was similar (30.43% DTG vs. 29.57% RAL). No differences were observed in the mean increase in CD4+/CD8+ ratio from baseline at both w48 & w96. Similarly, no significant differences in the CD4+/CD8+>29% were observed at w96 (72.95% DTG vs 69.28% RAL). The proportion of patients attaining MTMR criteria was also similar in the DTG group and the RAL group at w48 (20.33% vs. 18.26%; difference 2.07 (95%CI (-3.67;7.81) P = 0.481 and w96 (28.70% vs. 27.13; difference 1.56 (95%CI -5.22;8.34) P = 0.652).. After comparing DTG and RAL, no differences on immune recovery markers were observed.

Topics: Adult; Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; CD4-CD8 Ratio; Double-Blind Method; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Viral Load

The ANRS-163 ETRAL trial, a switch study to an etravirine 200 mg/raltegravir 400 mg twice-daily regimen in 165 patients with HIV-1 infection, showed durable efficacy until Week 96. The aim of this work was to investigate in detail the virological rebounds (VRs), defined as at least one plasma HIV viral load (VL) >50 copies/mL.. Quantification of HIV-DNA level was assessed at baseline, Week 48 and Week 96 (n = 157). VLs were measured in seminal plasma at Week 48 (n = 26). Genotypic resistance testing by ultra-deep sequencing (UDS) for reverse transcriptase (RT) and integrase regions was performed at baseline and at the time of VR.. In this study, 19 patients experienced VR, with 2 patients having virological failure (VF; two consecutive VLs >50 copies/mL). For the first patient with VF, UDS detected minority resistant variants only in RT (K103N, 9.6%; Y181C, 4.9%) at baseline. Some RT variants became dominant at VF (K101E, 86.3%; Y181C, 100.0%; G190A, 100.0%) and others emerged in integrase (Y143C, 2.4%; Q148R, 6.2%; N155H, 18.8%). For the second patient with VF, neither RT nor integrase mutations were detected at baseline and VF. Median HIV-DNA level was similar at baseline, Week 48 and Week 96 (2.17, 2.06 and 2.11 log10 copies/106 cells, respectively). Only one patient had a detectable seminal HIV VL (505 copies/mL).. The dual etravirine/raltegravir regimen as maintenance therapy was effective and the emergence of mutations in cases of VF was similar to that seen in other dual-regimen studies. No HIV-DNA level modification was evidenced by Week 96.

Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Raltegravir Potassium; Viral Load

Although antiretroviral regimens containing integrase inhibitors rapidly suppress HIV viral load in non-pregnant adults, few published data from randomised controlled trials have compared the safety and efficacy of any integrase inhibitor to efavirenz when initiated during pregnancy. We compared safety and efficacy of antiretroviral therapy with either raltegravir or efavirenz in late pregnancy.. An open-label, randomised controlled trial was done at 19 hospitals and clinics in Argentina, Brazil, South Africa, Tanzania, Thailand, and the USA. Antiretroviral-naive pregnant women (20-<37 weeks gestation) living with HIV were assigned to antiretroviral regimens containing either raltegravir (400 mg twice daily) or efavirenz (600 mg each night) plus lamivudine 150 mg and zidovudine 300 mg twice daily (or approved alternative backbone regimen), using a web-based, permuted-block randomisation stratified by gestational age and backbone regimen. The primary efficacy outcome was plasma HIV viral load below 200 copies per mL at (or near) delivery. The primary efficacy analysis included all women with a viral load measurement at (or near) delivery who had viral load of at least 200 copies per mL before treatment and no genotypic resistance to any study drugs; secondary analyses eliminated these exclusion criteria. The primary safety analyses included all women who received study drug, and their infants. This trial is registered with Clinicaltrials.gov, number NCT01618305.. From Sep 5, 2013, to Dec 11, 2018, 408 women were enrolled (206 raltegravir, 202 efavirenz) and 394 delivered on-study (200 raltegravir, 194 efavirenz); 307 were included in the primary efficacy analysis (153 raltegravir, 154 efavirenz). 144 (94%) women in the raltegravir group and 129 (84%) in the efavirenz group met the primary efficacy outcome (absolute difference 10%, 95% CI 3-18; p=0·0015); the difference primarily occurred among women enrolling later in pregnancy (interaction p=0·040). Frequencies of severe or life-threatening adverse events were similar among mothers (30% in each group; 61 raltegravir, 59 efavirenz) and infants (25% in each group; 50 raltegravir, 48 efavirenz), with no treatment-related deaths.. Our findings support major guidelines. The integrase inhibitor dolutegravir is currently a preferred regimen for the prevention of perinatal HIV transmission with raltegravir recommended as a preferred or alternative integrase inhibitor for pregnant women living with HIV.. Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Allergy and Infectious Diseases.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Outcome Assessment, Health Care; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Viral Load; Young Adult; Zidovudine

Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies.. Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks.. We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks.. Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group.. The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers.. NCT02577042.

Topics: Adult; Anti-HIV Agents; Anticholesteremic Agents; Atorvastatin; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunosenescence; Inflammation; Lymphocyte Activation; Male; Middle Aged; Pilot Projects; Raltegravir Potassium

The aim of this retrospective cohort study was to compare safety, efficacy and rates and reasons of discontinuation of the 3 currently approved integrase strand transfer inhibitors (INSTIs) elvitegravir (EVG), dolutegravir (DTG), and raltegravir (RAL) in HIV-infected treatment-naïve and -experienced patients in a real-world cohort. One hundred four treatment-naïve patients were prescribed an INSTI-based combined antiretroviral therapy (cART)-regimen (first-line group) and 219 patients were switched to an INSTI-based cART-regimen from another treatment regimen (switch group) at our institution between May 2007 and December 2014. Twelve months after initiation of treatment, 92% of patients in the first-line group (EVG: 96%, n = 22/23; DTG: 92%, n = 34/37; RAL: 90%, n = 28/31) and 88% of patients in the switch group (EVG: 94%, n = 32/34; DTG: 90%, n = 69/77; RAL: 85%, n = 67/79) showed full virological suppression (viral load <50 copies/mL). Side effects of any kind occurred in 12% (n = 12/104) of patients in the first-line group, and 10% (n = 21/219) of patients in the switch group. In the switch group neuropsychiatric side effects (depression, vertigo, and sleep disturbances) occurred more frequently in patients treated with DTG (11%, n = 10) compared to the 2 other INSTI-based cART-regimen (EVG: 2%, n = 1; RAL: 1%, n = 1). Side effects only rarely led to discontinuation of treatment (first-line-group: 2%, n = 2/104; switch-group: 1%, n = 3/219). In this real-world setting, INSTI-based ART-regimens were highly efficacious with no significant differences between any of the 3 INSTIs. Overall, side effects were only rarely observed and generally mild in all subgroups. In light of a slightly higher incidence of vertigo and sleep disturbances in patients switched to DTG, awareness of the potential onset of psychiatric symptoms is warranted during follow-up in those patients.

Topics: Adult; Aged; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies; Viral Load; Young Adult

Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naïve HIV-positive adults.. A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics.. Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.

Topics: Adult; Aged; Anti-Retroviral Agents; Cross-Sectional Studies; Darunavir; Emtricitabine; Female; HIV Infections; Humans; Logistic Models; Male; Middle Aged; Raltegravir Potassium; Ritonavir; RNA, Viral; Telomere; Tenofovir

Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.. Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.. In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.. Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.. EUDRACT number: 2011-005973-21.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Delayed Diagnosis; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Raltegravir Potassium; Ritonavir

Drug-drug interactions limit current antiretroviral treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and well tolerated dose of RAL when administered with RIF to HIV and TB co-infected children.. P1101 is a phase I/II open-label dose-finding study of RAL with RIF for children 2 to less than 12 years of age beginning treatment for HIV and active TB.. Four sites in South Africa.. Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after antiretroviral therapy was initiated; a fourth antiretroviral agent was then added.. Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old) and cohort 2 (6 to <12 years old). Pharmacological targets [geometric mean (GM) AUC12 h of 14-45 μmol/l h and GM C12 h ≥75 nmol/l) were reached in both cohort 1 (28.8 μmol/l h and 229 nmol/l) and cohort 2 (38.8 μmol/l h and 228 nmol/l). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment because of grade 4 hepatitis that was possibly treatment-related. At week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml; 19 of 24 (79%) were below 50 copies/ml.. Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infected children receiving RIF for TB.

Topics: Anti-HIV Agents; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Child; Child, Preschool; Coinfection; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Raltegravir Potassium; Rifampin; South Africa; Tuberculosis; Viral Load

Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection.. To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir.. Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg.. The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir.. Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Topics: Adult; Amides; Antiretroviral Therapy, Highly Active; Antiviral Agents; Benzofurans; Carbamates; Chromatography, Liquid; Coinfection; Cyclopropanes; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Imidazoles; Male; Mass Spectrometry; Middle Aged; Oxazines; Piperazines; Pyridones; Quinoxalines; Raltegravir Potassium; Sulfonamides; Treatment Outcome; Young Adult

Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL).. Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point.. Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject.. In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs.

Topics: Adult; Alanine Transaminase; Anti-Retroviral Agents; Creatine; Enfuvirtide; Healthy Volunteers; HIV Infections; Humans; Insulin Resistance; Kidney; Leukocytes, Mononuclear; Lipids; Liver; Male; Metabolism; Mitochondria; Raltegravir Potassium

There is an increasing interest in two-drug regimens. We hypothesized that maintenance therapy with raltegravir and lamivudine would keep HIV-1 suppressed and be well tolerated.. Virally suppressed HIV-1-infected adults without previous viral failures or known resistance mutations to integrase inhibitors or 3TC/FTC or chronic hepatitis B were randomized 2 : 1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. Primary outcome was the proportion of patients free of therapeutic failure (defined as viral failure, change in treatment for any reason, consent withdrawal, loss to follow-up or death) at week 24. Secondary outcomes were changes in laboratory, body composition, sleep quality, adherence, and adverse effects.. There were 75 patients included: men 78%; median age 50 years; median CD4 622/μl. At week 24, 7 (9%) patients had therapeutic failure: raltegravir and lamivudine 2 (4%) vs. control 5 (20%). The difference in proportions of therapeutic failures raltegravir and lamivudine minus control was -0.159 (95% confidence interval: -0.353 to -0.012). There was a trend to more weight gain with raltegravir and lamivudine, but no significant changes in other secondary outcomes. Sixty-four percent of patients in each arm had at least one adverse effect. Two (6%) patients in control arm and 4 (7%) patients in raltegravir and lamivudine arm had severe adverse effects.. This pilot study suggests that switching to raltegravir along with lamivudine in patients with viral suppression maintains efficacy and is well tolerated. A larger study of longer duration is required to confirm these findings.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; Humans; Lamivudine; Maintenance Chemotherapy; Male; Middle Aged; Pilot Projects; Raltegravir Potassium; Treatment Outcome; Young Adult

Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure.. A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367.. From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60-68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]).. Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance.. National Institutes of Health.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Darunavir; Developing Countries; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nitriles; Prospective Studies; Pyridazines; Pyrimidines; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load

Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.. We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.. Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.. Protease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.. European and Developing Countries Clinical Trials Partnership (EDCTP), UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO.

Topics: Adolescent; Adult; Africa South of the Sahara; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load; Young Adult

The OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values <50 copies/mL was lower in the pentatherapy arm than in the tritherapy arm. Here we compared antiretroviral drug concentrations between the two arms.. Plasma samples were collected from 50 patients at various times after drug administration. A Bayesian approach based on published population pharmacokinetic models was used to estimate residual drug concentrations (Ctrough) and exposures (AUC) in each patient. A mixed linear regression model was then used to compare the AUC and Ctrough values of each drug used in both groups.. Published models adequately described our data and could be used to predict Ctrough and AUC. No significant difference in tenofovir disoproxil fumarate, emtricitabine and ritonavir parameters was found between the two arms. However, darunavir Ctrough and AUC were significantly lower in the pentatherapy arm than in the tritherapy arm (P = 0.03 and P = 0.04, respectively).. Adding maraviroc and raltegravir to darunavir-based tritherapy decreased darunavir concentrations. Compliance issues, maraviroc-darunavir interaction and raltegravir-darunavir interaction were suspected and may affect the kinetics of viral decay during pentatherapy. A specific pharmacokinetic interaction study is needed to explore the interactions between darunavir and maraviroc and raltegravir.

Topics: Adult; Anti-HIV Agents; Darunavir; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Models, Statistical; Plasma; Raltegravir Potassium; Ritonavir; Viral Load; Young Adult

New options for first-line treatment of human immunodeficiency virus type 2 (HIV-2) infection are needed. We evaluated an integrase inhibitor (raltegravir)-containing regimen.. Antiretroviral therapy (ART)-naive adults with symptomatic infection by HIV-2 only, CD4 count <500 cells/μL or CD4 decrease >50 cells/μL/year over the past 3 years, or a confirmed plasma HIV-2 RNA (pVL) load ≥100 copies/mL were eligible for this noncomparative trial. The composite primary endpoint was survival at 48 weeks without any of the following: CD4 gain from baseline <100 cells/μL, confirmed pVL ≥40 copies/mL from week 24, raltegravir permanent discontinuation, or incident B or C event. HIV-2 ultrasensitive pVL (uspVL) and total DNA were assessed using in-house polymerase chain reaction (PCR) assays.. Baseline median CD4 count of 30 enrolled individuals (67% women) was 436 cells/µL (interquartile range [IQR], 314-507 cells/µL); pVL was ≥40 copies/mL in 67% of them, uspVL was ≥5 copies/mL in 92%, and total DNA was >6 copies by PCR in 32%. At week 48, the composite endpoint of success was reached in 40% [95% confidence interval, 22.7%-59.4%]. Failure was mainly (50%) due to CD4 gain <100 cells/µL; uspVL was <5 copies/mL in 87% and total DNA >6 copies by PCR in 12% of participants. Median CD4 gain was 87 cells/µL (IQR, 38-213 cells/µL; n = 28). No serious adverse reactions were reported.. Raltegravir-containing ART is a safe option for first-line treatment of HIV-2 infection, yielding a comparable success rate to protease inhibitors.. NCT 01605890.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-2; Humans; Integrase Inhibitors; Male; Middle Aged; Raltegravir Potassium; RNA, Viral; Tenofovir; Viral Load

Background Late-presenting pregnant women pose a challenge in the prevention of HIV-1 mother-to-child-transmission. We compared the safety and efficacy of raltegravir and lopinavir/ritonavir for this population. Methods We did a single-center, pilot, open-label, randomized trial in Brazil (N = 44). We randomly allocated late-presenting HIV-infected pregnant women (older than 18 years with a plasma HIV-1 RNA >1000 copies/mL) to receive raltegravir 400 mg twice a day or lopinavir/ritonavir 400/100 mg twice a day plus zidovudine and lamivudine (1:1). The primary endpoint was virological suppression at delivery (HIV-1 RNA <50 copies per mL), in all patients who received at least one dose of study drugs (modified intention-to-treat analysis). Missing information was treated as failure. We assessed safety in all patients. Results We enrolled and randomly assigned treatment to 33 patients (17 in raltegravir group) between June 2015 and June 2017. The study was interrupted by the IRB because a significant difference between arms was detected in an interim analysis. All patients completed follow up at delivery. At delivery, virological suppression was achieved by 13/17 (76.5%) of patients in raltegravir group, versus 4/16 (25.0%) in lopinavir/ritonavir group (RR 3.1, 95% CI: 1.3-7.4). Patients in raltegravir group had significantly higher proportion of virological suppression at 2, 4, and 6 weeks than lopinavir/ritonavir group. Adverse events were most of mild intensity, but patients in lopinavir/ritonavir group had significantly more gastrointestinal adverse events. There was neither discontinuation nor deaths in this trial. Conclusion Raltegravir might be a first-line option for treatment of HIV-infected late-presenting pregnant women.

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Pilot Projects; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Ritonavir; RNA, Viral; Sustained Virologic Response; Treatment Outcome; Viral Load; Young Adult

Monotherapy with ritonavir-boosted PIs (PI/r) has been used to simplify treatment of HIV-1-infected patients. In previous studies raltegravir intensification evidenced ongoing viral replication and reduced T cell activation, preferentially in subjects receiving PI-based triple ART. However, data about low-level viral replication and its consequences in patients receiving PI/r monotherapy are scarce.. We evaluated the impact of 24 weeks of intensification with raltegravir on markers of viral persistence, cellular immune activation and inflammation biomarkers in 33 patients receiving maintenance PI/r monotherapy with darunavir or lopinavir boosted with ritonavir. ClinicalTrials.gov identifier: NCT01480713.. The addition of raltegravir to PI/r monotherapy resulted in a transient increase in 2-LTR (long-terminal repeat) circles in a significant proportion of participants, along with decreases in CD8+ T cell activation levels and a temporary increase in the expression of the exhaustion marker CTLA-4 in peripheral T lymphocytes. Intensification with raltegravir also reduced the number of samples with intermediate levels of residual viraemia (10-60 HIV-1 RNA copies/mL) compared with samples taken during PI/r monotherapy. However, there were no changes in cell-associated HIV-1 DNA in peripheral CD4+ T cells or soluble inflammatory biomarkers (CD14, IP-10, IL-6, C-reactive protein and D-dimer).. Intensification of PI/r monotherapy with raltegravir revealed persistent low-level viral replication and reduced residual viraemia in some patients during long-term PI/r monotherapy. The concomitant change in T cell phenotype suggests an association between active viral production and T cell activation. These results contribute to understanding the lower efficacy rates of PI/r monotherapies compared with triple therapies in clinical trials.

Topics: Adult; Antiretroviral Therapy, Highly Active; Darunavir; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Immunity, Cellular; Inflammation; Lopinavir; Lymphocyte Activation; Male; Middle Aged; Pilot Projects; Proof of Concept Study; Raltegravir Potassium; RNA, Viral; Viremia; Virus Replication

In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only.. We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16-18 kg/m. Between June 18, 2013, and April 10, 2015, we randomly assigned 1805 participants to treatment: 897 to RUSF and 908 to no-RUSF. 56 (3%) were lost-to-follow-up. 96 (10·9%, 95% CI 9·0-13·1) participants allocated to RUSF and 92 (10·3%, 8·5-12·5) to no-RUSF died within 24 weeks (hazard ratio 1·05, 95% CI 0·79-1·40; log-rank p=0·75), with no evidence of interaction with the other randomisations (both p>0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45).. In severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present.. Joint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).

Topics: Adolescent; Adult; Africa South of the Sahara; Aged; Anti-Infective Agents; Anti-Retroviral Agents; Arachis; Body Mass Index; Body Weight; Child; Child, Preschool; Diet Therapy; Female; HIV Infections; Humans; Male; Micronutrients; Middle Aged; Raltegravir Potassium; Survival Analysis; Treatment Outcome; Young Adult

Raltegravir (RTG) and dolutegravir (DTG) have different pharmacokinetic patterns in the gastrointestinal tract. To determine if this results in pharmacodynamic differences, we compared HIV RNA, HIV DNA and immunological markers in gut-associated lymphoid tissue (GALT) of HIV-infected participants receiving RTG or DTG with tenofovir+emtricitabine (TDF/FTC).. GALT specimens from the terminal ileum, splenic flexure and rectum were obtained by colonoscopy at a single time point in 20 adults treated with RTG (n=10) or DTG (n=10) with HIV RNA <50 copies/ml. Flow cytometry, drug concentrations, and HIV RNA and DNA were analysed in tissue. CD4/8. A total of 15 men and 5 women were enrolled. There was no difference in time since HIV diagnosis for those on RTG (9.5 [4-22] years) and DTG (17 [1-24] years; P=0.6), although time on RTG (5.4 [2.3-6.7] years) was greater than DTG (1.0 [0.1-1.5] years; P<0.001). Concentrations of RTG and DTG in rectal tissue were similar to previous reports: median tissue:plasma ratio was 11.25 for RTG and 0.44 for DTG. RNA:DNA ratios were 1.14 (0.18-5.10) for the RTG group and 0.90 (0.30-18.87) for the DTG group (P=0.95). No differences (P≥0.1) between CD4. RTG produced higher tissue exposures than DTG, but no significant differences in GALT HIV RNA, DNA or most immunological markers were observed. ClinicalTrials.gov NCT02218320.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Colon, Transverse; DNA, Viral; Emtricitabine; Female; Gene Expression; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Ileum; Immunity, Innate; Lymphoid Tissue; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Receptors, Antigen, T-Cell, gamma-delta; Rectum; RNA, Viral; Tenofovir; Treatment Outcome

Raltegravir 1200mg (2×600mg tablets) once daily (QD) demonstrated noninferior efficacy and similar safety to raltegravir 400mg twice daily (BID) at week 48 of the ONCEMRK trial. Here, we report the week 96 results from this study.. ONCEMRK is a phase 3, multicenter, double-blind, noninferiority trial comparing raltegravir 1200mg QD with raltegravir 400mg BID in treatment-naive HIV-1-infected adults. Participants were assigned (2:1) to raltegravir 2×600mg QD or 400mg BID, both with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) for 96 weeks. Randomization was stratified by screening HIV-1 RNA and hepatitis B/C status. Efficacy was assessed as the proportion of participants with HIV-1 RNA <40 copies per milliliter (Food and Drug Administration Snapshot approach); the noninferiority margin was 10 percentage points.. Of the 797 participants who received study therapy (84.6% were men, 59.3% were white, and mean age was 35.9 years), 694 completed 96 weeks of treatment (87.6% QD; 84.4% BID), with few discontinuations because of lack of efficacy (1.1% for both groups) or adverse events (1.3% QD; 2.3% BID). At week 96, 81.5% (433/531) of QD recipients and 80.1% (213/266) of BID recipients achieved HIV-1 RNA <40 copies per milliliter (difference 1.4%, 95% confidence interval: -4.4 to 7.3). CD4 T-cell counts increased >260 cells/mm from baseline in both groups. Resistance to raltegravir was infrequent, occurring in 0.8% of each treatment group through week 96. Adverse event rates were similar for the 2 regimens.. In HIV-1-infected treatment-naive adults receiving FTC/TDF, raltegravir 1200mg QD demonstrated noninferior efficacy to raltegravir 400mg BID that was durable to week 96, with a safety profile similar to raltegravir 400mg BID.

Topics: Adenine; Adult; Anti-HIV Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Phosphorous Acids; Placebos; Raltegravir Potassium; RNA, Viral

Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are associated with increased cardiovascular risk and inflammation. In a previous cross-sectional study, individuals using a raltegravir (RAL)-based regimen were found to have reduced platelet reactivity and PMA compared with other antiretroviral regimens. Our aim was to investigate whether switching from a nonintegrase inhibitor regimen to a RAL-based regimen reduces platelet reactivity or PMA.. An investigator initiated, single-centre, prospective randomized, open-label, blinded endpoint trial.. Forty HIV-infected adults using a nonintegrase inhibitor containing regimen with undetectable viral load were randomized to either continue their regimen or switch to a RAL-based regimen for 10 weeks, continuing the same backbone. The primary outcome was the change in platelet reactivity at week 10, which was determined as the expression of the platelet activation marker P-selectin and binding of fibrinogen before and after ex-vivo stimulation with different platelet agonists. Secondary outcomes included PMA, plasma markers of platelet activation and markers of inflammation and immune cell activation.. Twenty-one participants were enrolled in the continuation group and 19 in the RAL group. Baseline characteristics were comparable between groups. There were no differences in the change in platelet reactivity to either platelet agonist at week 10, nor in plasma markers of platelet activation. PMA, C-reactive protein, T-cell activation (CD38HLA-DR) and monocyte (CD14CD16) subsets.. Switching a nonintegrase inhibitor containing regimen to a RAL-based regimen does not reduce platelet reactivity, platelet-leukocyte aggregation, inflammation and immune activation in virologically suppressed HIV-infected individuals.. NCT02383355.

Topics: Adult; Anti-HIV Agents; Blood Platelets; Cell Aggregation; Drug Substitution; Female; HIV Infections; Humans; Male; Monocytes; Prospective Studies; Raltegravir Potassium; Treatment Outcome; Viral Load

Ninety-six-week costs for antiretroviral drugs, adverse event management, and HIV care for individuals initiating RAL, ATV/r, or DRV/r as first-line therapy for HIV-1 infection were estimated using an economic model. Efficacy and safety data (mean CD4 cell count changes, discontinuation rates, grade 3/4 adverse event incidence) for each regimen through 96 weeks of treatment were taken from the ACTG 5257 clinical trial. Antiretroviral drug costs for each initial regimen and for each substitution regimen, as used by individuals who discontinued their initial regimen, were based on wholesale acquisition costs. Adverse event management costs and HIV care costs, stratified by CD4 cell count range, were taken from published sources and inflated to 2016 dollars. Scenario and sensitivity analyses were conducted to assess the robustness of the results. Cost outcomes were discounted at an annual rate of 3.0%.. Total 96-week costs were $81,231 for RAL, $88,064 for ATV/r, and $87,680 for DRV/r, where differences were primarily due to lower antiretroviral drug costs for RAL than for ATV/r or DRV/r. These results were found to be robust in scenario and sensitivity analyses.. Relative to the DRV/r and ATV/r regimens, the RAL regimen had the lowest cost for treatment-naive adults with HIV-1 infection in the United States.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Cost-Benefit Analysis; Darunavir; Drug Therapy, Combination; Female; Health Care Costs; HIV Infections; HIV-1; Humans; Male; Models, Economic; Raltegravir Potassium; Ritonavir; United States

In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events.. In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82-1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76-1.28], p = 0.91); in serious (aHR = 0.99 [0.81-1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71-1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63-1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76-1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p =. Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals.. ClinicalTrials.gov NCT01825031.. International Standard Randomised Controlled Trials Number ISRCTN 43622374.

Topics: Adolescent; Adult; Africa; Anti-HIV Agents; Anti-Retroviral Agents; Child; Child, Preschool; Disease Progression; Drug Administration Schedule; Female; Follow-Up Studies; Health Services Accessibility; HIV Infections; Humans; Kenya; Malawi; Male; Raltegravir Potassium; Uganda; Young Adult; Zimbabwe

Raltegravir is an integrase inhibitor approved for use in adults and children with HIV-1 infection, but there are no data on the long-term use of this medication in children. We aimed to assess the long-term safety, tolerability, pharmacokinetics, and efficacy of multiple raltegravir formulations in children aged 4 weeks to 18 years with HIV-1 infection.. In this phase 1/2 open-label multicentre trial (IMPAACT P1066), done in 43 IMPAACT network sites in the USA, South Africa, Brazil, Botswana, and Argentina, eligible participants were children aged 4 weeks to 18 years with HIV-1 infection who had previously received antiretroviral therapy (ART), had HIV-1 RNA higher than 1000 copies per mL, and no exposure to integrase inhibitors. Participants were separated into five age groups and enrolled in six cohorts. Three formulations of open-label raltegravir-adult tablets, chewable tablets, and granules for oral suspension-were added to individualised optimised background therapy, according to the age and weight of participants. The primary outcome at 48 weeks has been previously reported. In the 240-week follow-up, outcomes of interest included graded clinical and laboratory safety of raltegravir formulations during the study and virological efficacy (with virological success defined as HIV-1 RNA reduction of >1 log. Between August, 2007, and December, 2012, 220 patients were assessed for eligibility, and 153 were enrolled and treated. Of these patients, 122 received only the final selected dose of raltegravir (63 received adult tablets, 33 chewable tablets, and 26 oral granules), and one was not treated. There were few serious clinical or laboratory safety events noted, with two patients having a drug-related adverse event (skin rash), which led one patient to discontinue the study treatment. The addition of raltegravir to an individually optimised ART regimen resulted in virological success at week 240 in 19 (44·2%, 95% CI 29·1-60·1) of 43 patients receiving 400 mg tablets, 24 (77·4%, 58·9-90·4) of 31 patients receiving the chewable tablets, and 13 (86·7%, 59·5-98·3) of 15 patients receiving oral granules. Among patients with virological failure, raltegravir resistance was noted in 19 (38%) of 50 patients who had virological rebound after initial suppression and had samples at virological failure available for testing.. Our study suggests that raltegravir can be used for the treatment of HIV-1 infection in children as young as 4 weeks, with the expectation of long-term safety and efficacy, but should be used with caution among older children who had previous extensive antiretroviral therapy.. National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, and Merck.

Topics: Administration, Oral; Adolescent; Americas; Botswana; Child; Child, Preschool; Female; Follow-Up Studies; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infant; Male; Raltegravir Potassium; Treatment Outcome

Standard antiretroviral therapy (ART) is slow to reverse gut mucosal immune defects that cause persistent inflammation and immune activation. We examined whether intensifying early-administered ART through the addition of maraviroc and raltegravir would accelerate their resolution.. ART-naïve men with early HIV infection were randomized in a double-blind manner to receive ART (emtricitabine/tenofovir disoproxil fumarate + lopinavir/ritonavir), together with either combined placebo or raltegravir + maraviroc, for 48 weeks. In a predefined substudy, paired blood and sigmoid biopsies were collected at baseline and week 48. Mucosal CD4 T-cell immune subsets (Th1, Th17, and Th22 cells), CD8 T-cell immune activation, and soluble blood markers of inflammation (IL-6, IL-17, macrophage inflammatory protein-1b, soluble CD14, and IL-10) and coagulation (D-dimer) were measured.. A total of 22 participants were enrolled, a median of 4 months after HIV acquisition. At baseline, there was substantial systemic and mucosal immune activation, and gut CD4 T-cell numbers, Th22 cell numbers, and Th17 cell function were reduced compared with controls. Early ART restored gut Th22 numbers, improved but did not restore overall CD4 numbers, and had no impact on Th17 function. Plasma levels of soluble CD14 and D-dimer normalized, whereas other inflammatory cytokines were reduced but not normalized. ART intensification had no impact on any blood or gut immune parameters.. Early HIV infection causes substantial mucosal and systemic immune activation, and gut CD4 T-cell dysfunction. One year of ART improved but did not normalize most parameters, regardless of intensification with raltegravir and maraviroc, and did not restore mucosal Th17 function.

Topics: Adult; Anti-HIV Agents; Biomarkers; Canada; Cyclohexanes; Double-Blind Method; Drug Therapy, Combination; Fibrin Fibrinogen Degradation Products; Flow Cytometry; HIV Infections; Humans; Immunity, Mucosal; Inflammation; Intestinal Mucosa; Lymphocyte Activation; Male; Maraviroc; Middle Aged; Prospective Studies; Raltegravir Potassium; Th17 Cells; Treatment Outcome; Triazoles; Young Adult

Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV.. We did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12-16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039).. Baseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004).. Genotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs.. European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck.

Topics: Adolescent; Adult; Africa South of the Sahara; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Public Health; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load; Young Adult

The kinetics of HIV-1 decay under treatment depends on the class of antiretrovirals used. Mathematical models are useful to interpret the different profiles, providing quantitative information about the kinetics of virus replication and the cell populations contributing to viral decay. We modeled proviral integration in short- and long-lived infected cells to compare viral kinetics under treatment with and without the integrase inhibitor raltegravir (RAL). We fitted the model to data obtained from participants treated with RAL-containing regimes or with a four-drug regimen of protease and reverse transcriptase inhibitors. Our model explains the existence and quantifies the three phases of HIV-1 RNA decay in RAL-based regimens vs. the two phases observed in therapies without RAL. Our findings indicate that HIV-1 infection is mostly sustained by short-lived infected cells with fast integration and a short viral production period, and by long-lived infected cells with slow integration but an equally short viral production period. We propose that these cells represent activated and resting infected CD4+ T-cells, respectively, and estimate that infection of resting cells represent ~4% of productive reverse transcription events in chronic infection. RAL reveals the kinetics of proviral integration, showing that in short-lived cells the pre-integration population has a half-life of ~7 hours, whereas in long-lived cells this half-life is ~6 weeks. We also show that the efficacy of RAL can be estimated by the difference in viral load at the start of the second phase in protocols with and without RAL. Overall, we provide a mechanistic model of viral infection that parsimoniously explains the kinetics of viral load decline under multiple classes of antiretrovirals.

Topics: CD4-Positive T-Lymphocytes; Half-Life; HIV Infections; HIV-1; Humans; Integrase Inhibitors; Raltegravir Potassium; RNA Stability; RNA, Viral; Viral Load; Virus Integration; Virus Replication

Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues.. HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP.. Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1-Q3, 221-277) dB/m and 286 (Q1-Q3, 269-314) dB/m for the EFV group (P = .035). The median decrease in CAP values was -20 (Q1-Q3, -67 to 15) dB/m for the RAL arm and 30 (Q1-Q3, -17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029).. After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL.. NCT01900015.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Body Mass Index; Body Weight; Cyclopropanes; Dideoxynucleosides; Drug Substitution; Drug Therapy, Combination; Elasticity Imaging Techniques; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Raltegravir Potassium; Tenofovir; Triglycerides; Waist-Hip Ratio

Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation.. In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV-1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two-sided 95% CI was greater than -10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment. This study is registered with ClinicalTrials.gov, number NCT02131233.. Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0·5%, 95% CI -4·2 to 5·2). Drug-related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported.. A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy.. Merck & Co, Inc.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Biological Availability; Coinfection; Double-Blind Method; Emtricitabine; Female; Hepatitis B; Hepatitis C; HIV Infections; HIV-1; Humans; Male; Quality of Life; Raltegravir Potassium; RNA, Viral; Tenofovir; Viral Load

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclohexanes; Cyclopropanes; DNA, Viral; Duodenum; Female; HIV Infections; Humans; Lymphoid Tissue; Male; Maraviroc; Raltegravir Potassium; Rectum; RNA, Viral; Triazoles

A low CD4/CD8 ratio during treated HIV identifies individuals with heightened immunoactivation and excess mortality. Whether ART regimens elicit distinct CD4/CD8 ratio recovery remains unknown. We aimed to compare the efficacy of an integrase inhibitor versus a non-nucleoside to normalize the CD4/CD8 ratio.. We conducted a post hoc analysis of the STARTMRK study, a randomized, blinded, double-dummy Phase III trial of raltegravir versus efavirenz, and each in combination with tenofovir/emtricitabine, in treatment-naive HIV-infected adults. Blinding was maintained for the entire 5 year duration of the study. Kaplan-Meier methods for time-dependent variables were used to calculate the rates of CD4/CD8 normalization at different cut-offs and cumulative probabilities. Cox proportional hazard models were used to compare probabilities of CD4/CD8 normalization by treatment arm.. A total of 563 patients were analysed; 81% were males and the mean age (SD) was 37 (10) years. Raltegravir was associated with higher rates of CD4/CD8 ratio normalization at the >0.4 cut-off (median time to normalization = 56 versus 84 days; P = 0.048 by log-rank test). A Cox proportional hazard model stratified based on baseline CD4 counts showed an association between raltegravir and higher rates of CD4/CD8 ratio normalization (HR = 1.23; P = 0.02).. We herein show that normalization of the CD4/CD8 ratio above a clinically meaningful threshold may be dependent on the drug class used. Raltegravir showed faster CD4/CD8 ratio normalization compared with efavirenz, a finding with potential clinical implications. Whether other integrase inhibitors have a similar impact for this outcome remains to be explored.

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; CD4-CD8 Ratio; Cyclopropanes; Female; HIV Infections; Humans; Male; Middle Aged; Raltegravir Potassium; Treatment Outcome; Young Adult

The role of oxidized lipoproteins (high-density [HDLox] and low-density [LDLox]) and total lipoprotein particle (Lp) number and size in HIV-related cardiovascular disease (CVD) is unclear. The goal of this study was to evaluate changes of these biomarkers and their associations with rate of carotid intima media thickness progression over 3 years (ΔCIMT) in chronic HIV infection.. Prospective study of 234 HIV-infected antiretroviral treatment-naive participants without CVD who were randomized to receive tenofovir-emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir or raltegravir (RAL) and achieved plasma HIV-1 RNA <50 copies/ml by week 24 and thereafter. Biomarker changes over 24, 48 or 96 weeks from baseline and pairwise treatment group comparisons were examined. Associations of these biomarkers with ΔCIMT were analysed with mixed effects linear regression.. HDLp number increased with both protease inhibitors (PIs) over 48 weeks, while LDLp number declined with RAL; Lp size did not change. Over 96 weeks, normalized HDLox declined with both PIs; LDLox increased in all groups. Few treatment group differences were observed across all biomarkers. Associations between ΔCIMT and oxidized lipoproteins at all time points were not apparent (P≥0.10). There was some evidence of slower ΔCIMT for higher HDLp number (P=0.06) and for lower LDLp number (P=0.08) measured at baseline.. Unexpectedly, LDLox increased modestly in all treatment groups after ART initiation. Associations of plasma HDLox and LDLox with ΔCIMT were not apparent. While plasma levels of abnormal lipoproteins have been shown to be associated with CVD outcomes, clear associations with sub-clinical atherosclerosis progression were not apparent in our study.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Carotid Intima-Media Thickness; Darunavir; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Linear Models; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Prospective Studies; Raltegravir Potassium; Ritonavir; RNA, Viral; Tenofovir

Persons infected with HIV often have altered lipid profiles that may be affected by antiretroviral therapies (ART). Traditional lipid measurements may be insufficient to assess cardiovascular disease (CVD) risk in this population.. We report results from 39 ART-naive participants in a substudy of A5248, a single-arm study of raltegravir, emtricitabine/tenofovir administration. Samples were collected at baseline, 12, 24 and 48 weeks after ART initiation. We performed advanced lipid phenotyping using nuclear magnetic resonance spectroscopy (Liposcience, Raleigh, NC, USA) for lipid particle size and number, and examined high-density lipoprotein (HDL) function measuring reverse cholesterol transport using J774 macrophages.. We report significant increases in total cholesterol (13 mg/dl; P<0.001) and low-density lipoprotein (LDL; 8 mg/dl; P=0.03), with no change in triglycerides and without an increase in LDL particle number (P>0.1 all time points). HDL levels were increased over baseline levels at all time points (P<0.003), but reached a peak at week 12 and subsequently declined. HDL particle numbers also increased from baseline (P<0.002) and HDL function improved at week 48 (7% increase in efflux capacity; P<0.001). Oxidized LDL (oxLDL) levels decreased by week 12, but rose subsequently, and were not different from baseline at later time points.. HDL increases were associated with increases in beneficial HDL particles and HDL cholesterol efflux capacity, which may reduce future CVD events. Persistent inflammation in these HIV+ participants, may be a cause or consequence of oxLDL levels, and may contribute to declining levels of HDL over time. Clinicaltrials.gov NCT00660972.

Topics: Adult; Anti-HIV Agents; Biological Transport, Active; Cholesterol, HDL; Emtricitabine; Female; HIV Infections; Humans; Lipoproteins, LDL; Male; Middle Aged; Raltegravir Potassium; RNA, Viral; Tenofovir; Young Adult

Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir.. Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122.. Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1-20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI -0·1 to 1·3; p=0·10).. Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen.. The Kirby Institute and the Australian National Health and Medical Research Council.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; CD4 Lymphocyte Count; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; International Cooperation; Lamivudine; Lopinavir; Male; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22% at entry (N = 1,251) and was associated (p < 0.05) with older age (OR = 1.04 per year), female gender (OR = 1.64), Tuberculosis (TB; OR = 1.86), smoking (OR = 1.60), higher plasma creatinine (OR = 1.09 per 0.1 mg/dl increase), CD4 count (OR = 0.83 per doubling) and not consuming alcohol (OR = 0.55). SPN prevalence decreased to 17% by week 96 (p = 0.0002) following similar trends in all study groups (p = 0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29% (p = 0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p < 0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment.

Topics: Adult; Africa South of the Sahara; Alcohol Abstinence; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Drug Combinations; Female; HIV Infections; HIV-1; Humans; Isoniazid; Logistic Models; Lopinavir; Male; Middle Aged; Peripheral Nervous System Diseases; Raltegravir Potassium; Ritonavir; RNA, Viral; Smoking; Tuberculosis, Pulmonary; Viral Load

To assess neurocognitive function at the first-line antiretroviral therapy failure and change on the second-line therapy.. Randomized controlled trial was conducted in 5 sub-Saharan African countries.. Patients failing the first-line therapy according to WHO criteria after >12 months on non-nucleoside reverse transcriptase inhibitors-based regimens were randomized to the second-line therapy (open-label) with lopinavir/ritonavir (400 mg/100 mg twice daily) plus either 2-3 clinician-selected nucleoside reverse transcriptase inhibitors, raltegravir, or as monotherapy after 12-week induction with raltegravir. Neurocognitive function was tested at baseline, weeks 48 and 96 using color trails tests 1 and 2, and the Grooved Pegboard test. Test results were converted to an average of the 3 individual test z-scores.. A total of 1036 patients (90% of those >18 years enrolled at 13 evaluable sites) had valid baseline tests (58% women, median: 38 years, viral load: 65,000 copies per milliliter, CD4 count: 73 cells per cubic millimeter). Mean (SD) baseline z-score was -2.96 (1.74); lower baseline z-scores were independently associated with older age, lower body weight, higher viral load, lower hemoglobin, less education, fewer weekly working hours, previous central nervous system disease, and taking fluconazole (P < 0.05 in multivariable model). Z-score was increased by mean (SE) of +1.23 (0.04) after 96 weeks on the second-line therapy (P < 0.001; n = 915 evaluable), with no evidence of difference between the treatment arms (P = 0.35).. Patients in sub-Saharan Africa failing the first-line therapy had low neurocognitive function test scores, but performance improved on the second-line therapy. Regimens with more central nervous system-penetrating drugs did not enhance neurocognitive recovery indicating this need not be a primary consideration in choosing a second-line regimen.

Topics: Adult; Africa South of the Sahara; Anti-HIV Agents; CD4 Lymphocyte Count; Cognition; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Neurocognitive Disorders; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load

This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine.

Topics: Adult; Atazanavir Sulfate; Drug Substitution; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load; Young Adult

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CCR5 Receptor Antagonists; Chromatography, High Pressure Liquid; Cyclohexanes; Cyclopropanes; Drug Combinations; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; HIV Infections; HIV Integrase Inhibitors; Humans; Immunity, Mucosal; Lymphocyte Activation; Male; Maraviroc; Pilot Projects; Raltegravir Potassium; T-Lymphocyte Subsets; Triazoles

Fat gain after antiretroviral therapy (ART) occurs, and its association with protease inhibitors (PIs) is unclear.. Peripheral and central fat depots and lean mass were measured using standardized and centrally read abdominal CT scans and whole-body dual-energy absorptiometry scans over a 96-week period in human immunodeficiency virus (HIV)-infected treatment-naive participants. The patients were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) in ACTG A5260s, a substudy of A5257. Within arm changes were assessed with signed-rank tests. The 96-week percentage changes in fat and lean mass in the 2 PI arms were not different, thus the PI arms were combined and compared to the RAL arm. Associations between baseline biomarkers and changes in body composition were assessed. All analyses used linear regression models.. 328 patients were randomized (90% male, 44% white non-Hispanic). The median age was 36 years, HIV-1 RNA 4.6 log10 copies/mL, and CD4 349 cells/μL. Overall, at week 96, increases in limb fat (13.4%), subcutaneous (19.9%) and visceral abdominal fat (25.8%), trunk fat (18%), and lean mass (1.8%) were apparent (P < .001 for changes within each arm). Changes for all fat and lean outcomes were not different between the PI arms or between the RAL and the combined PI arms. Higher baseline HIV-1 RNA levels were associated with greater gains in peripheral and central fat.. In treatment-naive participants initiating ART with TDF/FTC, no differences in lean mass and regional fat were found with RAL when compared with ATV/r or DRV/r over 96 weeks.. NCT00811954 and NCT00851799.

Topics: Abdominal Fat; Adult; Anti-HIV Agents; Body Composition; Female; HIV Infections; Humans; Male; Middle Aged; Protease Inhibitors; Raltegravir Potassium; RNA, Viral; Viral Load; Weight Gain

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Raltegravir Potassium; Ritonavir; RNA, Viral; Surveys and Questionnaires; Tenofovir; Treatment Outcome

In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm.. We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses.. During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20-11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67-39.6], p < 10(-3)) were significantly associated with a grade 2 or more ALT elevation during follow-up.. The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT.. ClinicalTrials.gov identifier: NCT00454337.

Topics: Adult; Alanine Transaminase; Chemical and Drug Induced Liver Injury; Drug Substitution; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Incidence; Liver Function Tests; Male; Middle Aged; Peptide Fragments; Raltegravir Potassium; Risk Factors

For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings.. A5273 was a randomised, open-label, phase 3, non-inferiority study at 15 AIDS Clinical Trials Group (ACTG) research sites in nine resource-limited countries (three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe). Adults with plasma HIV-1 RNA concentrations of at least 1000 copies per mL after at least 24 weeks on a regimen based on a non-NRTI inhibitor were randomly assigned (1:1) to receive oral ritonavir-boosted lopinavir (100 mg ritonavir, 400 mg lopinavir) plus 400 mg raltegravir twice a day (raltegravir group) or to ritonavir-boosted lopinavir plus two or three NRTIs selected from an algorithm (eg, zidovudine after failure with tenofovir and vice versa; NRTI group). Randomised group assignment was done with a computer algorithm concealed to site personnel, and stratified by HIV-1 RNA viral load, CD4 cell count, and intention to use zidovudine, with the groups balanced by each site. The primary endpoint was time to confirmed virological failure (two measurements of HIV-1 RNA viral load >400 copies per mL) at or after week 24 in the intention-to-treat population. Non-inferiority (10% margin) was assessed by comparing the cumulative probability of virological failure by 48 weeks. This trial was registered with ClinicalTrials.gov, NCT01352715.. Between March 13, 2012, and Oct 2, 2013, we randomly assigned 515 participants: 260 to the raltegravir group and 255 to the NRTI group; two participants in the raltegravir group and one in the NRTI group were excluded from analyses because of ineligibility. By the end of follow-up (October, 2014), 96 participants had virological failure (46 in the raltegravir group and 50 in the NRTI group). By 48 weeks, the cumulative probability of virological failure was 10·3% (95% CI 6·5-14·0) in the raltegravir group and 12·4% (8·3-16·5) in the NRTI group, with a weighted difference of -3·4% (-8·4 to 1·5), indicating that raltegravir was non-inferior, but not superior, to NRTIs. 62 (24%) participants in the raltegravir group and 81 (32%) in the NRTI group had grade 3 or higher adverse events; 19 (7%) and 29 (11%), respectively, had serious adverse events. Three participants in each group died, all from HIV-related causes.. In settings with extensive NRTI resistance but no available resistance testing, our data support WHO's recommendation for ritonavir-boosted lopinavir plus NRTI for second-line antiretroviral therapy. Ritonavir-boosted lopinavir plus raltegravir is an appropriate alternative, especially if NRTI use is limited by toxicity.. National Institutes of Health.

Topics: Adult; Africa South of the Sahara; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brazil; CD4 Lymphocyte Count; Drug Resistance, Viral; Health Resources; Health Services Accessibility; HIV Infections; HIV-1; Humans; India; Lopinavir; Malawi; Male; Medically Underserved Area; Peru; Raltegravir Potassium; Reverse Transcriptase Inhibitors; RNA, Viral; Thailand; Viral Load

Topics: Anti-HIV Agents; Cardiovascular Diseases; Comorbidity; Drug Interactions; Drug Substitution; Drug Therapy, Combination; Health Behavior; HIV Infections; Humans; Life Style; Neoplasms; Precision Medicine; Raltegravir Potassium

We assessed the virological efficacy of a 6 month maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with maraviroc/raltegravir.. HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA <50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA <50 copies/mL at W48.. Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients.

Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cyclohexanes; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Maintenance Chemotherapy; Male; Maraviroc; Middle Aged; Raltegravir Potassium; Tenofovir; Treatment Outcome; Triazoles; Viral Load; Young Adult

The aim of this study was to compare an in-person, group-based behavioral weight loss intervention to technology-based interventions in adults with obesity.. Adults (. Findings provide initial information on the use of technology-based interventions that include wearable devices combined with brief monthly telephone calls for weight loss in adults with obesity.. A highly stable amino-coordinated metal-organic framework ZJU-198 has been synthesized and structurally characterized, exhibiting high CO. The use of statins in SLE reduced the serum lipid and high-sensitivity C-reactive protein levels, which suggests a role for the primary prevention of cardiovascular disease. Statins did not affect the SLEDAI score, and therefore their use for modifying SLE disease activity levels is not presently supported.

Topics: Absorptiometry, Photon; Adult; Air Pollutants; Alkynes; Alleles; Animals; Anthracenes; Anthraquinones; Anti-HIV Agents; Benzoxazines; Black or African American; Bone Density; Bone Density Conservation Agents; C-Reactive Protein; Calcium, Dietary; Capsid Proteins; Cardiomyopathy, Dilated; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Collagen Type I; Cyclopropanes; Darunavir; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Emtricitabine; Epitopes; Female; Femur Neck; Gene Expression Profiling; Genetic Predisposition to Disease; Hepatitis, Viral, Animal; Hip Joint; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunization; Inflammation Mediators; Lipoproteins, LDL; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred BALB C; Nitrates; Osteocalcin; Oxidation-Reduction; Parathyroid Hormone; Parvovirus B19, Human; Peptides; Phenotype; Pilot Projects; Polymorphism, Single Nucleotide; Raltegravir Potassium; Ritonavir; RNA, Viral; Sodium Chloride; Tenofovir; Transcriptome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaccines; Vascular Endothelial Growth Factor A; Vitamin D; Young Adult

The virological efficacy of switching from a ritonavir-boosted protease inhibitor (PI/r)- to a raltegravir (RAL)-containing regimen remains controversial according to the results of SWITCHMRK and SPIRAL studies. The aim of this analysis is to assess the impact of prior resistance mutations to nucleos(t)ides and other potential factors on the virological outcome.. This was a substudy of the prospective, open-label, multicentre SPIRAL study. Demographic, virological variables, prior episodes of virological failures (VF) and archived resistance mutations to nucleos(t)ides were identified from databases and its impact measured by genotypic sensitive scores (GSS) according to the genotypic resistance interpretation algorithm from the Stanford HIV Drug Resistance Database on outcome was analysed.. Of 250 patients (128 RAL and 122 PI/r) included in the main SPIRAL study, 74 (30%) had previous VF with prior genotypic resistance tests (GRT). Median time of virological suppression prior to inclusion in SPIRAL study was 63.5 months. GSS for backbone nucleos(t)ides was <1 in 15/38 (39%) in the RAL arm and in 9/36 (25%) in the PI/r arm (P=0.13). Among those with nucleos(t)ides GSS <1, 0/15 (0%) in the RAL versus 2/9 (22%) in the PI/r arm developed VF (P=0.13). Moreover 0/11 subjects with null or residual (GSS≤0.5) backbone activity developed VF in the RAL arm.. The 48-week virological efficacy of switching from a PI/r to RAL in subjects with long-term virological suppression was not compromised by a reduction of the nucleos(t)ide backbone activity.

Topics: Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Male; Prospective Studies; Raltegravir Potassium; Ritonavir; Viral Load

Previous studies of raltegravir and rifampicin have not studied the interaction when rifampicin is dosed intermittently. This study aimed to assess the pharmacokinetics of twice daily raltegravir and intermittently dosed rifampicin.. This was a prospective, open, single-arm, three-part, controlled study in healthy volunteers. Over a period of 38 days subjects received 5 days of standard-dose raltegravir (400 mg twice daily) followed by 28 days of standard-dose raltegravir plus rifampicin three times a week followed by 5 days of high-dose (800 mg twice daily) raltegravir plus rifampicin three times a week. Pharmacokinetic sampling was performed on days 5, 33 and 38. Raltegravir pharmacokinetic parameters were determined by non-compartmental analysis and reported as geometric means and 90% CIs. ClinicalTrials.gov: NCT01424826.. Sixteen subjects (12 females) completed the study. Raltegravir trough plasma concentration (C12) was significantly lower in the presence of rifampicin when dosed at 400 mg twice daily (40%), which was not observed with 800 mg twice daily dosing. Raltegravir Cmax and AUC0-12 were both significantly higher in the presence of rifampicin when dosed at 800 mg twice daily (76% and 84%, respectively), but this dose was well tolerated.. This study suggests that rifampicin induction of raltegravir is comparable between daily and intermittent rifampicin. In the absence of definitive clinical efficacy data to suggest otherwise, doses of 800 mg of raltegravir twice daily with rifampicin thrice weekly are well tolerated and yield higher AUCs and comparable C12 when compared with raltegravir alone.

Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Coinfection; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rifampin; Tuberculosis; Young Adult

We explored the relationship between virological response in the first year of treatment and long-term outcomes in the BENCHMRK studies.. Patients failing antiretroviral treatment with 3-class resistant HIV-1 received double-blinded raltegravir (or placebo) with optimized background therapy (OBT) until week 156, followed by open-label raltegravir with OBT up to week 240. In this exploratory analysis of patients randomized to raltegravir, virological response over weeks 16-48 was categorized as continuous suppression (CS; viral RNA [vRNA] always <50 copies/ml), low-level viraemia (LLV; vRNA always <400 copies/ml, >50 copies/ml at least once), or not suppressed (NS; vRNA >400 copies/ml at least once). The association between these first-year vRNA response categories and baseline factors was analysed with univariate and multivariate models. Virological and immunological outcomes for years 2-5 were assessed by first-year vRNA response category (observed failure approach).. Baseline vRNA, baseline CD4(+) T-cell count and rapid viral decay (vRNA <50 copies/ml between weeks 2-12) correlated with first-year vRNA response (P<0.001); only rapid viral decay remained significant by multiple regression. Virological response rates were similar in the LLV and CS groups and lowest in the NS group. CD4(+) T-cell count increased through week 240 in the CS and LLV groups. Time to loss of virological response (confirmed vRNA ≥400 copies/ml) through week 240 did not support as strong a difference between the LLV and CS groups (log-rank P=0.11) as previously reported through weeks 156 and 192 (P<0.05).. Treatment-experienced patients on a raltegravir-based regimen with early LLV may have long-term virological and immunological benefit when their therapy is maintained.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Microbial Sensitivity Tests; Raltegravir Potassium; Time Factors; Treatment Outcome; Viral Load

To determine the durability over 96 weeks of safety and efficacy of lopinavir/ritonavir (LPV/r) and raltegravir (RAL) which was demonstrated to have non-inferior efficacy relative to a regimen of LPV/r with nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) (Control) in primary analysis at 48 weeks.. Open label, centrally randomised trial.. Recruitment was from 37 primary and secondary care sites from Africa, Asia, Australia, Europe and Latin America.. 541 HIV-1 infected adults virologically failing first-line non-NRTI + 2N(t)RTI, with no previous exposure to protease inhibitors or integrase strand transfer inhibitors were analysed, 425 completed 96 weeks follow up on randomised therapy.. Randomisation was 1:1 to Control or RAL.. Differences between the proportion of participants with plasma HIV-1 RNA (VL) <200 copies/mL by intention to treat were compared with a non-inferiority margin of -12%. Differences in biochemical, haematological and metabolic changes were assessed using T-tests.. VL <200 copies/mL at 96 weeks was: RAL 80.4%, Control 76.0% (difference: 4.4 [95%CI -2.6, 11.3]) and met non-inferiority criteria. The RAL arm had a significantly higher mean change (difference Control-RAL; 95%CI) in haemoglobin (-2.9; -5.7, -1.1), total lymphocytes (-0.2; -0.3, -0.0), total cholesterol (-0.5; -0.8, -0.3), HDL cholesterol (-0.1; -0.1, -0.0) and LDL cholesterol (-0.3; -0.5, -0.2).. At 96 weeks, both RAL and Control maintained efficacy greater than 75% and continued to demonstrate similar safety profiles. These results support the use of a combination LPV/r and RAL regimen as an option following failure of 1st line NNRTI + 2N(t)RTIs.. ClinicalTrials.gov NCT00931463.

Topics: Adult; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Raltegravir Potassium; Ritonavir; Secondary Care

The initiation of antiretroviral therapy (ART) during primary infection may offer clinical benefits for HIV-infected individuals by reducing HIV DNA reservoir size and chronic T-cell activation. Current evidence for the advantages of early ART, however, are mostly derived from cross-sectional studies, with the long-term benefits yet to be ascertained.. We conducted an open-label, nonrandomized study, monitoring for 3 years: plasma viral load (pVL), T-cell phenotypes, and peripheral CD4(+) T-cell associated total, integrated and 2-long terminal repeat HIV DNA species. The study included 16 treatment-naive individuals initiating ART with raltegravir and Truvada during either primary (PHI, n = 8) or chronic (CHI, n = 8) HIV infection.. ART initiated during PHI compared with CHI generated significant reductions of peripheral CD4(+) T-cell HIV DNA reservoirs that were sustained for 3 years of therapy. Median log10 HIV DNA copies/10(6) CD4(+) T cells at the final visit: total; CHI = 3.23 > PHI = 2.72, P < 0.01; integrated; CHI = 2.64 > PHI = 1.77, P < 0.01. Similar trends were observed for pVL, however, did not reach significance: log10 HIV RNA copies/ml plasma at the final visit: CHI = 1.3 ≥ PHI = 0.39, P = 0.08. Both cohorts displayed similar and elevated levels of CD38/HLA-DR coexpression on CD4(+) and CD8(+) T cells relative to uninfected healthy controls.. The reduction in HIV DNA reservoirs generated by the early initiation of ART was sustained for 3 years of therapy. Although the PHI cohort trended to lower levels of pVL, and pVL was associated with CD8(+) T-cell activation, no differences in T-cell activation were observed between the PHI and CHI groups.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; Cross-Sectional Studies; DNA, Viral; Drug Therapy, Combination; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; HIV-1; Humans; Immunophenotyping; Lymphocyte Activation; Raltegravir Potassium; RNA, Viral; Viral Load

Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24).. Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression.. Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1).. Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation.. NCT 00811954.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Blood Glucose; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipids; Male; Raltegravir Potassium; Ritonavir

It is unclear whether the integrase inhibitor raltegravir (RAL) reduces inflammation and immune activation compared with ritonavir-boosted protease inhibitors (PIs).. In a prospective, randomized, multicenter clinical trial that included 328 human immunodeficiency type 1 (HIV-1)-infected, treatment-naive participants were randomized to receive tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or RAL. A total of 234 participants (71%) with HIV-1 RNA levels <50 copies/mL by week 24 were included. Plasma biomarkers of inflammation and coagulation that were analysed included high-sensitivity C-reactive protein, interleukin-6 (IL-6), GlycA, D-dimer, soluble CD14 (sCD14), sCD163, and sIL-2r; blood cellular markers included %CD38+DR+ of T-cell subsets and %CD14+CD16+ and%CD14(dim)CD16+ monocyte subsets. Changes from baseline were examined at earlier (24 or 48 weeks) and later (96 weeks) time points, with 95% confidence intervals on fold-change. Pairwise treatment groups were compared using Wilcoxon rank sum tests, with P values adjusted for false discovery rate control.. Changes in biomarkers varied by regimen during the 96 weeks of follow-up as follows: hsCRP declined with ATV/r and RAL, IL-6 declined only with RAL, and GLycA decreased in all groups. D-dimer declined with ATV/r and DRV/r and was unchanged with RAL. Markers of T-cell activation and sCD163 (but not sCD14 and CD14-+CD16+) declined in all groups.. Despite some differences in specific markers of inflammation and immune activation between the antiretroviral therapy (ART) regimens, we found no consistent evidence that the reduction of inflammation and immune activation with ART initiation was different between RAL and PI-based regimens.. NCT00811954 and NCT00851799.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Biomarkers; Darunavir; Female; HIV Infections; Humans; Inflammation; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Raltegravir Potassium; Treatment Outcome

Topics: Anti-HIV Agents; Chromatography, Liquid; Cyclohexanes; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Maraviroc; Middle Aged; Plasma; Raltegravir Potassium; Tandem Mass Spectrometry; Triazoles

The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women.. An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated.. Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9).. Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women.. NCT00825929.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Female; HIV Infections; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium

Specific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation.. We compared the percentage change in BMD over 96 weeks in 328 HIV-infected, treatment-naive individuals randomized equally to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). We also determined whether baseline levels of inflammation markers and immune activation were independently associated with BMD loss.. At week 96, the mean percentage changes from baseline in spine and hip BMDs were similar in the protease inhibitor (PI) arms (spine: -4.0% in the ATV/r group vs -3.6% in the DRV/r [P = .42]; hip: -3.9% in the ATV/r group vs -3.4% in the DRV/r group [P = .36]) but were greater in the combined PI arms than in the RAL arm (spine: -3.8% vs -1.8% [P < .001]; hip: -3.7% vs -2.4% [P = .005]). In multivariable analyses, higher baseline concentrations of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip BMD loss, whereas markers of CD4(+) T-cell senescence and exhaustion (CD4(+)CD28(-)CD57(+)PD1(+)) and CD4(+) T-cell activation (CD4(+)CD38(+)HLA-DR(+)) were associated with lumbar spine BMD loss.. BMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving PIs, ATV/r, or DRV/r but lowest among those receiving RAL. Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Bone Density; Darunavir; Drug Therapy, Combination; Emtricitabine; Female; HIV; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Middle Aged; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load; Young Adult

This study describes first dose and steady state pharmacokinetics of raltegravir (RAL) in cervicovaginal fluid (CVF) and blood plasma (BP).. Three cohorts of women were enrolled sequentially in a single-site, open-label pharmacokinetic study of oral raltegravir 400 mg twice daily: HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women. BP and CVF were collected over 12 h after a single observed dose and at steady state. RAL concentrations were measured by HPLC-MS methods. Data are expressed as median (IQR). The ANOVA rank-sum test was used to evaluate between-group differences in steady state raltegravir exposure (area under the concentration-time curve over the 12-h dosing interval [AUC0-12 h]).. First dose pharmacokinetics were obtained in HIV-negative premenopausal women and HIV-infected post-menopausal women only. The median (IQR) BP AUC0-12 h was 3,099 (985-5,959) and 4,239 (2,781-13,695) ng•h/ml and the median (IQR) CVF AUC0-12 h was 1,720 (305-5,288) and 13,797 (11,066-19,563) ng•h/ml for HIV-negative premenopausal and HIV-infected post-menopausal women, respectively. All cohorts contributed to steady-state pharmacokinetic profiles. Median (IQR) BP AUC0-12 h did not differ between the groups: 8,436 (3,080-10,111), 5,761 (1,801-10,095) and 6,180 (5,295-8,282) ng•h/ml in HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women, respectively. There was a trend for lower CVF AUC0-12 h among HIV-negative women 3,164 (1,156-9,540) compared to 11,465 (9,725-17,138) and 9,568 (4,271-24,306) ng•h/ml HIV-infected premenopausal and HIV-infected post-menopausal women, respectively, but this was not statistically significant (P=0.08). HIV-negative premenopausal women had a median (IQR) CVF:BP AUC0-12 h ratio of 0.46 (0.2-1.1), whereas HIV-infected premenopausal and post-menopausal women had median (IQR) CVF:BP AUC0-12 h ratio of 3.9 (1.2-6.7) and 1.4 (0.7-4.3), respectively.. This is the first study to investigate RAL exposure in BP and CVF in premenopausal HIV-negative and pre- and post-menopausal HIV-infected women. These data indicate HIV and menopausal status may influence antiretroviral distribution into the female genital tract.

Topics: Adolescent; Adult; Anti-HIV Agents; Cohort Studies; Female; Genitalia, Female; HIV Infections; Humans; Menopause; Middle Aged; Raltegravir Potassium; Young Adult

Topics: Age Factors; Aged; Comorbidity; Cross-Sectional Studies; Darunavir; Drug Interactions; Drug Therapy, Combination; Emtricitabine; HIV Infections; Humans; Middle Aged; Raltegravir Potassium; Tenofovir

Rifampicin (RIF) induces UGT1A1, an enzyme involved in raltegravir (RAL) elimination, thereby potentially lowering RAL exposure. We examined the pharmacokinetics of RAL in human immunodeficiency virus (HIV)-infected patients on RIF-based antitubercular therapy in the French National Agency for HIV/AIDS and Viral Hepatitis Research 12 180 Reflate Tuberculosis trial.. Patients started RAL in combination with tenofovir disoproxil fumarate and lamivudine after initiation of RIF (10 mg/kg/day). In arm 1 (n = 21), they received 400 mg RAL twice daily; in arm 2 (n = 16), they received RAL 800 mg twice daily initially then 400 mg twice daily 4 weeks after RIF discontinuation. Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of RAL together with RIF (period 1), 4 weeks after RIF discontinuation (period 2), and after the RAL dose reduction in arm 2 (period 3).. In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval [CI], .64-1.37) for the 12-hour area under the time-concentration curve (AUC0-12), and 0.69 (90% CI, .42-1.13) for the concentration at 12 hours (C12). In arm 2, the corresponding GMRs were 0.75 (90% CI, .48-1.17) and 1.10 (90% CI, .61-2.00) for period 1 vs period 2, and 1.10 (90% CI, .78-1.55) and 1.68 (90% CI, .88-3.23) for period 1 vs period 3.. The double dose of RAL overcompensated for RIF induction, but the standard dose was associated with only small decreases in AUC0-12 and C12 during RIF coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection.. NCT0082231.

Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Coinfection; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Raltegravir Potassium; Rifampin; Tenofovir; Tuberculosis

Regimen selection for highly treatment-experienced patients is complicated.. Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3-4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression.. A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR] = 2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR = 6.2) or boosted protease inhibitor (PI, OR = 6.6), prior use of integrase strand transfer inhibitor (INSTI, OR = 25), and race-ethnicity (all P ≤ 0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR = 0.5) and Hispanic participants from the continental US (OR = 0.2) were less likely to start a complex regimen, compared to white non-Hispanics.. In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race-ethnicity were key factors in decisions to select a more complex regimen.

Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Middle Aged; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy

ROCnRAL ANRS-157 was a single-arm study designed to evaluate a switch to a maraviroc (300 mg twice a day) plus raltegravir (400 mg twice a day) regimen in virologically suppressed HIV-1-infected patients (ClinicalTrials.gov: NCT01420523). The aim of this work was to investigate the factors associated with virological failure (VF) (5/44 patients) or virological rebound defined as one viral load (VL) >50 copies/mL or VL >1 copy/mL.. At baseline (BL), ultradeep sequencing (UDS) of DNA gp120 V3 and integrase regions and quantification of HIV DNA were performed in PBMCs. Tropism, VL, BL ultrasensitive HIV RNA VL, BL HIV DNA VL, subtype, age, ethnicity, transmission group, AIDS status, nadir CD4 and BL CD4 cell count, time since HIV diagnosis, duration of ART and suppressed viraemia, VL zenith, CD4/CD8 ratio and BL CD8 cell count were investigated as potential factors associated with virological rebound.. The proportion of patients with VL <1 copy/mL did not evolve over time. Among the 44 included patients, 3 had minority X4-tropic viruses determined by UDS at BL and one of them presented VF. Minority resistant variants in the integrase gene were detected at BL at two positions (E138 and G140) for three patients who did not have VF. Among all studied factors, none was associated with virological rebound.. Maraviroc plus raltegravir failed to maintain virological suppression in virologically suppressed HIV-1-infected patients. However, neither minority viral variants nor ultrasensitive viraemia was found to be a predictive factor of VF or virological rebound in this context.

Topics: Anti-HIV Agents; Cyclohexanes; HIV Infections; HIV-1; Maraviroc; Raltegravir Potassium; Risk Factors; Treatment Failure; Triazoles; Viral Load

Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen.. Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per μL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants.. Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group).. A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide.. The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Biomarkers; Bone Density; Bone Diseases, Metabolic; CD4 Lymphocyte Count; Comorbidity; Darunavir; Drug Therapy, Combination; Emtricitabine; Europe; Female; HIV Infections; Humans; Inflammation; Male; Middle Aged; Osteopetrosis; Raltegravir Potassium; Ritonavir; Tenofovir; Viral Load

IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth.. Dose selection of the oral suspension formulation for each cohort (IV: 6 months to <2 years and V: 4 weeks to <6 months) was based on review of short-term safety (4 weeks) and intensive PK evaluation. Safety data through Weeks 24 and 48 and Grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction from baseline at Week 24 (Success). For Cohort IV, optimized background therapy (OBT) could have been initiated with RAL either at study entry or after intensive PK sampling was completed at Day 5-12. An OBT was started when RAL was initiated for Cohort V subjects because they were not permitted to have received direct antiretroviral therapy before enrollment.. Total accrual was 27 subjects in these 2 cohorts, including 1 subject who was enrolled but never started study drug (excluded from the analyses). The targeted PK parameters (area under the curve [AUC]0-12hr and C12hr) were achieved for each cohort allowing for dose selection. Through Week 48, there were 10 subjects with Grade 3+ AEs. Two were judged related to study drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune reconstitution syndrome, and no drug-related deaths. At Week 48, for Cohorts IV and V, 87.5% of subjects achieved virologic success and 45.5% had HIV RNA <50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm(3) and 7.3% were observed.. A total of 6 mg/kg per dose twice daily of RAL for oral suspension was well tolerated and showed favorable virologic and immunologic responses.

Topics: Administration, Oral; Child, Preschool; Female; HIV Infections; HIV-1; Humans; Infant; Male; Raltegravir Potassium

Three-drug nonoccupational post-exposure prophylaxis (NPEP) typically includes co-formulated emtricitabine-tenofovir (FTC-TDF) and a protease inhibitor. However, protease inhibitors can cause significant toxicities, can interact with prescribed and illicit drugs, and work late in the viral cycle. Agents that act before viral integration into host DNA may have efficacy advantages. Raltegravir (RAL) is a good candidate for NPEP as it has few side effects or drug interactions and acts prior to HIV integration. The objective of this study was to investigate the use of RAL in 3-drug NPEP in terms of safety, adherence and tolerability.. We evaluated 28 days of RAL-FTC-TDF treatment in 86 men and FTC-TDF treatment in 34 men eligible for three- and two-drug NPEP, respectively. We assessed adherence (compared between groups and with nonstudy controls) and clinical and adverse events at weeks 1, 2 and 4, and efficacy at week 12. Analyses were by intention to treat, excluding from the adherence analysis subjects who ceased NPEP because their source was HIV-uninfected.. No participant became infected with HIV. For RAL-FTC-TDF and FTC-TDF, regimen completion rates were 92% and 91% and medication adherence rates were 89% and 90%, respectively. Eight (9%) RAL recipients developed mild myalgias, with four developing transient grade 4 elevations in creatine kinase (two developed both), all of which improved to grade 2 or less by week 4 without RAL discontinuation. Eight prescribed and 37 potential illicit drug interactions with a protease inhibitor were avoided by use of RAL.. RAL-FTC-TDF is well tolerated as NPEP, results in high levels of adherence and avoids potential drug-drug interactions. Patients and clinicians should be aware of the potential for acute muscle toxicity when RAL is used as NPEP.

Topics: Adenine; Adult; Anti-HIV Agents; Biomarkers; Creatine Kinase; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; HIV Infections; Homosexuality, Male; Humans; Male; Medication Adherence; Organophosphonates; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tenofovir

To describe raltegravir pharmacokinetics at steady-state in HIV/hepatitis C virus (HCV)-coinfected patients under antiretroviral (ARV) treatment with (n = 5) and without (n = 5) advanced liver cirrhosis (Child-Pugh C).. This was a non-randomized, Phase I, parallel-assignment, open-label pharmacokinetic study in HIV/HCV-coinfected patients with Child-Pugh grade C hepatic cirrhosis. We recruited clinically stable HIV/HCV-coinfected adult patients with controlled HIV viraemia (<50 copies/mL) for at least 6 months. Raltegravir (400 mg twice daily) was added under fasting conditions for 5 days to the successful ritonavir-boosted protease inhibitor-based ARV regimen. The trial was registered in the ClinicalTrials.gov database (NCT01289951) (LIVERAL).. Raltegravir AUC0-12 and C12 were increased 1.72-fold (90% CI, 1.02 to 2.92) and 6.58-fold (90% CI, 2.92 to14.85), respectively, in patients with advanced liver cirrhosis. No safety issues were identified and raltegravir was well tolerated by all patients.. Raltegravir plasma levels are increased in HIV/HCV-coinfected patients with advanced liver cirrhosis (Child-Pugh C). Despite the higher exposure, raltegravir was safe and well tolerated.

Topics: Adult; Female; Hepatitis C; HIV Infections; HIV Integrase Inhibitors; Humans; Liver Cirrhosis; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium

IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth.. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥ 3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥ 1 log10 reduction between baseline and week 24.. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%).. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥ 25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses.. NCT00485264.

Topics: Administration, Oral; Adolescent; Anti-HIV Agents; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Infant; Male; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

The Raltegravir Switch for Toxicity or Adverse Events (RASTA) Study is a 2-arm randomized pilot study exploring the safety and efficacy at 48 weeks of a treatment switch to raltegravir associated with tenofovir/emtricitabine or abacavir/lamivudine in patients with regimens with optimal virological control.. Patients treated with stable protease inhibitor (PI)-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or nucleoside reverse transcriptase inhibitor (NRTI)-based regimens, with HIV-RNA levels < 50 copies/ml for ≥ 3 months and a CD4 cell count > 200 cells/μl were eligible. Enrollment of 40 patients was planned: at baseline patients were randomized 1:1 to switch to raltegravir plus tenofovir/emtricitabine (arm A) or abacavir/lamivudine (arm B). Laboratory parameters, raltegravir plasma levels, self- reported adherence, quality of life parameters, neurocognitive performance, bone composition, and body fat distribution were monitored. Virological failure was defined as HIV-RNA > 50 copies/ml on 2 consecutive determinations.. After 48 weeks, 5/40 (12.5%) regimen discontinuations occurred: 2 were for low-level viremia virological failure (both in arm A, at weeks 24 and 48) and 3 were for adverse events (neurological disturbances and skin rash in arm B; proximal tubulopathy in arm A). Overall, a significant CD4 increase was observed at weeks 36 and 48, and a significant decrease in total cholesterol, non-high density lipoprotein cholesterol, and triglycerides was observed at each study visit. Physical health/satisfaction in therapy scores and neuropsychological performance improved. The lumbar column Z-score improved, with no modification in other bone composition and fat distribution parameters.. The investigated switch strategy was associated with rare virological failure. Improvements in lipid levels, quality of life measures, neuropsychological performance, and bone composition suggest good tolerability of raltegravir-based regimens.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Lipids; Male; Middle Aged; Pilot Projects; Pyrrolidinones; Quality of Life; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

Latent HIV-1-infected cells generated early in the infection are responsible for viral persistence, and we hypothesized that addition of maraviroc to triple therapy in patients recently infected with HIV-1 could accelerate decay of the viral reservoir.. Patients recently infected (<24 weeks) by chemokine receptor 5 (CCR5)-using HIV-1 were randomized to a raltegravir + tenofovir/emtricitabine regimen (control arm, n = 15) or the same regimen intensified with maraviroc (+MVC arm, n = 15). Plasma viral load, cell-associated HIV-1 DNA (total, integrated, and episomal), and activation/inflammation markers were measured longitudinally.. Plasma viral load decayed in both groups, reaching similar residual levels at week 48. Total cell-associated HIV-1 DNA also decreased in both groups during the first month, although subsequently at a slightly faster rate in the +MVC arm. The transient increase in two long terminal repeat (2-LTR) circles observed in both groups early after initiation of treatment decreased earlier in MVC-treated individuals. Early (week 12) increase of CD4 T-cell counts was higher in the +MVC arm. Conversely, CD8 T-cell counts and CD4 T-cell activation decreased slower in the +MVC arm. Absolute CD4 T-cell and CD8 T-cell counts, immune activation, CD4/CD8 T-cell ratio, and soluble inflammation markers were similar in both arms at the end of the study.. Addition of maraviroc in early integrase inhibitor-based treatment of HIV-1 infection results in faster reduction of 2-LTR newly infected cells and recovery of CD4 T-cell counts, and a modest reduction in total reservoir size after 48 weeks of treatment. Paradoxically, CCR5 blockade also induced a slower decrease in plasma viremia and immune activation.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cyclohexanes; DNA, Viral; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Triazoles; Viral Load

The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose.. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24.. Mean change in HIV-1 RNA at day 8 was -1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily.. DTG 50 mg BID-based therapy was effective in this highly treatment-experienced population with INI-resistant virus.. www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574).

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Pilot Projects; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; RNA, Viral; Viral Load

To understand whether combination antiretroviral therapy (cART) has been optimized, we asked whether 3-drug protease inhibitor (PI)-based cART intensified with raltegravir and maraviroc and initiated during early infection would improve outcomes when compared with similarly applied 3-drug PI-based cART.. Forty newly HIV-1-infected patients were randomized 1:2 to receive 3-drug (N = 14) or 5-drug (N = 26) therapy. The primary end point was the percent of subjects with undetectable plasma viremia using standard reverse transcriptase-polymerase chain reaction and the single copy assay after 48 weeks. Secondary end points included levels of cell-associated HIV-1 DNA and RNA and levels of infectious virus in resting CD4 T cells at week 96 and quantitative and qualitative immunologic responses.. At 48 weeks, 34 subjects remained on study and are included in the as-treated analysis. Three of 11 (27.3%) in the 3-drug arm and 9 of 21 (42.9%) in the 5-drug arm had plasma HIV-1 RNA levels below detection by both standard reverse transcriptase-polymerase chain reaction and single copy assay (P = 0.46, Fisher exact test). No significant differences in absolute levels of proviral DNA or changes in cell-associated RNA were seen during 96 weeks of therapy. Mean levels of infectious HIV-1 in resting CD4 T cells at week 96 in 7 subjects treated with 3-drugs and 13 with 5-drugs were 0.67 and 0.71 infectious units per million, respectively (P = 0.81). No differences were seen in quantitative or qualitative immunologic determinations including markers of immune activation.. Intensified 5-drug cART initiated during early infection fails to significantly further impact virologic or immunologic responses beyond those achieved with standard 3-drug PI-based cART.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cyclohexanes; DNA, Viral; Drug Combinations; Endpoint Determination; HIV Infections; Humans; Longitudinal Studies; Male; Maraviroc; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Triazoles; Viral Load; Viremia

Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV infection. We assessed 48-week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV-infected women switching to raltegravir (RAL) from a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI).. HIV-infected women with central adiposity and HIV-1 RNA < 50 HIV-1 RNA copies/mL continued their thymidine-sparing nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open-label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma.. Of the 37 evaluable subjects, 78% were non-White; the median age was 43 years, the median body mass index (BMI) was 32 kg/m(2) and the median CD4 count was 558 cells/μL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL [-21% (P < 0.001) vs. PI/NNRTI -5% (P = 0.49); between-group P < 0.01]. After 48 weeks, immediate-switch subjects maintained this decline and delayed-switch subjects experienced a similar decline following the switch to RAL (-10%; within-group P < 0.01). Immediate-switch subjects also experienced an initial increase in tumour necrosis factor (TNF)-α that was neither maintained after 48 weeks nor seen in delayed-switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant.. In this randomized trial of women with central adiposity, a switch to RAL from a PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared with PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.

Topics: Abdominal Fat; Adiposity; Adult; Biomarkers; Drug Substitution; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Lipopolysaccharide Receptors; Middle Aged; Overweight; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; RNA, Viral

Novel nucleoside reverse transcriptase inhibitor- and protease inhibitor-sparing strategies are needed in long-term-treated patients with lipohypertrophy. Given their potency and their excellent metabolic profile, maraviroc and raltegravir appear to be good candidates for such an approach.. This single-arm study enrolled lipohypertrophic HIV-infected patients with suppressed viraemia and an R5 tropic virus in HIV DNA; they switched from suppressive antiretroviral treatment to maraviroc plus raltegravir. The primary endpoint was the proportion of patients with treatment success at week 24, defined as no virological failure or treatment discontinuation. To ensure a success rate of at least 80%, a maximum of 10 failures were allowed for 90 patients enrolled. ClinicalTrials.gov: NCT01420523.. A total of 44 patients were enrolled; their median age was 55 years, median nadir CD4 cell count was 210 cells/mm(3), median time on antiretroviral treatment was 15 years and median duration of viral suppression was 5.2 years. Seven patients failed maraviroc/raltegravir therapy: five had virological failure and two discontinued treatment due to serious adverse events (one had hepatitis B virus reactivation and one had hypersensitivity syndrome). At failure, raltegravir resistance mutations were detected in 3/5 patients and CXCR4 tropic virus in 2/5. Upon DSMB recommendation, the study was prematurely discontinued on 3 September 2012. Lipid profile and bone mineral density improved with a decrease from baseline values in total cholesterol (-0.56 ± 0.95 mmol/L; P = 0.001), low-density lipoprotein cholesterol (-0.31 ± 0.81 mmol/L; P = 0.039) and triglycerides (-0.59 ± 1.12 mmol/L; P = 0.001) and an increase in total hip bone mineral density (+0.9 ± 1.5%; P = 0.013) CONCLUSIONS: In long-term-experienced patients, maraviroc/raltegravir therapy lacks virological robustness despite a benefit in lipid profile and bone density.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cyclohexanes; Female; HIV Infections; HIV-1; Humans; Lipodystrophy; Male; Maraviroc; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Risk Factors; Treatment Failure; Triazoles; Viral Load

The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs.. A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser.. Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454.. In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls.

Topics: Anti-HIV Agents; Drug Resistance, Viral; High-Throughput Nucleotide Sequencing; HIV Infections; HIV-1; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium; Treatment Failure

Concurrent treatment of HIV and tuberculosis is complicated by drug interactions. We explored the safety and efficacy of raltegravir as an alternative to efavirenz for patients co-infected with HIV and tuberculosis.. We did a multicentre, phase 2, non-comparative, open-label, randomised trial at eight sites in Brazil and France. Using a computer-generated randomisation sequence, we randomly allocated antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) to receive raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine (1:1:1; stratified by country). Patients began study treatment after the start of tuberculosis treatment. The primary endpoint was virological suppression at 24 weeks (HIV RNA <50 copies per mL) in all patients who received at least one dose of study drug (modified intention-to-treat analysis). We recorded death, study drug discontinuation, and loss to follow-up as failures to achieve the primary endpoint. We assessed safety in all patients who received study drugs. This study is registered in ClinicalTrials.gov, number NCT00822315.. Between July 3, 2009, and June 6, 2011, we enrolled and randomly assigned treatment to 155 individuals; 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment.. Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis.. French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Brazilian National STD/AIDS Program-Ministry of Health.

Topics: Adenine; Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Brazil; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; France; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Tenofovir; Treatment Outcome; Tuberculosis; Viral Load

Aim of this study was to report the 204-week efficacy and safety results of a novel PI- and NRTI-sparing regimen for salvage therapy including maraviroc, raltegravir, etravirine in 28 failing HIV-infected patients with R5-tropic virus. The trend of laboratory parameters was tested by ANOVA for repeated measures and Greenhouse-Geisser probabilities were reported. Results were described as median (Q1-Q3) values. Twenty-six (93%) out of 28 patients completed 204 weeks of treatment. Virological success (HIV-RNA<50 copies/mL) at week 204 was 96%. CD4+ counts significantly increased [244 (158-213) cells/mm3, p<0.0001] from baseline [247 (68-355) cells/mm(3)] as well as CD4+ percentage. Four serious adverse events (1 death due to Hodgkins's lymphoma, 1 anal cancer, 1 Hodgkins's lymphoma, 1 recurrence of mycobacterial spondylodiscitis) were observed; three events led to transitory discontinuation of the antiretroviral therapy due to drug-drug interaction. BMI (p<0.0001) and waist circumference (p<0.0001) significantly increased over 204 weeks. An amelioration was also observed in relation to haemoglobin (p=0.0006), platelets (p<0.0001), white blood cell (p=0.013), neutrophils (p=0.301), lymphocytes (p=0.207) and creatinine (p<0.0001). In highly treatment-experienced patients the maraviroc, raltegravir and etravirine combination is associated with a good long-term efficacy and safety profile.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blood Cell Count; Cyclohexanes; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Maraviroc; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Triazoles

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m(2) completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus -0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥ 50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study.

Topics: Adult; Cross-Sectional Studies; Eicosanoids; Female; HIV Infections; Humans; Integrases; Middle Aged; Obesity, Abdominal; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors

The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit.. In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%).. Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001).. When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).

Topics: Adolescent; Adult; Africa South of the Sahara; Aged; CD4 Lymphocyte Count; Child; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Viral Load; Young Adult

Topics: Acquired Immunodeficiency Syndrome; Atazanavir Sulfate; Darunavir; Drug Administration Schedule; Drug Therapy, Combination; Guideline Adherence; HIV Infections; HIV Protease Inhibitors; Humans; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Standard first-line antiretroviral therapy for HIV-1 infection includes two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs), but these drugs have limitations. We assessed the 96 week efficacy and safety of an NtRTI-sparing regimen.. Between August, 2010, and September, 2011, we enrolled treatment-naive adults into this randomised, open-label, non-inferiority trial in treatment-naive adults in 15 European countries. The composite primary outcome was change to randomised treatment before week 32 because of insufficient virological response, no virological response by week 32, HIV-1 RNA concentration 50 copies per mL or higher at any time after week 32; death from any cause; any new or recurrent AIDS event; or any serious non-AIDS event. Patients were randomised in a 1:1 ratio to receive oral treatment with 400 mg raltegravir twice daily plus 800 mg darunavir and 100 mg ritonavir once daily (NtRTI-sparing regimen) or tenofovir-emtricitabine in a 245 mg and 200 mg fixed-dose combination once daily, plus 800 mg darunavir and 100 mg ritonavir once daily (standard regimen). This trial was registered with ClinicalTrials.gov, number NCT01066962.. Of 805 patients enrolled, 401 received the NtRTI-sparing regimen and 404 the standard regimen, with median follow-up of 123 weeks (IQR 112-133). Treatment failure was seen in 77 (19%) in the NtRTI-sparing group and 61 (15%) in the standard group. Kaplan-Meier estimated proportions of treatment failure by week 96 were 17·8% and 13·8%, respectively (difference 4·0%, 95% CI -0·8 to 8·8). The frequency of serious or treatment-modifying adverse events were similar (10·2 vs 8·3 per 100 person-years and 3·9 vs 4·2 per 100 person-years, respectively).. Our NtRTI-sparing regimen was non-inferior to standard treatment and represents a treatment option for patients with CD4 cell counts higher than 200 cells per μL.. European Union Sixth Framework Programme, Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories.

Topics: Adenine; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cholesterol, HDL; Cholesterol, LDL; Darunavir; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Tenofovir; Treatment Outcome

We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum.. International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 μg/mL, the estimated 10th percentile in nonpregnant historical controls.. Median raltegravir area under the curve was 6.6 μg·h/mL for second trimester (n = 16), 5.4 μg·h/mL for third trimester (n = 41), and 11.6 μg·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.917 μg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected.. Median raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.

Topics: Adult; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimesters; Pyrrolidinones; Raltegravir Potassium; Young Adult

: International Maternal Pediatric Adolescent AIDS Clinical Trials P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data were available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with a median cord blood/maternal delivery plasma raltegravir concentration ratio of 1.48 (range, 0.32-4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t1/2 26.6 (range, 9.3-184) hours]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate because raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Subtherapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must also be avoided. Two ongoing International Maternal Pediatric Adolescent AIDS Clinical Trials studies are further investigating the pharmacology of raltegravir in neonates.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium

NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression.. In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48.. Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (-0.25 vs. -0.71 mg/dL (p = 0.270), and eGFR (-4.4 vs. -7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. -7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = -0.394, p = 0.003 for CTX; and R = -0.477, p<0.001 for P1NP).. The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health.. ClinicalTrials.gov NCT 00677300.

Topics: Adenine; Adult; Bone Density; Darunavir; Deoxycytidine; Emtricitabine; HIV Infections; HIV-1; Humans; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Tenofovir

HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies.. Longitudinal plasma samples (0-48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis.. At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040).. The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers.

Topics: Adult; Biomarkers; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Raltegravir Potassium

STARTMRK, a phase III noninferiority trial of raltegravir-based versus efavirenz-based therapy in treatment-naive patients, remained blinded until its conclusion at 5 years. We now report the final study results.. Previously untreated patients without baseline resistance to efavirenz, tenofovir, or emtricitabine were eligible for a randomized study of tenofovir/emtricitabine plus either raltegravir or efavirenz. Yearly analyses were planned, with primary and secondary end points stipulated at weeks 48 and 96, respectively. The primary efficacy outcome was the percentage of patients with viral RNA (vRNA) levels <50 copies per milliliter counting noncompleters as failures (NC=F). Changes from baseline CD4 count were computed using an observed-failure approach to missing data. No formal hypotheses were formulated for testing at week 240.. Overall, 71 of 281 raltegravir recipients (25%) and 98 of 282 efavirenz recipients (35%) discontinued the study; discontinuations due to adverse events occurred in 14 (5%) and 28 (10%) patients in the respective groups. In the primary NC=F efficacy analysis at week 240, 198 of 279 (71.0%) raltegravir recipients and 171 of 279 (61.3%) efavirenz recipients had vRNA levels <50 copies per milliliter, yielding a treatment difference {Δ [95% confidence interval (CI)] = 9.5 (1.7 to 17.3)}. Generally comparable between-treatment differences were seen in both the protocol-stipulated sensitivity analyses and the prespecified subgroup analyses. The mean (95% CI) increments in baseline CD4 counts at week 240 were 374 and 312 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Δ(95% CI) = 62 (22 to 102)]. Overall, significantly fewer raltegravir than efavirenz recipients experienced neuropsychiatric side effects (39.1% vs 64.2%, P < 0.001) or drug-related clinical adverse events (52.0% vs 80.1%, P < 0.001).. In this exploratory analysis of combination therapy with tenofovir/emtricitabine in treatment-naive patients at week 240, vRNA suppression rates and increases in baseline CD4 counts were significantly higher in raltegravir than efavirenz recipients. Over the entire study, fewer patients experienced neuropsychiatric and drug-related adverse events in the raltegravir group than in the efavirenz group. Based on better virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/emtricitabine seemed to have superior efficacy compared with efavirenz/tenofovir/emtricitabine.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Oxazines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

To evaluate the use of raltegravir with unboosted atazanavir in combination with one nucleoside reverse transcriptase inhibitor (NRTI) (lamivudine or emtricitabine) as a potentially well-tolerated once-daily (qd) maintenance regimen.. We compared the pharmacokinetics of raltegravir 400 mg twice daily (bid) with raltegravir 800 mg qd in HIV-infected patients (n=17) on unboosted atazanavir (600 mg qd) in combination with lamivudine or emtricitabine.. The area under the plasma concentration vs. time curve for a dose interval t (AUC0 -t ) of 800 mg qd divided by 2 was not significantly different from the AUC0 -t of 400 mg bid (P=0.664) but the minimum concentration (C min ) was 72% lower with the qd regimen (P=0.002). The regimen was well tolerated and the viral load remained undetectable in all patients during the 6 weeks of the study follow-up.. A qd regimen of raltegravir 800 mg, atazanavir 600 mg and lamivudine or emtricitabine resulted in favourable pharmacokinetic profiles and good short-term safety and efficacy data. Larger phase IIb studies are needed to explore this novel regimen.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Atazanavir Sulfate; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Viral Load; Young Adult

A model of reservoir activation and viral replication is introduced accounting for the production of 2-LTR HIV-1 DNA circles following antiviral intensification with the HIV integrase inhibitor raltegravir, considering contributions of de novo infection events and exogenous sources of infected cells, including quiescent infected cell activation. The model shows that a monotonic increase in measured 2-LTR concentration post intensification is consistent with limited de novo infection primarily maintained by sources of infected cells unaffected by raltegravir, such as quiescent cell activation, while a transient increase in measured 2-LTR concentration is consistent with significant levels of efficient (R0 > 1) de novo infection. The model is validated against patient data from the INTEGRAL study and is shown to have a statistically significant fit relative to the null hypothesis of random measurement variation about a mean. We obtain estimates and confidence intervals for the model parameters, including 2-LTR half-life. Seven of the 13 patients with detectable 2-LTR concentrations from the INTEGRAL study have measured 2-LTR dynamics consistent with significant levels of efficient replication of the virus prior to treatment intensification.

Topics: Antiretroviral Therapy, Highly Active; Disease Reservoirs; DNA, Circular; DNA, Viral; HIV Infections; HIV-1; Humans; Models, Biological; Pyrrolidinones; Raltegravir Potassium; Time Factors; Virus Replication

Two randomised, placebo-controlled trials-BENCHMRK-1 and BENCHMRK-2-investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study).. Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240.. 1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per μL versus 63 cells per μL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per μL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2.. Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options.. Merck Sharp & Dohme.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Placebos; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Treatment Outcome; Viral Load

Immune hyperactivation in immunodiscordant patients can induce residual HIV replication and limit CD4 T cell recovery. We assessed the impact of raltegravir intensification on CD4 T cell recovery and viral persistence.. We performed a randomized, controlled, pilot trial. Patients with CD4 T cell counts <350 cells/mm(3) despite suppressive antiretroviral therapy were randomized (2 : 1) to intensify with raltegravir (intensified arm, n = 30) or to continue with the same regimen (control arm, n = 14) for 48 weeks. Then, the control individuals intensified their treatment for 24 weeks (delayed-intensification arm). We analysed changes in CD4 T cell counts, total and episomal HIV DNA in peripheral blood mononuclear cells and predictive factors for response.. Raltegravir intensification induced a rapid increase in CD4 T cell counts (week 12) (P = 0.007), although this was not sustained over time. Control patients maintained constant but slow increases in CD4 T cell counts (present in the pre-study period), reaching CD4 T cell counts similar to those of patients in the intensification arm at week 48. This effect was confirmed by the analysis of the delayed-intensification arm. Proviral DNA levels remained stable in both arms over time; episomal DNA forms and ultrasensitive plasma viral load were barely detected during the study. Increases in CD4 T cell counts were associated with low baseline CD95 expression in CD4 and CD8 T cells (P = 0.020).. Raltegravir intensification modestly impacts viral dynamics and induces a rapid but limited gain in CD4 T cell counts in immunodiscordant patients. Residual viral replication does not seem to be the main cause of unsatisfactory CD4 T cell recovery in these patients.

Topics: Adult; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Blood; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Female; HIV Infections; Humans; Male; Middle Aged; Pilot Projects; Pyrrolidinones; Raltegravir Potassium; Viral Load

Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/μl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.

Topics: Adult; Anti-HIV Agents; Brazil; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Cyclohexanes; Darunavir; Drug Therapy, Combination; Female; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Maraviroc; Middle Aged; Protease Inhibitors; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Sulfonamides; Treatment Failure; Triazoles; Viral Load; Young Adult

Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen.. We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463.. We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI -4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal.. The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy.. University of New South Wales, Merck, AbbVie, the Foundation for AIDS Research.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Nucleosides; Nucleotides; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

The goal of this study was to define viral kinetics after initiation of raltegravir (RAL)-based antiretroviral therapy (ART).. ART-naive patients received RAL, tenofovir disoproxil fumarate, and emtricitabine for 72 weeks. Human immunodeficiency virus type 1 (HIV-1) RNA were measured by ultrasensitive and single-copy assays, and first (d1)-, second (d2)-, and, third (d3)-phase decay rates were estimated by mixed-effects models. Decay data were compared to historical estimates for efavirenz (EFV)- and ritonavir/lopinavir (LPV/r)-based regimens.. Bi- and tri-exponential models for ultrasensitive assay (n = 38) and single-copy assay (n = 8) data, respectively, provided the best fits over 8 and 72 weeks. The median d1 with ultrasensitive data was 0.563/day (interquartile range [IQR], 0.501-0.610/day), significantly slower than d1 for EFV-based regimens [P < .001]). The median duration of d1 was 15.1 days, transitioning to d2 at an HIV-1 RNA of 91 copies/mL, indicating a longer duration of d1 and a d2 transition at lower viremia levels than with EFV. Median patient-specific decay estimates with the single-copy assay were 0.607/day (IQR, 0.582-0.653) for d1, 0.070/day (IQR, 0.042-0.079) for d2, and 0.0016/day (IQR, 0.0005-0.0022) for d3; the median d1 duration was 16.1 days, transitioning to d2 at 69 copies/mL. d3 transition occurred at 110 days, at 2.6 copies/mL, similar to values for LPV/r-based regimens.. Models using single-copy assay data revealed 3 phases of decay with RAL-containing ART, with a longer duration of first-phase decay consistent with RAL-mediated blockade of productive infection from preintegration complexes.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Organophosphonates; Pilot Projects; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA Stability; RNA, Viral; Tenofovir; Viral Load

Stored plasma specimens from 164 participants in the ANRS 138 trial were analyzed to determine interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels at baseline and weeks 24 and 48. These virologically suppressed, treatment-experienced patients were randomly assigned to undergo an immediate switch (IS) or a deferred switch (DS; at week 24) from an enfuvirtide-based antiretroviral therapy (ART) regimen to a raltegravir-based regimen. At week 24, a significant decrease from baseline was observed in the IS arm, compared with the DS arm, for IL-6 level (-30% vs +10%; P < .002), hsCRP level (-46% vs +15%; P < .0001), and D-dimer level (-40% vs +6%; P < .0001). At week 48, there was a reproducible decrease in levels of all biomarkers in the DS arm.

Topics: Adult; Anti-HIV Agents; Biomarkers; Blood Coagulation; C-Reactive Protein; CD4 Lymphocyte Count; Enfuvirtide; Female; Fibrin Fibrinogen Degradation Products; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Specimen Handling; Viral Load

: This 96-week, double-blind, active-controlled, phase 3 study, randomized subjects to elvitegravir once daily or raltegravir twice daily with a fully active, ritonavir-boosted protease inhibitor plus a third agent. The proportion of subjects randomized to elvitegravir that achieved and maintained HIV-1 RNA < 50 copies/mL through week 96 was 47.6% (167/351) compared with 45.0% (158/351) for raltegravir with a treatment difference of 2.6% (95% confidence interval: 4.6% to 9.9%). Both regimens were well tolerated, with comparable rates of adverse events and laboratory abnormalities through week 96. Once-daily elvitegravir was noninferior to twice-daily raltegravir, showed durable long-term efficacy, and was well tolerated in HIV+ treatment-experienced patients.

Topics: Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Longitudinal Studies; Pyrrolidinones; Quinolones; Raltegravir Potassium; Ritonavir; RNA, Viral; Viral Load

Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance.. ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516.. Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir).. Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group.. ViiV Healthcare.

Topics: Adult; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

Therapeutic drug monitoring of raltegravir Ctrough levels was carried out in the setting of the Raltegravir Switch for Toxicity or Adverse events (RASTA) trial, a randomized pilot study exploring a 48-week safety and efficacy of treatment switch to raltegravir associated with tenofovir/emtricitabine or abacavir/lamivudine in patients with regimens with optimal virologic control. Blood sampling for measurement of raltegravir plasma levels was carried out at weeks 4, 12, 24, 36 and 48. Plasma samples were analysed by a recently developed and validated UPLC-MS method. A total of 164 samples from 39 patients were assayed. Analysis for intra- and inter-subject variability was restricted to those patients with 4 or more determinations, including 30 patients and 142 determinations. The intra- and inter-subject variability measures were 85.9 and 124.6%, respectively, with an intra-/inter-subject variability ratio of 69%. We also analysed data from a subset of patients with well-documented adherence to protocol, defined as protocol compliant population, including 21 patients and 93 determinations. In this subpopulation, we estimated intra- and inter-subject variability of 79.87% and 110%, respectively, with an intra-/inter-subject variability ratio of 72.6%. This study confirms the notion that raltegravir is a highly variable drug according to the European Medicines Agency criteria. While this condition does not favour the adoption of therapeutic drug monitoring in the clinical practice, the latter is deemed useful in patients with drug plasma concentrations below or near the threshold level of efficacy (since intracellular raltegravir levels might be as low as 5% of the corresponding plasma levels), or to identify drug-drug interactions of potential clinical relevance.

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; HIV Infections; Humans; Lamivudine; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Tenofovir

To compare changes over 48 weeks in bone mineral density (BMD) between participants randomized to lopinavir/ritonavir (LPV/r) + raltegravir (RAL) or LPV/r + 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second line therapy.. 48-week open-label sub-study of the Second Line trial conducted in South Africa, India, Thailand, Malaysia and Argentina.. Dual energy X-ray absorptiometry scans of proximal femur and lumbar spine were performed at baseline and week 48. Linear regression was used to compare means of differences between arms. McNemars test compared osteopenia and osteoporosis. Associations between percentage BMD changes and baseline variables were assessed by multivariate linear regression.. Two hundred and ten participants were randomized. Analyses were adjusted for sex, BMI and smoking status. Mean (95% CI) proximal femur BMD% reduced over 48 weeks by -5.2% (-6.7 to -3.8%) in the LPV/r+2-3N(t)RTIs arm and by -2.9% (-4.3 to -1.5%) in the LPV/r+RAL arm (P = 0.0001). Lumbar spine BMD reduced by -4.2% (-5.7 to -2.7%) in the LPV/r+2-3N(t)RTIs arm and by -2.0% (-3.5 to -0.6%) in the LPV/r+RAL arm (P = 0.0006). The incidence of osteopenia (7.6%) and osteoporosis (2.0%) assessed over 48 weeks were similar between arms. Reduced BMD over 48 weeks was significantly associated with longer duration of tenofovir on study [% change (SE) -1.58 (0.38) femur, -1.65 (0.38) spine, P = 0.0001] and low baseline BMI [% change (SE) 0.5 (0.13) femur, 0.17 (0.07) spine; P < 0.01].. An N(t)RTI-sparing antiretroviral regimen of LPV/r and raltegravir as second line therapy is associated with less bone loss than a LPV/r regimen containing N(t)RTIs.

Topics: Absorptiometry, Photon; Adult; Argentina; Bone Density; Bone Diseases, Metabolic; Female; Femur; HIV Infections; HIV Protease Inhibitors; Humans; India; Lopinavir; Lumbar Vertebrae; Malaysia; Male; Osteoporosis; Prevalence; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; South Africa; Thailand; Treatment Outcome

Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load.. This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation.. 58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary β2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD).. Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary β2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load.. ClinicalTrials.gov NCT01294761 http://clinicaltrials.gov/ct2/show/NCT01294761?term=SPARE&rank=2, Umin Clinical Trials Registry UMIN000005116 http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006083&language=J).

Topics: Adenine; Adult; Anti-HIV Agents; Darunavir; Deoxycytidine; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Kidney; Kidney Function Tests; Lopinavir; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Tenofovir; Viral Load

The degree to which human immunodeficiency virus (HIV) continues to replicate during antiretroviral therapy (ART) is controversial. We conducted a randomized, double-blind, placebo-controlled study to assess whether raltegravir intensification reduces low-level viral replication, as defined by an increase in the level of 2-long terminal repeat (2-LTR) circles.. Thirty-one subjects with an ART-suppressed plasma HIV RNA level of <40 copies/mL and a CD4(+) T-cell count of ≥350 cells/mm(3) for ≥1 year were randomly assigned to receive raltegravir 400 mg twice daily or placebo for 24 weeks. 2-LTR circles were analyzed by droplet digital polymerase chain reaction at weeks 0, 1, 2, and 8.. The median duration of ART suppression was 3.8 years. The raltegravir group had a significant increase in the level of 2-LTR circles, compared to the placebo group. The week 1 to 0 ratio was 8.8-fold higher (P = .0025) and the week 2 to 0 ratio was 5.7-fold higher (P = .023) in the raltegravir vs. placebo group. Intensification also led to a statistically significant decrease in the D-dimer level, compared to placebo (P = .045).. Raltegravir intensification resulted in a rapid increase in the level of 2-LTR circles in a proportion of subjects, indicating that low-level viral replication persists in some individuals even after long-term ART. Intensification also reduced the D-dimer level, a coagulation biomarker that is predictive of morbidity and mortality among patients receiving treatment for HIV infection.

Topics: Antiretroviral Therapy, Highly Active; Biomarkers; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; HIV Infections; HIV Integrase Inhibitors; HIV Long Terminal Repeat; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Virus Replication

In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results.. SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96.. Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4∙5%, 95% CI -1∙1% to 10∙0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir.. At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients.

Topics: Adenine; Adult; CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Kaplan-Meier Estimate; Lamivudine; Male; Organophosphonates; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Tenofovir

To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy.. Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status.. 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (-5.4% [-0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference -0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment.. In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks.. This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463 http://clinicaltrials.gov/ ct2/show/NCT00931463?term = NCT00931463&rank = 1.

Topics: Adult; Anti-HIV Agents; Body Fat Distribution; Body Mass Index; Cardiovascular Diseases; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipodystrophy; Logistic Models; Lopinavir; Male; Metabolic Syndrome; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; RNA, Viral; Viral Load; Virus Replication

We performed a randomized controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH) vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared with the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared with efavirenz but may impact renal function and monocyte activation.

Topics: Adenine; Adult; Alkaline Phosphatase; Anti-HIV Agents; Biomarkers; Bone and Bones; C-Reactive Protein; Cholesterol; Deoxycytidine; Drug Combinations; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Endothelium, Vascular; Female; HIV Infections; Humans; Indiana; Inflammation; Male; Organophosphonates; Oxazines; Pyrrolidinones; Raltegravir Potassium; Renal Insufficiency; Treatment Outcome; Viral Load

The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood.. Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy.. Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy.. ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis.. Clinicaltrials.gov NCT00660972.

Topics: Adenine; Adult; Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Deoxycytidine; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lymphocyte Activation; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Young Adult

Antiretroviral therapy (ART) intensification has been shown to reduce the reservoir of latently infected CD4 T cells. However, it is currently unknown whether this effect is maintained after discontinuation of the intensifying drug.. The effect of ART intensification during 48 weeks with maraviroc or raltegravir in chronically HIV-1-infected patients was assessed in two previous clinical trials. In this study, we analysed this effect at week 24 after discontinuation of the intensifying drugs, at baseline and 48 weeks of intensification.. We measured the latently infected memory CD4 T cells carrying replication-competent virus, 2-long terminal repeat (2-LTR) circles and CD4/CD8 T cells activation.. Fifteen patients were evaluated. After 48 weeks of intensification, HIV-1 reservoir size significantly decreased from 1.1 to 0.0 infectious units per million (IUPM) (P=0.004). After 24 weeks of drug discontinuation, the median size of the reservoir was still significantly lower than at baseline (P=0.008). 2-LTRs were undetectable in all individuals at baseline and after 48 weeks of intensification, continuing undetectable in all patients except two at week 24 after discontinuation (P=0.1). CD4 and CD8 T-cell activation significantly decreased at 48 weeks after intensification, without further increase after discontinuation.. The effects of ART intensification with maraviroc or raltegravir persist at least 24 weeks after discontinuation of the drug. In a global strategy, ART intensification should be considered as part of a combination approach to achieve a functional cure or HIV eradication.

Topics: Adult; Anti-Retroviral Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclohexanes; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Pilot Projects; Pyrrolidinones; Raltegravir Potassium; Triazoles; Virus Latency

Raltegravir has been demonstrated to have a favourable impact on several metabolic parameters, including a lack of changes in lipid and glucose concentrations. We aimed to assess the effect on endothelial function of switching from a ritonavir-boosted protease inhibitor (PI/r)-based regimen to raltegravir.. This is a substudy of the SPIRAL study, a multicentre, randomized, open-label clinical trial including HIV-infected patients on a stable PI/r-based antiretroviral regimen and virologically suppressed for at least the previous 6 months. Endothelial function was prospectively evaluated through flow-mediated dilatation (FMD) of the brachial artery at baseline and at weeks 24 and 48.. Thirty-five HIV-infected patients were included. Sixteen patients were randomly assigned to continue their current PI/r regimen and 19 to switch the PI/r to raltegravir. Total cholesterol, low-density lipoprotein cholesterol and triglycerides decreased at weeks 16 and 32 in the raltegravir-switch arm, while no changes were observed in the PI/r arm. Triglyceride levels were significantly lower in the raltegravir arm than in the PI/r arm at weeks 16, 32 and 48. No significant changes from baseline occurred in FMD at weeks 24 and 48 within or between the raltegravir and PI/r arms. Adjustment for baseline artery diameter did not have a significant effect on the FMD differences.. Switching from a PI/r-based antiretroviral regimen to raltegravir in patients with virological suppression has a beneficial impact on the lipid profile, but it does not seem to have a clear impact on endothelial function after a 1 year follow-up.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Endothelial Cells; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lipids; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir

Abstract The influence of efavirenz, etravirine, raltegravir, and nevirapine administration on the pharmacokinetics of ritonavir-boosted darunavir was investigated using population pharmacokinetics analysis. The population was composed of 142 patients infected with HIV: darunavir plus nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), 54 patients (group A); darunavir plus efavirenz±NRTI, 4 patients (group B); darunavir plus etravirine±NRTI, 5 patients (group C); darunavir plus nevirapine±NRTI, 21 patients (group D); darunavir plus raltegravir±NRTI, 38 patients (group E); and darunavir plus raltegravir and etravirine±NRTI, 20 patients (group F). A significant increase in darunavir clearance in combination with nevirapine (+66%) and efavirenz (+235%) was observed. A significant decrease (p<0.05) in trough plasma concentration was observed in groups B and D compared with the other groups. Our study indicates that the combination of ritonavir-boosted darunavir and etravirine or raltegravir has no significant influence on the pharmacokinetics of darunavir in contrast to the combination of ritonavir-boosted darunavir and nevirapine or efavirenz, which involves an increase in darunavir clearance and a decrease in the plasma concentration of darunavir.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Darunavir; Drug Synergism; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Nevirapine; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Racial differences in antiretroviral treatment responses remain incompletely explained and may be a consequence of differential pharmacokinetics (PK) associated with race. Raltegravir, an inhibitor of HIV-1 integrase, is commonly used in the treatment of HIV-infected patients, many of whom are African-American. However, there are few data regarding the PK of raltegravir in African-Americans. HIV-infected men and women, self-described as African-American and naive to antiretroviral therapy were treated with raltegravir (RAL) at 400 mg twice a day, plus a fixed dose of tenofovir-emtricitabine (TDF/FTC) at 300 mg/200 mg once daily. Intensive PK sampling was conducted over 24 h at week 4. Drug concentrations at two trough values of 12 and 24 h after dosing (C(12) and C(24)), area under the concentration-curve values (AUC), maximum drug concentration (C(max)), and the time at which this concentration occurred (T(max)) in plasma were estimated with noncompartmental pharmacokinetic methods and compared to data from a subset of white subjects randomized to the RAL twice a day (plus TDF/FTC) arm of the QDMRK study, a phase III study of the safety and efficacy of once daily versus twice daily RAL in treatment naive patients. A total of 38 African-American participants were enrolled (90% male) into the REAL cohort with the following median baseline characteristics: age of 36 years, body mass index (BMI) of 23 kg/m(2), and a CD4 cell count of 339/ml. Plasma HIV RNA levels were below 200 copies/ml in 95% of participants at week 4. The characteristics of the 16 white QDMRK study participants were similar, although fewer (69%) were male, the median age was higher (45 years), and BMI was lower (19 kg/m(2)). There was considerable interindividual variability in RAL concentrations in both cohorts. Median C(12) in REAL was 91 ng/ml (range, 10 to 1,386) and in QDMRK participants was 128 ng/ml (range, 15 to 1,074). The C(max) median concentration was 1,042 ng/ml (range, 196 to 10,092) for REAL and 1,360 ng/ml (range, 218 to 9,701) for QDMRK. There were no significant differences in any RAL PK parameter between these cohorts of African-American and white individuals. Based on plasma PK, and with similar adherence rates, the performance of RAL among HIV-infected African-Americans should be no different than that of infected patients who are white.

Topics: Adenine; Adult; Black or African American; Body Mass Index; CD4 Lymphocyte Count; Deoxycytidine; Drug Administration Schedule; Emtricitabine; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Racial Groups; Raltegravir Potassium; Tenofovir; Viral Load; White People

Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1-infected subjects with genotypic evidence of RAL resistance.. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log(10) copies/mL from baseline or was <400 copies/mL.. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen.. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Pilot Projects; Piperazines; Plasma; Pyridones; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

Raltegravir is uncommonly associated with rhabdomyolysis and grade 3-4 creatine kinase (CK) elevation. In this cross-sectional study, we compared the prevalence of skeletal muscle toxicity in HIV-infected adults receiving raltegravir with that of a control group.. Adults receiving combination antiretroviral therapy were recruited consecutively. Assessments included physical examination, an exercise questionnaire, and blood testing for CK, troponin T, and raltegravir trough levels. The primary endpoint was the prevalence of skeletal muscle toxicity, defined as a composite of any of the following: (1) isolated CK elevation; (2) myalgia; (3) proximal myopathy on examination; or (4) rhabdomyolysis.. A total of 318 participants (159 raltegravir, 159 control) were evaluated; 98% were male, 89% white, with median age 51 years, and 91% had HIV-1 RNA <50 copies per milliliter. Mean raltegravir exposure was 28 months. Skeletal muscle toxicity was present in 37% of the raltegravir vs. 19% of the control group (P < 0.001). By component, there were significant respective differences in myalgia (19% vs. 3%, P < 0.001) and proximal myopathy (4% vs. 0%, P = 0.030) but not CK elevation (14% vs. 16%, P = 0.639). No patient had rhabdomyolysis. In multivariate analysis, raltegravir therapy (P < 0.001) and strenuous exercise (P = 0.002) were independently associated with overall muscle toxicity. No component of muscle toxicity was associated with duration of raltegravir or the raltegravir level.. Raltegravir-based therapy is associated with a higher prevalence of symptomatic skeletal muscle toxicity, which does not seem to be concentration or time dependent, nor associated with elevated CK. Proximal myopathy may be an uncommon but significant side effect of raltegravir exposure.

Topics: Anti-HIV Agents; Creatine Kinase; Cross-Sectional Studies; Female; HIV Infections; HIV-1; Humans; Logistic Models; Male; Middle Aged; Muscle, Skeletal; Muscular Diseases; Pyrrolidinones; Raltegravir Potassium; Troponin T

Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1.. SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥ 18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤ 100,000 copies per mL or >100,000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824.. 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI -2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance.. The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients.. ViiV Healthcare.

Topics: Adolescent; Adult; Aged; Double-Blind Method; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; Viral Load; Young Adult

In the ANRS 139 TRIO trial, the use of 3 new active drugs (raltegravir, etravirine, and darunavir/ritonavir), resulted in a potent and sustained inhibition of viral replication in multidrug-resistant treatment-experienced patients. The aim of this virological sub-study of the ANRS 139 TRIO trial was to assess: (i) the evolution of HIV-1 DNA over the first year; and (ii) the association between baseline HIV-1 DNA and virological outcome.. Among the 103 HIV-1-infected patients included in the ANRS-139 TRIO trial, HIV-1 DNA specimens were available for 92, 84, 88, and 83 patients at Week (W)0, W12, W24, and W48, respectively. Quantification of total HIV-1 DNA was performed by using the commercial kit "Generic HIV DNA Cell" (Biocentric, Bandol, France).. Baseline median HIV-1 DNA of patients displaying virological success (n= 61), viral blip (n= 20), and virological failure (n = 11) were 2.34 log(10) copies/10(6) PBMC (IQR= 2.15-2.66), 2.42 (IQR = 2.12-2.48), and 2.68 (IQR= 2.46-2.83), respectively. Although not statistically significant, patients exhibiting virological success or viral blip had a tendency to display lower baseline HIV-1 DNA than patients experiencing virological failure (P = 0.06). Median decrease of HIV-1 DNA between baseline and W48 was -0.13 log(10) copies/10(6) PBMC (IQR = -0.34 to +0.10), mainly explained by the evolution from W0 to W4. No more changes were observed in the W4-W48 period.. In highly-experienced multidrug-resistant patients, HIV-1 DNA slightly decreased during the first month and then remained stable during the first year of highly potent antiretroviral regimen. In this population, baseline HIV-1 DNA might help to better predict the virological response and to tailor clinical therapeutic management as more aggressive therapeutic choices in patients with higher baseline HIV-1 DNA.

Topics: Anti-HIV Agents; Darunavir; DNA, Viral; HIV Infections; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sulfonamides

The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to ≤20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race.

Topics: Adult; Aged; Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Racial Groups; Raltegravir Potassium; Sex Factors; Treatment Outcome; Viral Load; Young Adult

To assess dynamics of HIV-1 DNA in highly antiretroviral (ARV)-experienced HIV-infected patients successfully treated with raltegravir (RAL)-containing therapy. Nineteen patients with virological failure whose ARV treatment was switched to a RAL-based salvage regimen with virological success were included (Group I). Ten patients in virological failure and responding to ARV salvage therapy not containing RAL were also included (Group II). The HIV-1 DNA level in peripheral blood mononuclear cells (PBMC) was assessed by real-time PCR at baseline, W12, W24, W36 or W48. In group I, a marked decrease in the HIV-1 DNA level was observed at W12 both in PBMC (median decrease = 0.38 log(10)copies/10(6)PBMC; P < 0.001) and in CD4 T cells (0.85 log(10)copies/10(6)CD4 T cells; P < 0.001). Plasma HIV-1 RNA decrease was correlated with HIV-1 DNA decrease expressed as copies/10(6)CD4 T cells (r = 0.55, P = 0.03). HIV-1 DNA level reached a steady state by W24. Thus, RAL-containing treatment in highly ARV-experienced patients was associated with a rapid HIV-1 DNA decrease, mainly in the circulating CD4 T cells compartment. Group II patients showed an early decrease in the HIV-1 DNA load until W12, which was 2.5-fold less pronounced in the CD4 T cells compartment than in the RAL-treated patients. The potent action of RAL-containing treatment observed in the CD4 T cells compartment may suggest a pronounced reduced inhibition in the pool of regenerating CD4 T cells on a RAL-based therapy.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Leukocytes, Mononuclear; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Salvage Therapy; Treatment Outcome; Viral Load

The aim was to examine the long-term safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coinfection in three double-blind, randomized, controlled Phase III studies.. In STARTMRK, treatment-naïve patients received raltegravir 400 mg twice a day (bid) or efavirenz 600 mg at bedtime, both with tenofovir/emtricitabine. In BENCHMRK-1 and -2, highly treatment-experienced patients with multi-drug resistant virus and prior treatment failure received raltegravir 400 mg bid or placebo, both with optimized background therapy. Patients with chronic HBV and/or HCV coinfection were enrolled if baseline liver function tests were ≤5 times the upper limit of normal. HBV infection was defined as HBV surface antigen positivity for all studies; HCV infection was defined as HCV RNA positivity for STARTMRK and HCV antibody positivity for BENCHMRK.. Hepatitis coinfection was present in 6% (34 of 563) of treatment-naïve patients (4% HBV only, 2% HCV only and 0.2% HBV+HCV) and 16% (114 of 699) of treatment-experienced patients (6% HBV only, 9% HCV only and 1% HBV+HCV). The incidence of drug-related adverse events was similar in raltegravir recipients with and without hepatitis coinfection in both STARTMRK (50 vs. 47%) and BENCHMRK (34 vs. 38.5%). Grade 2-4 liver enzyme elevations were more frequent in coinfected vs. monoinfected patients, but were not different between the raltegravir and control groups. At week 96, the proportion of raltegravir recipients with HIV RNA <50 HIV-1 RNA copies/mL was similar between coinfected and monoinfected patients (93 vs. 90% in STARTMRK; 63 vs. 61% in BENCHMRK).. Raltegravir was generally well tolerated and efficacious up to 96 weeks in HIV-infected patients with HBV/HCV coinfection.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Double-Blind Method; Female; Hepatitis B; Hepatitis C; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

The potential drug-to-drug interaction between darunavir and raltegravir in the setting of HIV infection is a highly debated issue still unresolved. In the present study we have evaluated the pharmacokinetics of darunavir and ritonavir in 53 HIV-1 infected patients with or without concomitant raltegravir administration. The assessment of trough plasma drug concentrations was carried out in all subjects and the potential influence of raltegravir on darunavir and ritonavir disposition, assessed by specific pharmacokinetic evaluations in a subgroup of 25 patients. No significant differences on darunavir and ritonavir plasma trough levels were observed between patients receiving or not raltegravir. Co-administration of raltegravir was, however, associated with a 40% reduction in darunavir C(max) and estimated AUC(0-24), as well a 60% increase in the estimated darunavir clearance compared with values measured in patients not given raltegravir. Notably, this interaction was independent of the dosage of darunavir and not due to effects of raltegravir on the pharmacokinetics of ritonavir. These results should be taken into account when darunavir-based regimens are implemented in the setting of HIV, especially considering that this drug is usually administered at fixed daily dose and no therapeutic drug monitoring is performed in most centres.

Topics: Adult; Darunavir; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Elvitegravir is a once daily inhibitor of HIV-1 integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 integrase inhibitor, in patients in whom previous antiretroviral treatment failed.. We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA <50 copies per mL) through week 48. Non-inferiority was prespecified with a margin of 10%. We did a modified intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT00708162.. Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1·1%, 95% CI -6·0 to 8·2), meeting the criterion for non-inferiority (p=0·001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0·023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0·020) or aspartate aminotransferase (p=0·009).. Elvitegravir used in combination with a ritonavir-boosted protease inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence.. Gilead Sciences.

Topics: Adult; Alanine Transaminase; Anti-Retroviral Agents; Aspartate Aminotransferases; Atazanavir Sulfate; CD4 Lymphocyte Count; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrrolidinones; Quinolones; Raltegravir Potassium; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

Controversy continues regarding the extent of ongoing viral replication in HIV-1-infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication.. We previously reported the outcome of a randomized placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies per milliliter that showed no effect on residual viremia measured by single copy assay. We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication as follows: 2-LTR HIV-1 circles, total cellular HIV-1 DNA, and T-cell activation.. Of 50 patients tested, 12 (24%) had 2-LTR circles detected at baseline. Patients who were 2-LTR-positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR-negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T-cell activation.. In HIV-1-infected individuals on effective ART, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Lymphocyte Activation; Polymerase Chain Reaction; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; T-Lymphocytes; Viremia; Virus Replication

Highly active antiretroviral therapy (HAART) dramatically reduces plasma HIV-1 viremia. However, despite completely suppressive HAART, it has been suggested that low-levels of viral replication may persist in the gut mucosa and elsewhere in individuals on long-term HAART.. We conducted a double-blind randomized, placebo-controlled trial evaluating whether intensification of HAART in long-term virologically suppressed individuals with raltegravir is associated with a reduction in the level of proviral HIV-1 DNA in CD4(+) T cells in blood and the sigmoid colon (gut).. Long-term (>4 years) virologically suppressed HIV-infected individuals on standard HAART were randomized 1 : 1 in a double-blind fashion to receive raltegravir (400  mg twice/day) or placebo for 48 weeks. After week 48, all participants were treated with raltegravir to week 96. Blood and sigmoid biopsies were sampled and the frequency of CD4(+) T cells carrying HIV-1 proviral DNA was determined.. Twenty-four study patients were recruited. At 48 weeks, no difference was apparent between participants receiving raltegravir or placebo in blood HIV-1 proviral levels (P = 0.62), CD4(+) T-cell counts (P = 0.25) and gut proviral loads (P = 0.74). Similarly, prolonged raltegravir intensification up to week 96 had no further effect on both blood and gut HIV-1 proviral loads and blood CD4(+) T-cell counts.. In long-term virologically suppressed patients on standard HAART, intensification with raltegravir did not result in further decay of CD4(+) T cells carrying HIV-1 proviral DNA in either the blood or gut after 48 or 96 weeks of therapy, or in any increase in CD4(+) T-cell counts.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; DNA, Viral; Dose-Response Relationship, Drug; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Intestinal Mucosa; Male; Middle Aged; Prospective Studies; Proviruses; Pyrrolidinones; Raltegravir Potassium; Viral Load; Viremia

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC₀₋₁₂) was 15.6 mg/liter-h and the minimum plasma drug concentration (C(trough)) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC₀₋₂₄ was 33.6 mg/liter-h and the C(trough) was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC₀₋₂₄ was 18.6 mg/liter-h and the C(trough) was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC₀₋₂₄ for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC₀₋₂₄ and those on raltegravir at 400 mg QD had a similar AUC₀₋₂₄. More patients had a C(trough) of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low C(trough) values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C(trough) and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.

Topics: Adult; Age Factors; Aged; Area Under Curve; Body Weight; Cohort Studies; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Likelihood Functions; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Regression Analysis; RNA, Viral; Software; Thailand; Viral Load

Antiretroviral drugs have been recommended for postexposure prophylaxis (PEP) after high-risk sexual exposures for more than a decade. Three drug regimens could offer the highest levels of protection, particularly if the infectious source is taking medication, but drug intolerance has often led to suboptimal adherence. The current study evaluated a novel 3-drug PEP regimen, consisting of raltegravir, tenofovir DF, and emtricitabine. Of 100 participants enrolled in this study at a Boston community health center that has had a comprehensive PEP program for more than a decade, 85 were evaluable at 3 months and none became HIV infected. Fifty seven percent of those enrolled completed the regimen as prescribed, and 27% took their medicine daily, but sometimes missed the second daily dose of Raltegravir. The most common side effects reported included nausea or vomiting (27%), diarrhea (21%), headache (15%), fatigue (14%), abdominal symptoms (including pain, gas, or bloating) (16%), and myalgias or arthralgias (8%), all of which were mild and tended to be self-limited, not resulting in drug discontinuation. The side effects were significantly less common than those reported by historical controls, who used a 3-drug PEP regimen including zidovudine, lamivudine, and a ritonavir-boosted protease inhibitor. Raltegravir, tenofovir DF, and emtricitabine may be useful as a 3-drug regimen for PEP.

Topics: Adenine; Adult; Anti-HIV Agents; Boston; Deoxycytidine; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Organophosphonates; Patient Compliance; Post-Exposure Prophylaxis; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Young Adult

Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily.. HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs.. A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir.. There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Darunavir; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

Residual viraemia is a major obstacle to HIV-1 eradication in subjects receiving HAART. The intensification with raltegravir could impact latent reservoirs and might lead to a reduction of plasma HIV-1 viraemia (viral load [VL]), complementary DNA intermediates and immune activation.. This was a prospective, open-label, randomized study comprising 69 individuals on suppressive HAART randomly assigned 2:1 to add raltegravir during 48 weeks.. Total and integrated HIV-1 DNA, and ultrasensitive VL remained stable despite intensification. There was a significant increase in episomal HIV DNA at weeks 2-4 in the raltegravir group returning to baseline levels at week 48. Median CD4(+) T-cell counts increased 124 and 80 cells/µl in the intensified and control groups after 48 weeks (P=0.005 and P=0.027, respectively), without significant differences between groups. No major changes were observed in activation of CD4(+) T-cells. Conversely, raltegravir intensification significantly reduced activation of CD8(+) T-cells at week 48 (HLA-DR(+)CD38(+), P=0.005), especially in the memory compartment (CD38(+) of CD8(+)CD45RO(+), P<0.0001). Linear mix models also depicted a larger decrease in CD8(+) T-cell activation in the intensification group (P=0.036 and P=0.010, respectively). Raltegravir intensification was not associated to any particular adverse event.. Intensification of HAART with raltegravir during 48 weeks was safe and associated with a significant decrease in CD8(+) T-cell activation, and a transient increase of episomal HIV-1 DNA. However, raltegravir did not significantly contribute to changes in CD4(+) T-cell counts, ultrasensitive VL, and total and integrated HIV-1 DNA. These findings suggest that raltegravir impacts residual HIV-1 replication and support new strategies to impair HIV-1 persistence. ClinicalTrials.gov identifier: NCT00554398.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; DNA, Viral; Female; HIV Infections; HIV-1; Humans; Lymphocyte Activation; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load; Viremia

New antiretroviral drug classes provide opportunities to explore novel regimens.. HIV+ adults (<50 copies/mL) receiving atazanavir (ATV) were randomized to raltegravir (RAL) 400 mg + ATV 300 mg twice daily (q12h) for 4 weeks followed by RAL 800 mg + ATV/ritonavir 300/100 mg once daily (q24h) for 4 weeks or vice versa. Validated assays quantitated RAL and ATV plasma concentrations. Primary endpoint was geometric mean ratio (GMR) of ATV minimum concentration (Cmin) for q24h/q12h. Equivalence was 90% confidence interval (CI) of GMR lying between 0.80 and 1.25. Participants could consent to a total 48-week follow-up.. Twenty-five men, mean age 45 (range, 35-57) years, were evaluated. ATV and RAL demonstrated considerable pharmacokinetic variability. There was no period or sequence effect for pharmacokinetic parameters (P > 0.1 all measures). Ninety percent CIs of ATV GMR C(min) [1.30 (90% CI: 1.08 to 1.58)] and RAL GMR C(min) [0.48 (90% CI: 0.31 to 0.75)] demonstrated nonequivalence. Seventy-six percent consented to follow-up. There were no serious adverse events and no discontinuations due to adverse events over 48 weeks; HIV RNA remained undetectable.. In virologically suppressed adults, regimens comprising ATV plus RAL were efficacious and safe. ATV q12h troughs were lower than ritonavir-boosted atazanavir q24h; RAL q24h troughs were lower than q12h.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Plasma; Pyridines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Raltegravir as initial HIV therapy was examined in a double-blind study; 160 patients were randomized to raltegravir (400 mg bid after dose-ranging), 38 to efavirenz, both with tenofovir/lamivudine. At week 240, HIV-RNA remained <50 copies per milliliter in 68.8% (raltegravir) versus 63.2% (efavirenz), and CD4 increases were 302 versus 276 cells per microliter, respectively. Early HIV-RNA decline predicted later CD4 increases in both groups. Raltegravir resistance was observed in 3 of 10 raltegravir recipients with virologic failure. Few drug-related adverse events were reported after week 48. Raltegravir had minimal effect on laboratory values, including lipids. Raltegravir with tenofovir/lamivudine showed durable efficacy and good tolerability over 5 years.

Topics: Adult; Aged; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2-34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Female; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Salvage Therapy; Viral Load

To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated HIV-infected individuals.. : Randomized, double-blinded, placebo-controlled study.. Fifty-six subjects with treatment-mediated viral suppression for at least 1 year were randomized to add 400 mg of raltegravir twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function [as assessed by flow-mediated vasodilation (FMD) of the brachial artery] from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence.. At baseline, the median CD4 T-cell count was 498 cells/mm, nadir CD4 T-cell count was 191 cells/mm, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group: +0.032% per week, placebo group: +0.023% per week; P = 0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4 T-cell count and current abacavir use were associated with lower hyperemic velocity.. The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713).

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Double-Blind Method; Endothelium, Vascular; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Vasodilation; Viral Load

To analyze the effect of switching the ritonavir-boosted protease inhibitor (PI/r) in a stable combined antiretroviral therapy (cART) regimen to raltegravir on low-density lipoprotein (LDL) particles, and lipoprotein-associated phospholipase A2 (Lp-PLA2).. Substudy of a multicenter randomized trial that compared the efficacy of switching a PI/r to raltegravir-based cART in stable HIV-infected patients.. LDL size and phenotype (by gel-gradient electrophoresis), Lp-PLA2 (by 2-thio-PAF [Cayman]), proprotein convertase subtilisin/kexin type 9 (PCSK9) (by ELISA), and standard lipid parameters were measured at baseline and week 48.. Eighty-one (PI/r n = 41 and raltegravir n = 40) patients were evaluated. No differences in baseline demographic and metabolic variables between arms were found except in apolipoprotein (Apo) B (p = 0.042). At week 48, total cholesterol (TC) (p < 0.001), LDL-c (p = 0.023), non-high density lipoprotein cholesterol non-high-density lipoprotein cholesterol (non-HDL-c) (p < 0.001), TC/HDL (p = 0.026), triglyceride (p < 0.001), Apo B (p < 0.001), Apo A-I (p = 0.004) and Lp (a) (p = 0.005) decreased in raltegravir arm compared to PI/r arm. At week 48, a shift from LDL phenotype B to the less atherogenic phenotype A was observed only in raltegravir arm (p < 0.001). LDL size increased (PI/r 2.1 nm, p = 0.019; raltegravir 3.8 nm, p = 0.001) and cholesterol content in small and dense LDL subfractions (LDL 4,5,6) decreased (PI/r p = 0.007, raltegravir p = 0.006) at week 48 in both arms. Total Lp-PLA2 activity (PI/r p = 0.037 and raltegravir p = 0.051) and PCSK9 plasma concentration decreased in both arms (PI/r p = 0.034 and raltegravir p < 0.001).. Switching a PI/r to a raltegravir-based cART in virologically suppressed HIV-infected patients was associated with an overall improvement in lipid profile, including a shift to a less atherogenic LDL phenotype.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Aged; Cholesterol, LDL; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lipids; Lipoproteins, LDL; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium

Immunodiscordant HIV-infected patients show viral suppression during antiretroviral therapy but fail to recover CD4 T cells. Immunodiscordance is characterized by partial CD4 T-cell immunodeficiency and increased inflammation, activation and immunosenescence in both CD4 and CD8 T cells.. A randomized, controlled, 48-week intensification study to assess the effect of raltegravir on immunological parameters in immunodiscordant patients (CD4 cell counts <350 cells/μl; viral load <50 copies/ml for >2 years). Patients were randomized (2 : 1) to intensify therapy with raltegravir (intensified arm, n = 30) or continue with the same therapy (control arm, n = 14).. Both groups showed similar immunological baseline characteristics. CD4 T-cell counts increased faster in the intensified arm (P = 0.01, week 12). However, no differences between groups were observed at week 48. Additionally, no changes in thymic output (CD45RA(+)CD31(+) cells), activation (HLA-DR(+)CD95(+) cells) or ex-vivo cell death were observed in CD4 T cells at any time point intergroups or intragroups. Conversely, intensified arm showed significant decreases in the expression of the CD8 T-cell activation marker CD38 at weeks 24-48, which were more evident in memory cells. Despite this, the levels of HLA-DR expression in CD8 T cells and plasma soluble CD14 remained stable in both arms overtime.. Long-term (48-week) raltegravir intensification failed to counterbalance CD4 T-cell deficiency and its associated features: hyperactivation and death of CD4 T cells. However, raltegravir induced a specific reduction of CD38 expression in CD8 T cells, suggesting a beneficial effect on CD8 T-cell hyperactivation, which has been linked with HIV-associated comorbidities.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Flow Cytometry; Ganciclovir; HIV Infections; Humans; Hydroxychloroquine; Inflammation; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Valganciclovir; Viral Load

: Switching from boosted protease inhibitors (PI/r) to raltegravir (RAL) results in a better plasma lipid profile than continuing PI/r. Whether this strategy affects plasma biomarkers associated with atherosclerosis is unknown.. : We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein 1 (MCP-1), osteoprotegerin, interleukin (IL) 6, IL-10, tumor necrosis factor alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and P-selectin, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients treated with PI/r who randomly switched from PI/r to RAL or continued with PI/r in the SPIRAL trial. Biomarkers and lipids at baseline and 48-week changes between both study arms were compared. Correlations between changes in biomarkers and changes in lipids were also evaluated.. : Of 273 patients initiating study drugs in the SPIRAL trial, 233 (119 RAL, 114 PI/r) remained on allocated therapy for 48 weeks and had sera available for the purpose of this substudy. Triglycerides (-28%, P < 0.0001), total (-14%, P < 0.0001), low-density lipoprotein (-9%, P = 0.0069), and high-density lipoprotein (-10%, P = 0.0017) cholesterol decreased in RAL relative to the PI/r group. Among biomarkers, hsCRP (-40%, P < 0.0001), MCP-1 (-20%, P = 0.0003), osteoprotegerin (-13%, P = 0.0024), IL-6 (-46%,P < 0.0001), TNF-α (-27%, P = 0.0011), insulin (-26%, P < 0.0001), and D-dimer (-8%, P = 0.0187) decreased in RAL relative to PI/r group, whereas IL-10 (+1%, P = 0.7773), ICAM-1 (-6%, P = 0.1255), VCAM-1(0%, P = 0.8671), E-selectin (-9%, P = 0.2174), P-selectin (-6%, P = 0.3865), and adiponectin (+8%, P = 0.2028) remained unchanged. Biomarkers and lipids changes at 48 weeks were weakly correlated.. : Switching from PI/r to RAL induced significant changes in several cardiovascular biomarkers that were not completely explained by lipid changes.

Topics: Adult; Anti-HIV Agents; Atherosclerosis; Biomarkers; C-Reactive Protein; Chemokine CCL2; Drug Administration Schedule; E-Selectin; Fasting; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Interleukin-10; Interleukin-6; Lipids; Male; Middle Aged; Osteoprotegerin; P-Selectin; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Topics: Antiretroviral Therapy, Highly Active; Antiviral Agents; Coinfection; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Interferon-alpha; Liver Cirrhosis; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Proline; Pyrrolidinones; Raltegravir Potassium; Recombinant Proteins; Ribavirin

Topics: Adolescent; Adult; Cross-Over Studies; Dietary Fats; Female; Food-Drug Interactions; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Young Adult

Raltegravir is highly efficacious in the treatment of HIV-1 infection. The prevalence and impact on virologic outcome of low-frequency resistant mutations among HIV-1-infected patients not previously treated with raltegravir have not been fully established. Samples from HIV treatment-experienced patients entering a clinical trial of raltegravir treatment were analyzed using a parallel allele-specific sequencing (PASS) assay that assessed six primary and six secondary integrase mutations. Patients who achieved and sustained virologic suppression (success patients, n = 36) and those who experienced virologic rebound (failure patients, n = 35) were compared. Patients who experienced treatment failure had twice as many raltegravir-associated resistance mutations prior to initiating treatment as those who achieved sustained virologic success, but the difference was not statistically significant. The frequency of nearly all detected resistance mutations was less than 1% of viral population, and the frequencies of mutations between the success and failure groups were similar. Expansion of pre-existing mutations (one primary and five secondary) was observed in 16 treatment failure patients in whom minority resistant mutations were detected at baseline, suggesting that they might play a role in the development of drug resistance. Two or more mutations were found in 13 patients (18.3%), but multiple mutations were not present in any single viral genome by linkage analysis. Our study demonstrates that low-frequency primary RAL-resistant mutations were uncommon, while minority secondary RAL-resistant mutations were more frequently detected in patients naïve to raltegravir. Additional studies in larger populations are warranted to fully understand the clinical implications of these mutations.

Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cyclohexanes; Female; HIV Infections; Humans; Male; Maraviroc; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Salvage Therapy; Treatment Outcome; Triazoles; Viral Load

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV Integrase Inhibitors; Humans; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Treatment Outcome

Some human immunodeficiency virus (HIV)-infected individuals are not able to achieve a normal CD4(+) T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size.. Thirty treated subjects with CD4(+) T cell counts of <350 cells/mm(3) despite viral suppression for ≥ 1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in peripheral blood mononuclear cells (PBMCs).. The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue.. Low-level viremia is not likely to be a significant cause of suboptimal CD4(+) T cell gains during HIV treatment.. NCT00631449.

Topics: ADP-ribosyl Cyclase 1; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; HIV Infections; HLA-DR Antigens; Humans; Membrane Glycoproteins; Placebos; Pyrrolidinones; Raltegravir Potassium; T-Lymphocyte Subsets; Treatment Outcome; Viral Load; Viremia

The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (C(tot)) predicts cellular concentration (C(cell)).. Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. C(tot) and C(cell) of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the C(cell)/C(tot) ratio.. Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (C(max)), minimum concentration (C(min)) and area under the time-concentration curve from 0-12 h (AUC(0-12)) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular C(max), C(min) and AUC(0-12) were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir C(cell) corresponded to 5.3% of C(tot) measured simultaneously. Both concentrations fluctuate in parallel, with C(cell)/C(tot) ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUC(cell)/AUC(tot) GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively.. Raltegravir C(cell) correlated with C(tot) (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated.

Topics: Adult; Aged; Anti-HIV Agents; Chromatography, Liquid; Cytoplasm; Female; HIV Infections; Humans; Leukocytes, Mononuclear; Male; Mass Spectrometry; Middle Aged; Plasma; Prospective Studies; Pyrrolidinones; Raltegravir Potassium

We evaluated the long-term efficacy of raltegravir according to HIV-1 subtype (B and non-B) using data from three phase III studies in treatment-experienced (BENCHMRK-1 and 2) and treatment-naive (STARTMRK) HIV-infected patients.. HIV-1 subtypes were identified from baseline plasma specimens using genotypic data of the PhenoSense GT test (Monogram Biosciences, South San Francisco, California, USA). Non-B subtypes were combined for the current analyses due to small numbers of each specific subtype. An observed failure approach was used (only discontinuations due to lack of efficacy were treated as failures). Resistance evaluation was performed in patients with documented virologic failure.. Seven hundred and forty-three patients received raltegravir and 519 received comparator (efavirenz in STARTMRK; optimized background therapy in BENCHMRK). Non-B subtype virus (A, A/C, A/D, A/G, A1, AE, AG, B/G, BF, C, D, D/F, F, F1, G, and complex) was isolated at baseline in 98 (13%) raltegravir recipients and 62 (12%) comparator recipients. Subtypes AE and C were most common, isolated in 41 and 43 patients, respectively. The proportion of raltegravir recipients achieving HIV RNA less than 50 copies/ml was similar between non-B and B subtypes (STARTMRK: 94.5 vs. 88.7%; BENCHMRK-1 and 2: 66.7 vs. 60.7%); change in CD4 cell count also was similar between non-B and B subtypes (STARTMRK: 243 vs. 221 cells/μl; BENCHMRK-1 and 2: 121 vs. 144 cells/μl). Phenotypic resistance to raltegravir in non-B virus was associated with integrase mutations observed previously in subtype B virus.. In phase III studies in treatment-naive and treatment-experienced patients, raltegravir showed comparable and potent clinical efficacy against B and non-B HIV-1 subtypes.

Topics: Adult; Anti-Retroviral Agents; CD4 Lymphocyte Count; Double-Blind Method; env Gene Products, Human Immunodeficiency Virus; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; United States; Viral Load

Efavirenz (EFV) causes neuropsychiatric side-effects and an unfavorable blood lipid profile. We investigated the effect of replacing EFV with raltegravir (RAL) on patient preference, daytime sleepiness, sleep quality, anxiety, and lipid levels.. Switch-ER was a randomized, double-blind, cross-over study. Patients who tolerated EFV, with less than 50 copies/ml HIV-RNA, were randomized into two groups: the RAL-first group started with RAL (400 mg twice daily) and EFV placebo, and the EFV-first group with EFV (600 mg once daily) and RAL placebo. After 2 weeks, both groups switched to the alternate regimen. The primary endpoint was patient preference for the first or the second regimen, assessed after 4 weeks.. Fifty seven participants were enrolled with a median CD4 cell count 600/μl, and duration of previous EFV therapy 3.4 years. Fifty three participants completed the study. When asked about treatment preference after 4 weeks, 22 preferred RAL and 12 preferred EFV, whereas 19 did not express a preference. A significant difference in anxiety and stress scores favoring RAL (P = 0.04 and 0.03, respectively) was observed. Median plasma cholesterol levels decreased by 0.4 mmol/l (16 mg/dl, P < 0.001), triglycerides by 0.2 mmol/l (18 mg/dl, P = 0.036), and low-density lipoprotein by 0.2 mmol/l (8 mg/dl, P = 0.004) after replacing EFV with RAL. After study completion, 51% of patients switched to RAL.. Half of patients previously on a stable EFV preferred to switch to RAL, after double-blind exposure to RAL for 2 weeks. Substitution of EFV by RAL significantly impacted on lipid levels, stress, and anxiety scores.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Anxiety Disorders; Benzoxazines; CD4 Lymphocyte Count; Cross-Over Studies; Cyclopropanes; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Practice Guidelines as Topic; Pyrrolidinones; Raltegravir Potassium; Sleep Initiation and Maintenance Disorders; Surveys and Questionnaires; Treatment Outcome

To assess the sustainable efficacy and safety of a switch from enfuvirtide to raltegravir in patients with multidrug-resistant HIV infection.. One hundred and seventy patients with multidrug-resistant HIV infection and suppressed plasma HIV RNA levels < 400 copies/mL under an enfuvirtide-based regimen were randomized to maintain their regimen or to switch to a raltegravir-based regimen (immediate group) in a 48 week prospective, randomized, open-label trial. At week 24, patients in the maintenance arm also switched to raltegravir (deferred group). Baseline genotypic susceptibility scores (GSSs) were calculated using available historical resistance tests. Efficacy was assessed by the cumulative proportion of patients with virological failure, defined as a confirmed plasma HIV RNA ≥ 400 copies/mL up to week 48. The EASIER ANRS 138 trial is registered at ClinicalTrials.gov (NCT00454337).. At baseline, 86% of patients had plasma HIV RNA levels <50 copies/mL and 86% had a GSS ≥ 1. Through to week 48, in the on-treatment analysis, only one patient in the immediate group, with a GSS of 0, developed virological failure. At week 48, 90% of patients in both the immediate and deferred groups had plasma HIV-1 RNA levels <50 copies/mL. Median CD4 cell counts remained stable during follow-up. Of note, 12 of 66 (18.2%) patients receiving a regimen combining raltegravir and ritonavir-boosted tipranavir experienced alanine aminotransferase elevations, which led to a switch from tipranavir to darunavir in 8 cases, without discontinuation of raltegravir.. In well-suppressed patients with multidrug-resistant HIV infection, a switch from enfuvirtide to raltegravir is generally well tolerated and has sustained antiviral efficacy when combined with a potent background regimen.

Topics: Adult; Alanine Transaminase; CD4 Lymphocyte Count; Drug Resistance, Multiple, Viral; Endpoint Determination; Enfuvirtide; Female; France; Genotype; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Peptide Fragments; Pilot Projects; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome

To explore darunavir/ritonavir (DRV/r) plus raltegravir (RAL) combination therapy in antiretroviral-naive patients.. Phase IIb, single-arm, open-label, multicenter study.. One hundred and twelve antiretroviral-naive, HIV-1-infected patients received DRV/r 800/100 mg once daily and RAL 400 mg twice daily. Primary endpoint was virologic failure by week 24. Virologic failure was defined as confirmed viral load of 1000 copies/ml or more at week 12, or an increase of more than 0.5 log(10) copies/ml in viral load from week 4 to 12, or a confirmed viral load of more than 50 copies/ml at or after week 24. Protease and integrase genes were sequenced in patients experiencing virologic failure.. Virologic failure rate was 16% [95% confidence interval (CI) 10-24] by week 24 and 26% (95% CI 19-36) by week 48 in an intent-to-treat analysis. Viral load at virologic failure was 51-200 copies/ml in 17/28 failures. Adjusting for age and sex, virologic failure was associated with baseline viral load of more than 100,000 copies/ml [hazard ratio 3.76, 95% CI (1.52-9.31), P = 0.004] and lower CD4 cell count [0.77 per 100 cells/μl increase (95% CI 0.61-0.98), P = 0.037]. When trough RAL concentrations were included as a time-varying covariate in the analysis, virologic failure remained associated with baseline viral load more than 100,000 copies/ml [hazard ratio = 4.67 (95% CI 1.93-11.25), P < 0.001], whereas RAL level below detection limit in plasma at one or more previous visits was associated with increased hazard [hazard ratio = 3.42 (95% CI 1.41-8.26), P = 0.006]. All five participants with integrase mutations during virologic failure had baseline viral load more than 100,000 copies/ml.. DRV/r plus RAL was effective and well tolerated in most patients, but virologic failure and integrase resistance were common, particularly in patients with baseline viral load more than 100,000 copies/ml.

Topics: Adolescent; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Medication Adherence; Middle Aged; Odds Ratio; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

We compared 3 years of antiretroviral therapy with raltegravir or efavirenz as part of a combination regimen in the ongoing STARTMRK study of treatment-naive patients infected with human immunodeficiency virus (HIV).. Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies/mL and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind, noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Outcomes included viral suppression, adverse events, and changes from baseline metabolic parameters. Dual energy X-ray absorptiometry scans were obtained on a convenience sample of patients at prespecified time points to assess changes in body fat composition.. At week 156 counting noncompleters as failures, 212 (75.4%) of 281 versus 192 (68.1%) of 282 had vRNA levels <50 copies/mL in the raltegravir and efavirenz groups, respectively [Δ (95% CI) = 7.3% (-0.2, 14.7), noninferiority P < .001]. Mean changes from baseline CD4 count were 332 and 295 cells/mm³ in the raltegravir and efavirenz arms, respectively [Δ (95% CI) = 37 (4, 69)]. Consistent virologic and immunologic efficacy was maintained across prespecified demographic and baseline prognostic subgroups for both treatment groups. Fewer drug-related clinical adverse events (49% vs 80%; P < .001) occurred in raltegravir than efavirenz recipients, with discontinuations due to adverse events in 5% and 7%, respectively. Elevations in fasting lipid levels (including LDL- and HDL-cholesterol) were consistently lower in the raltegravir than efavirenz group (P < .005). Fat gain was 19% in 25 raltegravir recipients and 31% in 32 efavirenz recipients at week 156.. When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir produced durable viral suppression and immune restoration that was at least equivalent to efavirenz through 156 weeks of therapy. Both regimens were well tolerated, but raltegravir was associated with fewer drug-related clinical adverse events and smaller elevations in lipid levels. Clinical Trials Registration. NCT00369941.

Topics: Absorptiometry, Photon; Adenine; Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Tenofovir; Treatment Outcome; Viral Load

To investigate the pharmacokinetics of darunavir/ritonavir and raltegravir, in HIV-infected subjects, in both plasma and at the intracellular (IC) site of action.. HIV-infected patients on antiretroviral therapy received raltegravir 400 mg twice daily for 21 days (period 1); darunavir/ritonavir 800/100 mg once daily was added for 14 days (period 2), and patients were randomized to continue raltegravir twice daily (group 1) or to switch to 800 mg once daily (group 2), then they all stopped raltegravir intake and continued darunavir/ritonavir once daily for 14 days (period 3). Drug concentrations in plasma and cells (peripheral blood mononuclear cell) were measured, and differences in geometric mean ratios (GMR) and 90% confidence intervals (CI) between period 2 versus period 3 and period 2 versus period 1 were assessed.. Twenty-four patients completed the study. Group 1 GMR (90% CI) of darunavir area under the curve (AUC) with and without raltegravir was 1.24 (1.13 to 1.45) for plasma and 1.24 (1.07 to 1.73) for cells and for group 2 was 1.14 (1.07 to 1.24) and 1.03 (0.94 to 1.16). GMR (90% CI) of raltegravir AUC without and with darunavir/ritonavir (plasma and cells) for group 1 was 0.90 (0.73 to 1.44) and 1.02 (0.81 to 1.67) and for group 2 was 1.21 (1.03 to 1.77) and 1.27 (1.07 to 1.94). Geometric mean IC to plasma AUC ratios were 5.3 and 4.9 for darunavir in groups 1 and 2 when darunavir/ritonavir was given alone and 4.9 and 5.6 for raltegravir when given alone. These ratios were not altered by the coadministered drug.. No remarkable interactions between darunavir/ritonavir and raltegravir in plasma or cells were seen. Raltegravir IC concentrations are higher than previously reported; the difference being due to modified cell isolation procedures that reduced drug loss caused by washing.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Darunavir; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Young Adult

Despite virally suppressive combination antiretroviral therapy (cART), some HIV-infected patients exhibit suboptimal CD4(+) T-cell recovery. This study aimed to determine the effect of intensification of cART with raltegravir or addition of hyperimmune bovine colostrum (HIBC) on CD4(+) T-cell count in such patients.. We randomized 75 patients to 4 treatment groups to receive raltegravir, HIBC, placebo, or both raltegravir and HIBC in a factorial, double-blind study. The primary endpoint was time-weighted mean change in CD4(+) T-cell count from baseline to week 24. T-cell activation (CD38(+) and HLA-DR(+)), plasma markers of microbial translocation (lipopolysaccharide, 16S rDNA), monocyte activation (soluble (s) CD14), and HIV-RNA (lowest level of detection 4 copies/mL) were monitored. Analysis was performed using linear regression methods.. Compared with placebo, the addition of neither raltegravir nor HIBC to cART for 24 weeks resulted in a significant change in CD4(+) T-cell count (mean difference, 95% confidence interval [CI]: 3.09 cells/μL, -14.27; 20.45, P = .724 and 9.43 cells/μL, -7.81; 26.68, P = .279, respectively, intention to treat). There was no significant interaction between HIBC and raltegravir (P = .275). No correlation was found between CD4(+) T-cell count and plasma lipopolysaccharide, 16S rDNA, sCD14, or HIV-RNA.. The determinants of poor CD4(+) T-cell recovery following cART require further investigation.. ClinicalTrials.gov identifier: NCT00772590, Australia New Zealand Clinical Trials Registry: ACTRN12609000575235.

Topics: Adult; Animals; Cattle; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Colostrum; Double-Blind Method; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Linear Models; Lymphocyte Activation; Male; Middle Aged; Pregnancy; Pyrrolidinones; Raltegravir Potassium; RNA, Viral

Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules.. In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823.. From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group.. Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing.. Merck.

Topics: Adult; Aged; CD4 Lymphocyte Count; Drug Administration Schedule; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load; Young Adult

Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation.. This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4(+) and CD8(+) T-cell surface antigen expression.. Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4(+) and CD8(+) T-cell activation.. Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. Clinical Trials Registration. NCT00672932.

Topics: ADP-ribosyl Cyclase 1; Anti-Retroviral Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; HIV Infections; HIV-1; HLA-DR Antigens; Humans; Male; Middle Aged; Neopterin; Pilot Projects; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; RNA, Viral

Raltegravir concentrations and human immunodeficiency virus type 1 (HIV-1) RNA levels in semen samples from 10 treatment-experienced HIV-1-infected patients were measured after 24 weeks of raltegravir-based highly active antiretroviral therapy (HAART). Semen and plasma HIV-1 RNA levels were below 100 copies/ml and 50 copies/ml, respectively, in all samples. The median raltegravir concentrations in semen samples (n=10) and in plasma samples (n=9) drawn simultaneously were 345 (range, 83 to 707) ng/ml and 206 (range, 106 to 986) ng/ml, respectively. The median semen-to-plasma ratio of raltegravir concentration was 1.42 (range, 0.52 to 6.66), indicating good although variable levels of drug penetration of raltegravir in the seminal compartment.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Semen

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Darunavir; Drug Administration Schedule; Female; HIV; HIV Infections; Humans; Immunosuppression Therapy; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome

To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy.. The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov, numbers NCT00443703 and NCT00443729.. 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0.0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol -12.6%vs 1.0%, non-HDL cholesterol -15.0%vs 2.6%, and triglycerides -42.2%vs 6.2%. At week 24, 293 (84.4%, 95% CI 80.2-88.1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90.6%, 87.1-93.5) of 352 patients in the lopinavir-ritonavir group (treatment difference -6.2%, -11.2 to -1.3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group.. Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir.. Merck.

Topics: Adult; Anti-HIV Agents; Cholesterol, LDL; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Treatment Outcome; Viremia

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load

Etravirine, a nonnucleoside reverse transcriptase inhibitor, was provided through an international early access program (EAP) prior to regulatory approval.. The Phase III, nonrandomized, open-label EAP investigated etravirine 200 mg twice daily plus a background regimen (BR) in patients who had failed multiple antiretroviral regimens. Efficacy and safety are reported for HIV-infected adults from the United States through week 48, including subgroups receiving etravirine +/- darunavir/ritonavir and/or raltegravir.. The intent-to-treat population included 2578 patients; 62.4% and 56.7% of patients received darunavir/ritonavir and raltegravir, respectively, in their BR. At week 48, 62.3% of patients achieved viral loads <75 copies per milliliter; responses across subgroups were similar. Median CD4 count increase from baseline was >100 cells per cubic millimeter. No unexpected safety concerns emerged; serious AEs and deaths due to AEs, considered possibly related to etravirine, occurred in 2.0% and 0.3% of patients, respectively. Discontinuations due to AEs were low overall (4.4%) and comparable across subgroups.. Etravirine combined with a BR, often including other new antiretrovirals, such as darunavir/ritonavir and/or raltegravir, provided an effective treatment option in treatment-experienced patients with HIV-1.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; United States; Viral Load

Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART.. Patients with plasma HIV RNA<50 c/mL added sustained-release VPA (Depakote ER) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA).. In three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (>50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA.. The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued.

Topics: Antiretroviral Therapy, Highly Active; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Drug Administration Schedule; Drug Therapy, Combination; Enfuvirtide; Enzyme Inhibitors; Histone Deacetylase Inhibitors; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Peptide Fragments; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Valproic Acid; Viremia

Raltegravir in combination therapy has demonstrated potent suppression of HIV-1 with a favorable safety profile. This report provides 96-week efficacy and safety data from Protocol 005, a Phase II study.. HIV-infected patients with very limited treatment options and failing antiretroviral therapy were randomized to raltegravir 200, 400, or 600 mg or placebo b.i.d., plus optimized background therapy for >or=24 weeks; all patients were then offered open-label raltegravir 400 mg b.i.d. Efficacy measurements included changes in viral load and CD4 count from baseline and percent of patients with HIV-1 RNA <400 and <50 copies/mL.. One hundred and thirty-three patients received raltegravir and 45 received placebo. No dose-dependent differentiation in the safety or antiviral activity of raltegravir was observed during the double-blind phase. For the combined raltegravir groups, mean change in viral load from baseline was -1.60 log10 copies/mL at week 48 and -1.38 log10 copies/mL at week 96 (observed failure approach). At week 48, HIV-1 RNA levels were <400 copies/mL in 68% of raltegravir recipients and <50 copies/mL in 55%; these levels were maintained in 55% and 48% of raltegravir recipients, respectively, at week 96 (noncompleter = failure). There were few discontinuations of raltegravir (4%) due to adverse events.. In patients with limited treatment options, raltegravir with OBT had a potent and sustained antiretroviral effect and was generally well tolerated through 96 weeks.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Raltegravir and maraviroc represent new, important resources for HIV-infected patients with intolerance or resistance to other antiretroviral agents. The safety and efficacy of both drugs have been investigated, but there is no information on possible pharmacokinetic interactions between these 2 drugs in clinical practice.. To evaluate raltegravir plasma concentrations in heavily treatment-experienced patients receiving salvage regimens and explore, in a preliminary assessment, the potential influence of maraviroc coadministration and other cofactors on raltegravir trough concentrations (C(trough)).. Fifty-four HIV-infected patients with triple class (nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, protease inhibitor) treatment experience starting raltegravir 400 mg twice daily, with (n = 11) or without (n = 43) concomitant maraviroc 300 mg twice daily, were evaluated. All regimens included at least 3 drugs of at least 2 different classes. Raltegravir plasma Ctrough, after at least 1 month of treatment, were analyzed to compare groups of patients taking raltegravir only and raltegravir plus maraviroc. Immunovirological (CD4, HIV-RNA) and clinical data after 6 months of treatment were also collected and described.. Raltegravir plasma Ctrough showed a large variability (range <0.020-2.47 microg/mL). Median levels were similar in the 2 groups (raltegravir + maraviroc 0.104 microg/mL, range 0.025-0.826; raltegravir 0.090 microg/mL, range <0.020-2.47, p = 0.400). Detectable (>0.02 microg/mL) raltegravir concentrations were observed in all patients receiving raltegravir + maraviroc and in 74% of patients receiving raltegravir alone (p = 0.060). After 6 months of treatment, the 2 groups had similar clinical, virologic, and immunologic conditions.. Coadministration of maraviroc does not seem to have any relevant effects on raltegravir plasma Ctrough in heavily treatment-experienced patients receiving salvage regimens. Further studies should evaluate the potential additional benefits of maraviroc coadministration in terms of virologic and immunologic response.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Cyclohexanes; Drug Administration Schedule; Drug Interactions; HIV Infections; Humans; Male; Maraviroc; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Triazoles; Young Adult

Nucleoside-sparing combination antiretroviral therapy (cART) regimens might be an attractive therapeutic option for HIV type-1 (HIV-1)-infected patients; however, the pharmacokinetic profiles of such regimens are frequently unknown.. Fourteen HIV-1-infected patients (age 21-55 years, 64% male) on stable cART with plasma HIV RNA <50 copies/ml entered this Phase I pharmacokinetic study. In period 1, patients received tenofovir/emtricitabine/-darunavir/ritonavir (300/200/800/100 mg) all once daily. During period 2, raltegravir 400 mg twice daily was added to the regimen and in period 3 tenofovir/emtricitabine was discontinued. At steady state, intensive pharmacokinetic sampling was undertaken. Differences in the geometric mean ratio (GMR) for pharmacokinetic parameters between periods 2 versus 1 and period 3 versus 1 were assessed for darunavir and ritonavir (period 3 versus 2 for raltegravir).. No statistically significant differences in pharmacokinetic parameters were observed between period 2 versus period 1. During period 3, darunavir GMR (95% confidence interval) values for trough and maximum plasma concentration (C(trough) and C(max)), area under the plasma concentration-time curve (AUC) and elimination half-life (t(1/2)) were 0.64 ng/ml (0.44-0.93), 1.05 ng/ml (0.90-1.24), 0.92 ng h/ml (0.78-1.08) and 0.69 h (0.46-1.05), respectively, when compared with period 1. No statistically significant changes were observed in ritonavir or raltegravir pharmacokinetic parameters. Darunavir C(trough)<550 ng/ml (the minimum effective concentration for protease-resistant HIV viral isolates) was observed in four patients during period 3 only. No clinically significant safety concerns were reported.. Darunavir C(trough) is reduced by 36% when administered without tenofovir/emtricitabine in HIV-1-infected patients. This interaction might be of clinical significance in the management of individuals with protease-resistant HIV viral isolates.

Topics: Adenine; Adult; Anti-HIV Agents; Darunavir; Deoxycytidine; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Tenofovir; Treatment Outcome; Young Adult

We analyzed the 96-week results in the overall population and in prespecified subgroups from the ongoing STARTMRK study of treatment-naive HIV-infected patients.. Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies per milliliter and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine.. At week 96 counting noncompleters as failures, 81% versus 79% achieved vRNA levels <50 copies per milliliter in the raltegravir and efavirenz groups, respectively [Delta (95% confidence interval) = 2% (-4 to 9), noninferiority P < 0.001]. Mean change in baseline CD4 count was 240 and 225 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Delta (95% confidence interval) = 15 (-13 to 42)]. Treatment effects were consistent across prespecified baseline demographic and prognostic subgroups. Fewer drug-related clinical adverse events (47% versus 78%; P < 0.001) occurred in raltegravir than efavirenz recipients. Both regimens had modest effects on serum lipids and glucose levels and on body fat composition.. When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir exhibited durable antiretroviral activity that was noninferior to the efficacy of efavirenz through 96 weeks of therapy. Subgroup analyses were generally consistent with the overall findings. Both regimens were well tolerated.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

Switching to raltegravir in selected patients treated with ritonavir-boosted protease inhibitors may result in similar efficacy and lower plasma lipids.. SPIRAL is a 48-week multicentre, open-label trial in which HIV-infected adults with less than 50 copies/ml of plasma HIV RNA for at least the previous 6 months on ritonavir-boosted protease inhibitor-based therapy were randomized (1: 1) to switch from the ritonavir-boosted protease inhibitor to raltegravir or to continue on ritonavir-boosted protease inhibitor-based therapy. Primary endpoint was the proportion of patients free of treatment failure (noncompleter = failure) at 48 weeks. SPIRAL study was powered to show noninferior efficacy of raltegravir-based therapy with a margin of -12.5%.. Two hundred and seventy-three patients assigned to switch to raltegravir (n = 139) or to continue ritonavir-boosted protease inhibitor (n = 134) were included in the efficacy analysis. At 48 weeks, 89.2% (raltegravir-based therapy) and 86.6% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of treatment failure [difference 2.6%; 95% confidence interval (CI) -5.2 to 10.6]. A total of 96.9% (raltegravir-based therapy) and 95.1% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of virological failure (difference 1.8%; 95% CI -3.5 to 7.5). Switching to raltegravir was associated with significant decreases in plasma lipids and total-to-HDL cholesterol ratio relative to continuing ritonavir-boosted protease inhibitor. Severe adverse events and study drug discontinuations due to any adverse event occurred in 4 and 2% of the patients in each group.. In patients with sustained virological suppression on ritonavir-boosted protease inhibitor-based therapy, switching from ritonavir-boosted protease inhibitor to raltegravir demonstrated noninferior efficacy and resulted in a better lipid profile at 48 weeks than continuing ritonavir-boosted protease inhibitor.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

Early integration of HIV proviral DNA into the host cell genome prevents viral eradication, despite suppressive HAART. In vitro, integrase inhibitors reduce proviral DNA levels and rapidly increase 2-long-terminal repeat (LTR) circle levels. We examined the effect of raltegravir on the time course of HIV-1 DNA forms in patients with controlled viremia.. The EASIER-ANRS 138 randomized trial demonstrated that switching from enfuvirtide to raltegravir maintained virological suppression in treatment-experienced patients with viral load below 400 copies/ml. We analyzed total HIV-1 DNA and 2-LTR circle levels measured at weeks (W)0 and 24 in the first 30 patients enrolled in each arm, and at W48 in the raltegravir arm.. At W0 the total DNA level was 3.6 log(10)/10(6) peripheral blood mononuclear cell (PBMC) in both groups, and 2-LTR circles were detected in six patients (median 89 copies/10(6) PBMC). At W24 the total DNA level was 3.6 log(10)/10(6) PBMC in both groups, and 2-LTR circles were detected in three new patients. At W48 the total HIV DNA level in the raltegravir group was 3.5 log(10)/10(6) PBMC, and 2-LTR circles were undetectable. No significant change in total HIV DNA occurred between W0 and W24 in either arm (P = 0.71) and no significant change was observed in the raltegravir arm at W48.. In most patients on effective HAART, including regimens containing an integrase inhibitor, the viral reservoir, reflected by the HIV-1 DNA load, is stable and nondynamic during the 48 weeks of follow-up.

Topics: Antiretroviral Therapy, Highly Active; DNA, Circular; DNA, Viral; Female; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA; Viral Load; Viremia

Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients.. Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.. In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.. ClinicalTrials.gov NCT00515827

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cross-Over Studies; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Viral Load; Viremia

The efficacy of raltegravir plus optimized background therapy (OBT) has been demonstrated for antiretroviral (ARV)-experienced HIV-1-infected patients in randomized clinical trials. We studied viro-immunological response, pharmacokinetic parameters and genotypic test results in an observational cohort of multiple ARV class-experienced patients starting a raltegravir-based regimen.. Already enrolled ANRS CO3 Aquitaine Cohort patients with virological failure were included in this study after starting a raltegravir-based regimen (400 mg twice a day, week 0). Virological success was defined by the plasma HIV-1 RNA level [viral load (VL)] <2.7 log(10) copies/mL at week 12 and <1.7 log(10) copies/mL at week 24. One patient was excluded from further analysis (no follow-up after week 4).. Fifty-one patients [male/female = 43/8, median age = 48 (interquartile range = 43, 55) years] were included. At week 0, median CD4 count was 244 (110; 310)/mm(3) and median VL was 4.2 (3.6, 4.7) log(10) copies/mL. At week 24, 39 (78%) patients experienced virological success: 4 (44%), 14 (82%) and 21 (87%) patients with a genotypic sensitivity score <1, > or =1 and <2 and > or =2 (P = 0.02), respectively. Raltegravir-related mutations emerged in 9 of 11 failing patients (82%): Q148H/R (n = 5), N155S/H (n = 3) and S230N (n = 1). Median CD4 increases from week 0 to week 4 and week 24 were 28 (-4, 85) and 57 (0, 156) cells/mm(3), respectively. A poor immune response was independently associated with a lower VL decline (week 0 to week 12) [odds ratio (OR): 3.5, 95% confidence interval (CI): 1.4, 8.4, for 1 log(10) less] and CD4+% at baseline (OR: 2.6, 95% CI: 0.97, 8.3, for 10% lower).. Raltegravir plus OBT provided a good virological success rate in highly pre-treated patients under clinical routine conditions.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients.. Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941.. 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per microL or less. The main analysis (with non-completion counted as failure) showed that 86.1% (n=241 patients) of the raltegravir group and 81.9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4.2%, 95% CI -1.9 to 10.3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0.0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44.1%]) than those on efavirenz (n=217 [77.0%]; difference -32.8%, 95% CI -40.2 to -25.0, p<0.0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group.. Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients.. Merck.

Topics: Adenine; Adult; Alkynes; Analysis of Variance; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Prognosis; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Safety; Tenofovir; Treatment Outcome; Viral Load

The purpose of this study was to evaluate the safety and efficacy of raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection.. Multicenter, double-blind, randomized study of raltegravir (100, 200, 400, or 600 mg twice a day) vs efavirenz (600 mg every day), both with tenofovir/lamivudine (TDF/3TC), for 48 weeks, after which raltegravir arms were combined and all dosed at 400 mg twice a day. Eligible patients had HIV-1 RNA > or =5000 copies per milliliter and CD4 T cells > or =100 cells per microliter.. One hundred ninety-eight patients were randomized and treated; 160 received raltegravir and 38 received efavirenz. At week 96, 84% of patients in both groups achieved HIV-1 RNA <400 copies per milliliter; 83% in the raltegravir group and 84% in the efavirenz group achieved <50 copies per milliliter (noncompleter = failure). Both groups showed similar increases in CD4 T cells (221 vs 232 cells/uL, respectively). An additional 2 patients (1 in each group) met the protocol definition of virologic failure between weeks 48 and 96; no known resistance mutations were observed in the raltegravir recipient; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations. Investigator reported drug-related clinical adverse events (AEs) were less frequent with raltegravir (51%) than efavirenz (74%). Drug-related AEs occurring in >10% of patients in either group were nausea in both groups and dizziness and headache in the efavirenz group. Laboratory AEs remained infrequent. Raltegravir had no adverse effect on total or low-density lipoprotein cholesterol or on triglycerides. Neuropsychiatric AEs remained less frequent with raltegravir (34%) than efavirenz (58%). There were no drug-related serious AEs in patients receiving raltegravir.. In antiretroviral therapy-naive patients, raltegravir with TDF/3TC had potent antiretroviral activity, which was similar to efavirenz/TDF/3TC and was sustained to week 96. Raltegravir was generally well tolerated; drug-related AEs were less frequent in patients treated with raltegravir compared with efavirenz.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; HIV Infections; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Lamivudine; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tenofovir; Time Factors; Treatment Outcome

Among patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection, salvage regimens including enfuvirtide have demonstrated sustained efficacy. Because of reluctance to use subcutaneous injections, raltegravir may be an alternative to replace enfuvirtide within a suppressive regimen. We conducted a prospective, randomized, open-label trial to compare the antiviral efficacy and safety of a switch to raltegravir with the efficacy and safety of continuing enfuvirtide.. A total of 170 patients with multidrug-resistant HIV-1 infection and plasma HIV-1 RNA levels <400 copies/mL who were receiving enfuvirtide-based regimens were randomized 1:1 to maintain enfuvirtide or to switch to raltegravir. The primary efficacy end point was the cumulative proportion of patients with virologic failure, defined as a confirmed plasma HIV-1 RNA level >or=400 copies/mL, over 24 weeks. The secondary end points mainly involved safety.. The switch to raltegravir was non-inferior to the maintenance of enfuvirtide, with virologic failure rates of 1.2% in both treatment arms in the intention-to-treat analysis (beta = 0.01%; 95% confidence interval, -6.7 to 6.8) and 1.2% and 0%, respectively, in the on-treatment analysis (beta = 1.22%; 95% confidence interval, -5.6 to 8.1). At week 24, 88%-89% of patients in both arms had plasma HIV-1 RNA levels <50 copies/mL. No significant CD4 cell count changes occurred in either arm. Grade 3-4 adverse events and laboratory abnormalities were uncommon and were not different between the treatment arms.. A switch to raltegravir was safe, well tolerated, and virologically non-inferior to the maintenance of enfuvirtide in patients infected with multidrug-resistant HIV-1 infection who were receiving suppressive antiretroviral therapy.. NCT00454337

Topics: Adult; Anti-HIV Agents; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

The introduction of 2 or 3 fully active drugs in human immunodeficiency virus (HIV)-infected patients receiving failing antiretroviral therapy is a key determinant of subsequent treatment efficacy. The aim of this study was to assess the safety and efficacy of a regimen containing raltegravir, etravirine, and darunavir/ritonavir for treatment-experienced patients infected with multidrug-resistant HIV.. Patients enrolled in this phase II, noncomparative, multicenter trial were naive to the investigational drugs and had plasma HIV RNA levels >1000 copies/mL, a history of virologic failure while receiving nonnucleoside reverse-transcriptase inhibitors (NNRTI), > or =3 primary protease inhibitor and nucleoside reverse transcriptase inhibitor (NRTI) mutations, and < or =3 darunavir and NNRTI mutations. The primary end point was the proportion of patients with plasma HIV RNA levels <50 copies/mL at 24 weeks.. A total of 103 patients enrolled in the study. At baseline, genotypic resistance profiles showed a median of 4 primary protease inhibitor mutations, 1 NNRTI mutation, and 6 NRTI mutations. In addition to the investigational drugs, 90 patients (87%) received optimized background therapy that included NRTIs (86 patients) or enfuvirtide (12 patients). At week 24, 90% of patients (95% confidence interval, 85%-96%) had an HIV RNA level <50 copies/mL. At week 48, 86% (95% confidence interval, 80%-93%) had an HIV RNA level <50 copies/mL. The median CD4 cell count increase was 108 cells/mm(3). Grade 3 or 4 clinical adverse events were reported in 15 patients (14.6%). Only 1 patient discontinued the investigational antiretroviral regimen, because of an adverse event.. In patients infected with multidrug-resistant virus who have few remaining treatment options, the combination of raltegravir, etravirine, and darunavir/ritonavir is well tolerated and is associated with a rate of virologic suppression similar to that expected in treatment-naive patients.

Topics: Adult; Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; Female; HIV Infections; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Treatment Outcome

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC(0-12)) and peak plasma drug concentration (C(max)) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C(12)) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C(24), AUC, and C(max) GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.

Topics: Adenine; Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome

Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs.. We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio.. In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups.. In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Topics: Adolescent; Adult; Aged; CD4 Lymphocyte Count; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Logistic Models; Male; Middle Aged; Neoplasms; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed.. We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure.. Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations.. When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Topics: Adolescent; Adult; Aged; CD4 Lymphocyte Count; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation; Organic Chemicals; Phenotype; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load

Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients.. HIV-infected patients with HIV-1 RNA viral load over 5000 copies per mL, CD4 cell counts over 50 cells per muL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, and one protease inhibitor were randomly assigned to receive raltegravir (200 mg, 400 mg, or 600 mg) or placebo orally twice daily in this multicentre, triple-blind, dose-ranging, randomised study. The primary endpoints were change in viral load from baseline at week 24 and safety. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00105157.. 179 patients were eligible for randomisation. 44 patients were randomly assigned to receive 200 mg raltegravir, 45 to receive 400 mg raltegravir, and 45 to receive 600 mg raltegravir; 45 patients were randomly assigned to receive placebo. One patient in the 200 mg group did not receive treatment and was therefore excluded from the analyses. For all groups, the median duration of previous antiretroviral therapy was 9.9 years (range 0.4-17.3 years) and the mean baseline viral load was 4.7 (SD 0.5) log10 copies per mL. Four patients discontinued due to adverse experiences, three (2%) of the 133 patients across all raltegravir groups and one (2%) of the 45 patients on placebo. 41 patients discontinued due to lack of efficacy: 14 (11%) of the 133 patients across all raltegravir groups and 27 (60%) of the 45 patients on placebo. At week 24, mean change in viral load from baseline was -1.80 (95% CI -2.10 to -1.50) log10 copies per mL in the 200 mg group, -1.87 (-2.16 to -1.58) log10 copies per mL in the 400 mg group, -1.84 (-2.10 to -1.58) log10 copies per mL in the 600 mg group, and -0.35 (-0.61 to -0.09) log(10) copies per mL for the placebo group. Raltegravir at all doses showed a safety profile much the same as placebo; there were no dose-related toxicities.. In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen. The safety profile of raltegravir is comparable with that of placebo at all doses studied.

Topics: Adolescent; Adult; Aged; Atazanavir Sulfate; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Multiple; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Logistic Models; Male; Middle Aged; Oligopeptides; Organic Chemicals; Pyridines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Raltegravir is an HIV-1 integrase strand-transfer inhibitor with potent in vitro activity. This study explored the antiretroviral activity and safety of raltegravir in treatment-naive patients with plasma HIV-1 RNA levels > or = 5000 copies/mL and CD4 T-cell counts > or = 100 cells/mm.. Multicenter, double-blind, randomized, controlled study of raltegravir at doses of 100, 200, 400, and 600 mg twice daily versus efavirenz at a dose of 600 mg/d, all in combination with tenofovir at a dose of 300 mg/d and lamivudine at a dose of 300 mg/d (clinicaltrials.gov identifier: NCT00100048).. In the 198 patients treated (160 on raltegravir and 38 on efavirenz), the mean HIV-1 RNA level ranged from 4.6 to 4.8 log10 copies/mL at baseline. At weeks 2, 4, and 8, the proportion of patients achieving an HIV-1 RNA level <50 copies/mL was greater in each of the raltegravir treatment groups than in the efavirenz group. By week 24, all treatment groups appeared similar, with plasma HIV-1 RNA levels <400 copies/mL in 85% to 98% of patients and <50 copies/mL in 85% to 95% of patients. These reductions were maintained through week 48 in 85% to 98% of patients and in 83% to 88% of patients, respectively. Five (3%) patients on raltegravir and 1 (3%) on efavirenz experienced virologic failure before week 48. Drug-related clinical adverse events were less common with raltegravir than with efavirenz. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides.. Raltegravir at all doses studied was generally well tolerated in combination with tenofovir and lamivudine. Raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate.

Topics: Adenine; Adolescent; Adult; Aged; Australia; Canada; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Lamivudine; Latin America; Male; Middle Aged; Organic Chemicals; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Tenofovir; Thailand; Time Factors; Treatment Outcome; United States

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; HIV Infections; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Raltegravir (MK-0518) belongs to the new class of HIV integrase inhibitors. To date, there have been no reports investigating the potential for differential effects on viral dynamics with integrase inhibitors relative to current antiretroviral drugs.. Patients in this phase II study (P004) were antiretroviral treatment naive. Part 1 of this study compared monotherapy with raltegravir (100 mg, 200 mg, 400 mg, or 600 mg twice daily) with placebo over 10 days. In part 2, patients were enrolled for 48 weeks of combination therapy, with randomization to one of the four dosages of raltegravir or to efavirenz, in addition to tenofovir and lamivudine. Mathematical models were used to investigate processes underlying viral dynamics.. From day 15 through to day 57, individuals in the raltegravir arm were significantly more likely to have HIV RNA < 50 copies/ml (P < or = 0.047). Plasma viral loads were 70% lower at initiation of second-phase decay for individuals taking raltegravir than for those taking efavirenz (P < 0.0001). This challenges the current hypothesis that second-phase virus originates from infected long-lived cells, as an integrase inhibitor should not impact on viral production from this cell population. Mathematical modeling supported two hypotheses as consistent with these observations: (i) that second-phase virus arises from cells newly infected by long-lived infected cells and (2) that it arises from activation of latently infected cells with full-length unintegrated HIV DNA.. These observations challenge the current understanding of HIV-1 turnover and compartmentalization. They also indicate the promise of this new integrase inhibitor raltegravir.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Lamivudine; Linear Models; Organic Chemicals; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Statistics, Nonparametric; Tenofovir; Time Factors; Viral Load; Virus Integration; Virus Latency; Virus Replication

MK-0518 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration [IC95] = 33 nM in 50% human serum) and good bioavailability in uninfected subjects. This study explored the antiretroviral activity and safety of MK-0518 versus placebo for 10 days as monotherapy in antiretroviral therapy-naive HIV-1-infected patients with plasma HIV-1 RNA levels of at least 5000 copies/mL and CD4 T-cell counts of at least 100 cells/mm.. This was a multicenter, double-blind, randomized, placebo-controlled 2-part study, with the first part using MK-0518 in 1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized 1:1:1:1:1) given twice daily for 10 days of monotherapy. Patients were monitored for safety, pharmacokinetic parameters, and antiretroviral effect.. Thirty-five patients were enrolled (6-8 patients per treatment group) and completed 10 days of therapy; the mean baseline log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group. On day 10, the mean decrease from baseline in the log10 HIV RNA level was -0.2 copies/mL for the placebo group and -1.9, -2.0, -1.7 and -2.2 log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment groups, respectively. All dose groups had superior antiretroviral activity compared with placebo (P < 0.001 for comparison of each dose with placebo). At least 50% of patients in each MK-0518 dose group achieved an HIV RNA level <400 copies/mL by day 10. Mean trough MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study therapy was generally well tolerated. The most common adverse experiences were headache and dizziness; these were similar between active and control groups. There were no discontinuations because of adverse experiences and no serious adverse experiences.. MK-0518 showed potent antiretroviral activity as short-term monotherapy and was generally well tolerated at all doses. Based on these results, part 2 of the study, a dose-ranging 48-week trial of MK-0518 versus efavirenz in a combination regimen, has been initiated.

Topics: Adult; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load

Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors(INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women's Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women were previously defined as primarily having well-controlled HIV with vascular comorbidities, 463 with legacy effects(CD4 nadir < 250cells/mL), 274 aged ≤ 45 with hepatitis, 453 between 35-55 years, and 339 with poorly-controlled HIV/substance users. INSTIs, but not efavirenz, were associated with symptoms among key subgroups of WWH. Among those with HIV legacy effects, dolutegravir and elvitegravir were associated with greater stress/anxiety and avoidance symptoms(P's < 0.01); dolutegravir was also associated with greater re-experiencing symptoms(P = 0.005). Elvitegravir related to greater re-experiencing and hyperarousal among women with well-controlled HIV with vascular comorbidities(P's < 0.022). Raltegravir was associated with less hyperarousal, but only among women aged ≤ 45 years(P = 0.001). The adverse neuropsychiatric effects of INSTIs do not appear to be consistent across all WWH. Key characteristics (e.g., age, hepatitis positivity) may need consideration to fully weight the risk-benefit ratio of dolutegravir and elvitegravir in WWH.

Topics: Anti-HIV Agents; Benzoxazines; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Raltegravir Potassium

Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir's characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.

Topics: Adult; Anti-HIV Agents; HIV Infections; Humans; Polymorphism, Genetic; Raltegravir Potassium; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Lymphoma; Neutropenia; Pyrrolidinones; Raltegravir Potassium; Viral Load

Effectiveness of anti-HIV in the prevention of perinatal transmission has been established. Assessing the tolerance of drug exposure during pregnancy is of the utmost importance given the number of children exposed. HIV integrase and the recombinase-activating gene enzyme involved in the establishment of the T-lymphocyte repertoire show structural similarity. The inhibition of recombinase-activating (RAG) gene by anti-integrases is observed in vitro, in a variable way according to the molecules. Here, we show that in utero exposure to raltegravir did not alter the T-lymphocyte repertoire of 12 newborns. These reassuring data merit verification for other anti-integrases. ( ClinicalTrial.org NCT04024150).

Topics: Child; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Pregnancy; Raltegravir Potassium; Receptors, Antigen, T-Cell

To assess the efficacy of raltegravir, etravirine and darunavir/ritonavir (TRIO regimen) in treatment-experienced patients with human immunodeficiency virus-1 (HIV-1) infection by describing the proportion of patients who experienced virological failure (VF) at Week 24. The secondary objectives were to assess the HIV-1 plasma viral load (pVL) after Week 24, the proportion of patients who were receiving dual therapy or monotherapy at the last visit, and the number of deaths.. Patients from the ANRS CO3 Aquitaine Cohort who were prescribed the TRIO regimen between February 2007 and September 2018 were classified into two groups based on their pVL at study inclusion: the virological failure group (VFG; pVL >50 copies/mL) and the virologically suppressed group (VSG; pVL <50 copies/mL). The impact of baseline pVL and genotypic susceptibility score (GSS) on VF was analysed.. In total, 184 patients were enrolled in this study, with 123 (66.8%) in the VFG and 61 (33.2%) in the VSG. The median length of follow-up was 7.5 (interquartile range 4.1-9.6) years, and 29 (15.8%) patients died. Thirty-seven (25.5%) patients experienced VF at Week 24, including 32/145 (32.7%) in the VFG and 5/47 (10.6%) in the VSG (P<0.01). Resistance-associated mutations were detected in integrase, reverse transcriptase and protease for 7/37 (18.9%), 3/37 (8.1%) and 1/37 (2.7%) patients, respectively. High pVL and GSS at baseline were independently associated with VF. At the last visit, 76/184 (41.3%) patients were still receiving the TRIO regimen, while 55/184 (29.9%) were receiving dual therapy and 1/184 (0.5%) was receiving protease inhibitor monotherapy. Among the 56 patients receiving dual therapy or monotherapy, 51 (96.2%) had pVL <50 copies/mL.. Despite a high level of mutation resistance at baseline, long-term virological follow-up was favourable and one-third of patients were eligible for drug-reducing strategies.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Viral; Follow-Up Studies; HIV Infections; HIV-1; Humans; Raltegravir Potassium; Ritonavir; Treatment Outcome; Viral Load

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral therapy (ART) medications with a good tolerability profile and a high genetic barrier to HIV drug resistance. However, several studies report significant weight gain among persons receiving INSTI-based ART regimens compared with other regimens.. In-vitro model of adipogenesis.. We used 3T3-L1 cells to investigate the effects of the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), alone or in combination with INSTIs: raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG), and bictegravir (BIC) on adipose differentiation. To monitor adipocyte differentiation, expression levels of PPARɣ and C/EBPα and the intracellular lipid accumulation by Red Oil staining were used. Furthermore, we evaluated the immunohistochemical expression of ER-TR7, a fibroblastic marker, after INSTIs treatment.. Compared with control, INSTIs were able to increase adipogenesis, especially RAL and ELV. TAF and TDF inhibited adipogenesis alone and in combination with INSTIs. This ability was more evident when TAF was used in combination with DTG and BIC. Finally, INSTIs increased the expression of ER-TR7 compared with control and cells treated with TAF or TDF.. Our data support the evidence that in-vitro challenge of 3T3-L1 cells with INSTIs is able to increase adipocytic differentiation and to drive a number of these cells toward the expression of fibroblastic features, with a different degree according to the various drugs used whereas TAF and TDF have an antagonistic role on this phenomenon.

Topics: 3T3-L1 Cells; Adenine; Adipocytes; Animals; Anti-HIV Agents; Cell Differentiation; HIV Infections; Humans; Integrases; Mice; Raltegravir Potassium; Tenofovir

In recent years, integrase strand transfer inhibitor (INSTI)-containing regimens have been increasingly adopted in treatment for HIV/AIDS and promoted as non-occupational post-exposure prophylaxis in China. This study aims to describe the prevalence of resistance to integrase and drug resistance mutations (DRMs) among ART-naive patients in Shenzhen, China.. Serum samples and demographic information were collected from newly reported ART-naive patients in Shenzhen in 2020. The study sequenced the coding sequence of the HIV-1 integrase gene and determined the DRMs.​.. In this study, 1682 newly reported cases were included and 1071 of them were successfully sequenced finally. The prevalence of primary drug resistance was 1.77%, with 19 samples showing varying degrees of resistance to INSTIs. The study detected six major DRMs in 16 individuals and eight accessory DRMs in 24 individuals. The prevalence of transmitted drug resistance (TDR) mutations was 1.21%, with five transmitted mutations detected in 13 individuals. The prevalence of drug resistance to raltegravir and elvitegravir was statistically higher than to bictegravir, cabotegravir and dolutegravir.. The prevalence of INSTI resistance in Shenzhen in 2020 was relatively high. ​Continued surveillance for resistance to INSTIs is recommended and treatment regimens should be adopted based on the pattern of resistance to INSTIs. ​Dolutegravir or bictegravir is first recommended when considering INSTIs as treatment regimens.

Topics: Anti-HIV Agents; China; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Integrases; Mutation; Prevalence; Pyridones; Raltegravir Potassium

An efficient one-pot synthetic method has been developed for the preparation of bicyclic carbamoyl pyridones from the known common intermediate methyl 5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (

Topics: Antiviral Agents; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Pyridones; Raltegravir Potassium

Cohort studies suggest higher discontinuation rates with integrase strand transfer inhibitors (INSTIs) than are seen in clinical trials. We assessed discontinuations and adverse events (AEs) that were considered related to the initial INSTI in the first year following initiation among treatment-naïve people living with HIV (PLWH).. Newly diagnosed PLWH initiating raltegravir, elvitegravir/cobicistat, dolutegravir or bictegravir in combination with emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate between 10/2007 and 1/2020 at the Orlando Immunology Center were included. Unadjusted incidence rates (IRs) and incidence rate ratios (IRRs) were calculated for treatment-related discontinuations and AEs associated with the initial INSTI in the first year following initiation.. Of 331 enrolled, 26 (8%) initiated raltegravir, 151 (46%) initiated elvitegravir/cobicistat, 74 (22%) initiated dolutegravir and 80 (24%) initiated bictegravir. Within the first year, treatment-related discontinuations occurred in 3 on elvitegravir/cobicistat (IR 0.02 per person-years (PPY)) and 5 on dolutegravir (IR 0.08 PPY); no treatment-related discontinuations occurred among those initiating raltegravir or bictegravir. Eleven treatment-related AEs occurred in 7 on raltegravir (IR 0.46 PPY), 100 treatment-related AEs occurred in 63 on elvitegravir/cobicistat (IR 0.72 PPY), 66 treatment-related AEs occurred in 37 on dolutegravir (IR 0.97 PPY) and 65 treatment-related AEs occurred in 34 on bictegravir (IR 0.88 PPY). Unadjusted IRRs did not reveal any significant difference between INSTIs in terms of early treatment-related discontinuations or AEs.. In our cohort, treatment-related AEs occurred in 43% initiating INSTIs but were responsible for early discontinuation in only 2% with no treatment-related discontinuations observed among those initiating RAL or BIC.

Topics: Anti-HIV Agents; Cobicistat; Emtricitabine; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Integrase Inhibitors; Pyridones; Raltegravir Potassium

Zimbabwe introduced raltegravir (RAL) granules at 14 facilities providing point-of-care HIV birth testing, aiming to initiate all newborns with HIV on a RAL-based regimen. From June 2020 to July 2021, we tested 3172 of the 6989 (45%) newborns exposed to HIV; we diagnosed 59(2%) with HIV infection, of whom 27 (46%) initiated RAL. The SARS-CoV-2 coronavirus disease pandemic exacerbated supply chain and trained provider shortages, contributing to low birth testing, RAL uptake and 6-month viral load testing.

Topics: Anti-HIV Agents; COVID-19; Female; HIV Infections; Humans; Infant, Newborn; Pandemics; Pregnancy; Raltegravir Potassium; SARS-CoV-2; Viral Load; Zimbabwe

Raltegravir, the first integrase inhibitor approved for the treatment of HIV infection, has been implicated as a promising potential in cancer treatment. Therefore, the present study aimed to investigate the repurposing of raltegravir as an anticancer agent and its mechanism of action in multiple myeloma (MM). Human MM cell lines (RPMI-8226, NCI H929, and U266) and normal peripheral blood mononuclear cells (PBMCs) were cultured with different concentrations of raltegravir for 48 and 72 h. Cell viability and apoptosis were then measured by MTT and Annexin V/PI assays, respectively. Protein levels of cleaved PARP, Bcl-2, Beclin-1, and phosphorylation of histone H2AX were detected by Western blotting. In addition, the mRNA levels of V(D)J recombination and DNA repair genes were analyzed using qPCR. Raltegravir treatment for 72 h significantly decreased cell viability, increased apoptosis, and DNA damage in MM cells while having minimum toxicity on cell viability of normal PBMCs approximately from 200 nM (0.2 μM; p < .01 for U66 and p < .0001 for NCI H929 and RPMI 8226 cells). Furthermore, raltegravir treatment altered the mRNA levels of V(D)J recombination and DNA repair genes. We report for the first time that treatment with raltegravir is associated with decreased cell viability, apoptosis induction, DNA damage accumulation, and alteration of mRNA expression of genes involved in V(D)J recombination and DNA repair in MM cell lines, all of which show its potential for anti-myeloma effects. Hence, raltegravir may significantly impact the treatment of MM, and further studies are required to confirm its efficacy and mechanism of action in more detail in patient-derived myeloma cells and in-vivo models.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Damage; HIV Infections; HIV-1; Humans; Integrase Inhibitors; Leukocytes, Mononuclear; Multiple Myeloma; Raltegravir Potassium; RNA, Messenger

Management of heavily treatment experienced (HTE) people with HIV remains a challenge. Tailored antiretroviral therapy (ART) is needed in this fragile population who almost invariably harbor viral quasispecies with resistance-associated mutations (RAMs). The reference method for HIV genotypic resistance testing (GRT) has long been Sanger sequencing (SS), but next-generation sequencing (NGS), following recent progress in workflow and cost-effectiveness, is replacing SS because of higher sensitivity. From the PRESTIGIO Registry, we present a case of a 59-year-old HTE woman who failed darunavir/ritonavir plus raltegravir at low-viremia levels due mainly to high pill burden and poor adherence. NGS-GRT was performed on HIV-RNA at failure and the results were compared to all past SS-GRT data available (historical genotype). In this case, NGS-GRT did not detect any minority drug-resistant variants. After discussing several therapeutic options, the treatment was changed to dolutegravir 50 mg twice daily plus doravirine 100 mg once a day, based on clinical history, adherence issues, and pill burden, as well as the historical SS-GRT and the latest NGS-GRT results. At six months follow-up visit, the patient had HIV-RNA below 30 copies/ml and CD4+ T cell count increased from 673 cells/ mm3 to 688 cells/ mm3. Close follow-up of this patient is ongoing.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Viral; HIV Infections; HIV Seropositivity; HIV-1; Humans; Raltegravir Potassium; Ritonavir; RNA; Treatment Outcome; Viral Load

This work aimed to evaluate the total, unbound, renal, and hepatic clearances of raltegravir (RAL) and the formation and elimination clearances of raltegravir glucuronide (RAL GLU) in pregnant women living with HIV. The participants received RAL 400 mg twice daily during the third trimester (n = 15) of gestation, delivery (n = 15), and the postpartum period (n = 8). Pharmacokinetic parameter values were calculated on the basis of plasma and urine data using noncompartmental methods. RAL clearances for the third trimester of gestation were as follows: total clearance: geometric mean, 63.63 L/h (95% CI, 47.5-85.25); renal clearance: geometric mean, 2.56 L/h (95% CI, 1.96-3.34); hepatic clearance: geometric mean, 60.52 L/h (95% CI, 44.65-82.04); and unbound clearance: geometric mean, 281.14 L/h (95% CI, 203.68-388.05). RAL GLU formation and elimination clearances for the third trimester of gestation were 7.57 L/h (95% CI, 4.94-11.6) and 8.71 L/h (95% CI, 6.71-11.32), respectively. No differences were observed in RAL GLU pharmacokinetic parameters between the third trimester of gestation and the postpartum period, except for higher formation (7.57 vs 4.03 L/h) and elimination (8.71 vs 4.92 L/h) clearances during the third trimester. The findings based on plasma and urine data are consistent with an increase in the hepatic uridine 5' diphospho-glucuronosyltransferase isoenzymes activities involved in RAL metabolism during pregnancy, and the formation of RAL GLU is a minor route of RAL elimination. Compared to the postpartum period, in the third trimester of gestation, the similar RAL plasma exposure in pregnant women reinforces the maintenance of an RAL regimen including a 400-mg oral dose twice daily during pregnancy.

Topics: Female; Glucuronides; HIV Infections; Humans; Postpartum Period; Pregnancy; Pregnant Women; Raltegravir Potassium

Our objectives were to investigate the characteristics of people living with HIV who presented with new or recurrent symptoms in the context of re-emergence of cerebrospinal fluid HIV RNA escape after antiretroviral therapy (ART) modification (termed relapse of CSF HIV RNA escape).. People living with HIV-1 with known CSF HIV RNA escape were identified, with clinical and laboratory data obtained from records in a tertiary centre. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in the presence of unquantifiable plasma HIV-RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV-RNA was quantifiable. Relapse was defined as a re-emergence of CSF HIV RNA escape with new symptoms after ART therapy intensification post-initial CSF HIV RNA escape.. Among 40 people living with HIV who presented with neurosymptomatic CSF HIV RNA, eight (20%) presented with a relapse of CSF HIV RNA escape. Symptoms on relapse included confusion (n = 2), cognitive decline (n = 2), cerebellar dysfunction (n = 2) and worsening of pre-existing seizures (n = 1). Prior to their relapse, three people underwent drug therapy modification, with two people stopping raltegravir intensification, and one person switched from tenofovir alafenamide, emtricitabine and raltegravir for a new regimen.. People with a relapse of CSF HIV RNA escape within this cohort presented with varied symptoms similar to their initial CSF HIV RNA escape. Clinicians should be vigilant of relapse of symptoms, particularly when simplifying ART regimens in people with CSF HIV RNA escape.

Topics: Anti-Retroviral Agents; Cerebrospinal Fluid; HIV Infections; HIV Seropositivity; Humans; Raltegravir Potassium; RNA, Viral; Viral Load

Topics: Gastric Bypass; HIV Infections; Humans; Lamivudine; Raltegravir Potassium; Tenofovir

Few data are available about the efficacy, durability, and tolerability of doravirine (DOR) + integrase strand inhibitors (INI) as a switching strategy among antiretroviral therapy (ART)-experienced people living with HIV (PLWH).. Retrospective, multicenter cohort study investigating the durability, efficacy, and tolerability of 2 off-label drug associations of DOR + INI among ART-experienced PLWH.. The study included PLWH who switched to DOR combined with either raltegravir (RAL) or dolutegravir (DTG) between June 1, 2020, and December 31, 2021, with at least 1 follow-up (FU) visit. Virologic, biometric, and metabolic parameters were evaluated at baseline (T0) and at 1-3 (T1), 6 (T2), and 12 (T3) months. Univariate and multivariate survival analyses assessed the 28-week probability of persistence on the regimens. Patient satisfaction was measured using the HIV Treatment Satisfaction Questionnaire.. Ninety-five PLWH were included, 52 in DOR + RAL and 43 in DOR + DTG. Six treatment discontinuations were reported during a mean of 37 (±17) weeks of FU (incidence of 2.7 × 1000 person-weeks FU). Only 2 were the result of virological failure without resistance mutations. DOR + DTG demonstrated significantly higher 28-week persistence than DOR + RAL (HR 1.90, 95% CI: 1.24-2.90, log-rank: P = 0.003). Weight, waist circumference, and fasting lipids reduced considerably at T3 vs T0. Overall, high satisfaction with the new treatment was reported, particularly in the DOR + RAL (68 (64-72)/72), compared with the DOR + DTG group (58 (50-65)/72, P < 0.001).. Our experience revealed few treatment discontinuations, improved metabolic parameters, and high patient satisfaction among ART-experienced PLWH switching to DOR combined with INI, irrespective of the specific INI used.

Topics: Anti-HIV Agents; Cohort Studies; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Integrases; Off-Label Use; Pyridones; Raltegravir Potassium; Retrospective Studies

Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan-Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.

Topics: Adult; Anti-HIV Agents; Darunavir; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Raltegravir Potassium; Retrospective Studies; Salvage Therapy; Treatment Outcome; Viral Load

Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%-5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings.. A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens.. E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure.. The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium; Retrospective Studies

HIV-1 integrase enzyme is responsible for the integration of viral DNA into the host genomic DNA. Integrase strand transfer inhibitors (INSTIs) are highly potent antiretroviral agents that inhibit this process, and are internationally approved for the treatment of both naïve and treated HIV-1 patients. However, their long-term efficacy is threatened by development of drug resistance strains resulting in resistance mutations. This work aimed to examine the effect of INSTI resistance-associated mutations (RAMs) and polymorphisms on the structure of HIV-1 subtype C (HIV-1C) integrase. Genetic analysis was performed on seven HIV-1C infected individuals with virologic failure after at least 6 months of INSTI-based antiretroviral therapy, presenting at the King Edward VIII hospital in Durban, South Africa. These were compared with sequences from 41 INSTI-naïve isolates. Integrase structures of selected isolates were modeled on the SWISS model online server. Molecular docking and dynamics simulations were also conducted using AutoDock-Vina and AMBER 18 force fields, respectively. Only one INSTI-treated isolate (14.28%) harboured major mutations (G140A + Q148R) as well as the E157Q minor mutation. Interestingly, S119T and V151I were only found in patients failing raltegravir (an INSTI drug). Molecular modeling and docking showed that RAMs and polymorphisms associated with INSTI-based therapy affect protein stability and this is supported by their weakened hydrogen-bond interactions compared to the wild-type. To the best of our knowledge, this is the first study to identify a double mutant in the 140's loop region from South African HIV-1C isolates and study its effects on Raltegravir, Elvitegravir, and Dolutegravir binding.Communicated by Ramaswamy H. Sarma.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Docking Simulation; Mutation; Pyridones; Raltegravir Potassium; South Africa

Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use in neonates (≥2 kg). Anticipating that neonatal administration would be performed primarily by mothers with varying degrees of health literacy, a health literate, patient-focused, iterative process was conducted to update/redesign the raltegravir granules for oral suspension pediatric kit and instructions for use (IFU) for neonatal use to be ready for regulatory submission.. Prototypes of an updated/redesigned raltegravir IFU were systematically assessed through multi-stage, iterative testing and evaluation involving untrained lay individuals with varying levels of health literacy, healthcare professionals and health literacy experts.. This iterative process resulted in numerous refinements to the IFU and kit, including wording, layout, presentation, colored syringes and additional instructional steps. The revised raltegravir pediatric kit and IFU (to include neonatal dosing) were approved by the US Food and Drug Administration in 2017 and the European Union in 2018. No reported medication errors related to IFU utilization had been reported as of March 2021, reflecting >3 years of commercial use worldwide.. This patient-focused process produced health literate instructions for preparing and administering an antiretroviral for neonatal use with complex dosing requirements. Testing demonstrated that lay users with a range of health literacy levels were able to accurately mix, measure and administer the product. This process demonstrates how a neonatal medication can be optimized for use through collaboration between the infectious disease expert community and a manufacturer.

Topics: Health Literacy; Health Personnel; HIV Infections; HIV Integrase Inhibitors; Humans; Infant, Newborn; Medication Errors; Patient-Centered Care; Raltegravir Potassium

HIV-2 resistance to integrase strand-transfer inhibitors (INSTIs) is characterized by two main pathways: (i) mutations at codons 143, 148 and155; and (ii) amino acid insertion after integrase codon 231 (231ins).. To complete INSTI resistance data on HIV-2 by determining the viral replicative capacity and INSTI phenotypic susceptibility of integrase mutants obtained through site-directed mutagenesis.. Site-directed mutants (SDMs) were constructed and viral stocks produced. Viral replicative capacity was assessed by measuring HIV-2 viral load at days 3, 7 and 14. In vitro phenotypic susceptibility was measured using the ANRS PBMC assay.. Viruses bearing 231ins did not present impaired replicative capacity, except the 231ins GIRGK mutant. A 231ins GK SDM was resistant to raltegravir and cabotegravir, but remained susceptible to dolutegravir and bictegravir. SDMs harbouring a 5 amino acid insertion (GYKGK or SREGK) were both resistant to all INSTIs. The SDM with T97A+N155H, with or without E92Q, was resistant to all INSTIs, except bictegravir.. These first data on the newly described resistance pathway 231ins, using site-directed mutagenesis, showed no measurable impact on viral fitness and confirmed the decreased susceptibility to a first-generation INSTI (raltegravir) and cabotegravir. Resistance to second-generation INSTIs (dolutegravir and bictegravir) occurred for mutants with a 5 amino acid 231ins.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; HIV-2; Humans; Leukocytes, Mononuclear; Pyridones; Raltegravir Potassium

We present a case report of a neonate receiving raltegravir-based postnatal HIV prophylaxis after in utero dolutegravir exposure. High levels of raltegravir and dolutegravir can potentially cause bilirubin toxicity as they compete for albumin binding and follow the same metabolic pathway through UGT1A1. This case suggests delaying initiation of raltegravir-based postnatal prophylaxis by 24-48 hours after in utero dolutegravir exposure.

Topics: Anti-HIV Agents; Antibiotic Prophylaxis; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Maternal Exposure; Oxazines; Piperazines; Pregnancy; Pregnancy Complications, Infectious; Pyridones; Raltegravir Potassium

Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy.. The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm.. Of 100 participants 91% maintained viral suppression (95% CI: 83.6-95.8) at week 24 and 89% (81.2-94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3-4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007).. RAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes.. Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.

Topics: Adult; HIV Infections; HIV Seropositivity; HIV-1; Humans; Quality of Life; Raltegravir Potassium; Treatment Outcome; Viral Load

Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA. However, there are only a few studies focused on virus-targeted cells. We aimed our study on the impact of RLT inclusion on total intra-cellular viral DNA (TID) in cellular subsets and immune effects in patients with newly acquired undetectable plasmatic viral load (UVL). Six patients having UVL using an antiretroviral combination for 6 months and CD4 T-cells > 350/mL and <500/mL were selected to receive RLT for 3 months from M0 to M3. Patients had 7 sequential viro-immunological determinations from M-1 to M5. Immune phenotypes were determined by flow cytometry and TID quantification was performed using PCR assay on purified cells. TID (median values) at the initiation of RLT in CD4 T-cells was 117 copies/millions of cells, decreased to 27.5 on M3, and remained thereafter permanently under the cut-off (<10 copies/millions of cells) in 4 out of 6 patients. This was associated with an increase of CD4 and CD4 + CD28+ T-cells and a decrease of HLA-DR expression and apoptosis of CD4 T-cells. RLT inclusion led to decreases in the viral load along with positive immune reconstitution, mainly for CD4 T-cells in HIV patients.

Topics: Adult; Aged; Apoptosis; CD28 Antigens; CD4-Positive T-Lymphocytes; Cell Proliferation; DNA, Viral; Female; HIV Infections; Humans; Kinetics; Lymphocyte Count; Male; Middle Aged; Monocytes; Phenotype; Raltegravir Potassium; Viral Load

Routine HIV drug resistance genotyping identified an integrase sequence harbouring T97A, E138K, G140S and Q148H, with high predicted resistance to all integrase strand transfer inhibitors (INSTIs).. To assess the impact of these substitutions alone and together on phenotypic INSTI susceptibility.. We constructed recombinant NL4.3 viruses harbouring all mutation combinations in the autologous integrase sequence. Viruses were grown in GFP-reporter CD4+ T-cells in the presence of 0.01-1000 nM raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. Infection was measured by imaging cytometry.. Q148H-containing viruses lacking G140S failed to propagate or mutated in vitro, consistent with fitness costs. Statistically significant reductions in INSTI susceptibility were observed for several mutation combinations, as follows. T97A or G140S alone conferred 3.6- to 5.6-fold decreased susceptibility to raltegravir and elvitegravir. Two-mutation combinations conferred low-to-moderate resistance to raltegravir and elvitegravir only, except G140S/Q148H which eliminated raltegravir and elvitegravir activity and conferred 24.6-, 7.9-, and 107.5-fold reduced susceptibility to dolutegravir, bictegravir and cabotegravir. Addition of E138K to G140S/Q148H conferred 35.5, 11.6 and 208-fold reduced susceptibility to dolutegravir, bictegravir, and cabotegravir, while addition of T97A to G140S/Q148H conferred 318, 121 and >1000-fold reduced susceptibility to these drugs. T97A/E138K/G140S/Q148H in the autologous backbone conferred >300-fold reduced susceptibility to all INSTIs. Notably, bictegravir EC50 was significantly lower when T97A/E138K/G140S/Q148H was introduced into NL4.3, suggesting that other mutations in the autologous sequence enhanced resistance.. High-level dolutegravir, bictegravir and cabotegravir resistance requires multiple integrase substitutions including compensatory mutations. T97A and E138K further enhance the resistance conferred by G140S/Q148H, yielding >300-fold decreased susceptibility to all INSTIs when all four mutations are present.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyridones; Raltegravir Potassium

Integrase inhibitors (INIs) are a key component of antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. Although INI resistance pathways are well-defined for HIV-1, mutations that emerge in HIV-2 in response to INIs are incompletely characterized.. We performed systematic searches of GenBank and HIV-2 drug resistance literature to identify treatment-associated mutations for phenotypic evaluation. We then constructed a library of 95 mutants of HIV-2ROD9 that contained single or multiple amino acid changes in the integrase protein. Each variant was tested for susceptibility to raltegravir and dolutegravir using a single-cycle indicator cell assay.. We observed extensive cross-resistance between raltegravir and dolutegravir in HIV-2ROD9. HIV-2-specific integrase mutations Q91R, E92A, A153G, and H157Q/S, which have not been previously characterized, significantly increased the half maximum effective concentration (EC50) for raltegravir when introduced into 1 or more mutational backgrounds; mutations E92A/Q, T97A, and G140A/S conferred similar enhancements of dolutegravir resistance. HIV-2ROD9 variants encoding G118R alone, or insertions of residues SREGK or SREGR at position 231, were resistant to both INIs.. Our analysis demonstrates the contributions of novel INI-associated mutations to raltegravir and dolutegravir resistance in HIV-2. These findings should help to improve algorithms for genotypic drug resistance testing in HIV-2-infected individuals.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; HIV-2; Humans; Mutation; Oxazines; Piperazines; Pyridones; Raltegravir Potassium

We aimed to investigate the incidence of low-level viremia (LLV) and its impact on virologic failure (VF) in people living with HIV (PLWH) on stable antiretroviral therapy (ART) who switched to co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (EVG/c/FTC/TAF).. PLWH aged 18 years or older who had received ART with plasma HIV RNA load (PVL) <50 copies/mL for 6 months or longer and switched to EVG/c/FTC/TAF between March and October 2018 were retrospectively included. The incidence of LLV (defined as PVL of 50-999 copies/mL) and VF (PVL ≥1000 copies/mL) was calculated and represented by Kaplan-Meier plots. The generalised estimating equation model was constructed to identify factors associated with LLV and VF. Resistance-associated mutations were determined using population sequencing.. A total of 1078 PLWH were included. The incidence rates of LLV and VF after the switch to EVG/c/FTC/TAF were 3.5 and 0.8 events per 100 person-years of follow-up, respectively, whereas the respective cumulative incidence of LLV and VF reached 11.7% and 2.9% within 3 years of follow-up. LLV was associated with any LLV episode before or after the switch and prior exposure to integrase strand transfer inhibitor-based ART. VF was associated with any LLV before or after the switch and prior exposure to raltegravir, but not the level or frequency of LLV.. The risks of LLV and VF were low in PLWH who had achieved virologic suppression and switched to EVG/c/FTC/TAF, and the presence of LLV and prior exposure to raltegravir increased the risk of VF.

Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; HIV-1; Humans; Incidence; Quinolones; Raltegravir Potassium; Retrospective Studies; Viremia

Integrase strand transfer inhibitors (INSTIs) are currently the standard of practice for first-line HIV therapy for most patients. We evaluated the mutations associated with INSTI resistance in naive HIV-1 infected patients and treated them with antiretrovirals (ART).. The study, conducted in the 2018 - 2020 period, included 50 ART-naïve patients, 69 INSTI free ART-experienced patients, and 82 INSTI-experienced patients. INSTI resistance mutations were interpreted using the Stanford University HIVdb Program algorithm.. INSTI resistance was not detected in ART naïve patients. At least one INSTI resistance mutation was detected in 10% of the INSTI-free patients and 29% of the INSTI-treated patients. Major INSTI-mutations E138K, Y143R, S147G, Q148R, N155H, and E157Q were found in raltegravir. Additional mutations, E92Q, E138K, G140A, S147G, and Q148R were found in elvitegravir; E192Q, E138K/T, G140A/S, S147G, Q148H/R, N155H, E157Q were found in dolutegravir (DTG) experienced patients. According to all drug classes, drug resistance mutation prevalences were determined at the rate of 60%, 46%, and 46% in the RAL, EVG, and DTG groups, respectively.. Our findings provide data for treatment and resistance management of INSTIs and may provide feedback for INSTIs resistance surveillance consensus-building efforts. In viral rebound under INSTI treatment, INSTI-resistant mutations follow typical INSTI resistance pathways and high resistance rates. INSTI resistance genotypic analysis should be considered before any DTG-based regimes can be initiated in the future, and reduced DTG susceptibility should be carefully monitored and investigated.

Topics: Anti-Retroviral Agents; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV Seropositivity; HIV-1; Humans; Integrases; Mutation; Raltegravir Potassium

Although raltegravir has been available since 2007, data are lacking on the Portuguese population living with HIV who initiated this antiretroviral therapy. Hence, this study aimed to characterize the patients who initiated raltegravir-based regimens between January 2015 and December 2017, on sociodemographics, clinical features, and treatment satisfaction.. Observational, retrospective, multicentre study conducted at 11 reference sites. Sociodemographic and clinical data were collected retrospectively from hospital medical records. For participants continuing raltegravir at study inclusion, the HIV Treatment Satisfaction Questionnaire was administered to assess satisfaction with raltegravir-based therapy. Descriptive statistics were performed. Treatment-naïve and treatment-experienced subgroups were compared for demographic and clinical variables.. A total of 302 patients were included; mostly men (69.5%) with a mean age of 49 years old. Approximately half of the patients had at least one non-AIDS-related comorbidity at baseline (53.3%), such as hypercholesterolemia, arterial hypertension, diabetes mellitus, and depression. Moreover, 52.3% were treatment-experienced patients with up to two treatments prior to raltegravir. Across the study time points, there was a reduction in the viral load and improvement in CD4 counts in both the treatment-naïve and treatment-experienced subgroups. Continuing users of raltegravir reported high treatment satisfaction (55.4 ± 7.2 points).. Raltegravir-based regimens seem like a valid therapeutic option in heterogeneous populations of HIV-infected patients, in patients with previous ART experience and as part of first-line therapeutic options alongside with the latest generation of drugs from its class.. Introdução: Apesar de o raltegravir estar disponível desde 2007, os dados na população portuguesa com VIH que iniciou esta terapêutica antirretroviral são escassos. Deste modo, este estudo teve por objetivo caracterizar os doentes que iniciaram um regime terapêutico baseado em raltegravir entre janeiro de 2015 e dezembro de 2017, relativamente a dados sociodemográficos, características clínicas e satisfação com o tratamento. Material e Métodos: Estudo observacional, retrospetivo, multicêntrico conduzido em 11 centros de referência. Os dados sociodemográficos e clínicos foram recolhidos retrospetivamente nos processos clínicos. Os participantes que continuaram o regime com raltegravir após a inclusão no estudo preencheram o HIV Treatment Satisfaction Questionnaire para avaliar a satisfação com a terapêutica. Foram efetuadas análises de estatística descritiva e comparações para as variáveis sociodemográficas e clínicas nos subgrupos de doentes naïve de tratamento e de doentes com experiência terapêutica. Resultados: Foram incluídos 302 doentes, maioritariamente do sexo masculino (69,5%) com idade média de 49 anos. Aproximadamente metade dos doentes tinha pelo menos uma comorbilidade não relacionada com SIDA no início do estudo (53,3%), tais como hipercolesterolemia, hipertensão arterial, diabetes mellitus ou depressão. Adicionalmente, 52,3% eram doentes com experiência terapêutica com até dois tratamentos anteriores ao raltegravir. Ao longo do estudo verificou-se uma redução na carga viral e uma melhoria nas contagens de CD4 em ambos os subgrupos de doentes (doentes naïve de tratamento e doentes com experiência terapêutica). Os doentes com uso continuado de raltegravir reportaram uma elevada satisfação com o tratamento (55,4 ± 7,2 pontos). Conclusão: Os regimes terapêuticos baseados em raltegravir parecem ser uma opção terapêutica válida em populações heterogéneas de doentes infetados com VIH, em doentes com experiência em ART e como tratamento de primeira linha, em paralelo com outras terapêuticas de última geração.

Topics: Female; HIV Infections; Humans; Male; Middle Aged; Portugal; Raltegravir Potassium; Retrospective Studies; Viral Load

There are limited data comparing the efficacy and safety of raltegravir and dolutegravir to that of efavirenz in HIV-1/tuberculosis (TB) coinfected patients.. We conducted a 10-year retrospective study in 4 centers in France. We included all HIV-1/tuberculosis coinfected patients starting antiretroviral therapy with a rifampicin-based regimen, with a plasma HIV RNA level (VL) > 1000 copies/mL. The primary endpoint was the proportion of patients with virological success that is, with VL <50 copies/mL at W48 using an Intention-To-Treat analysis, using last-observation-carried-forward to impute missing data. We also assessed antiretroviral therapy safety, analyzing treatment discontinuation for adverse events.. Between 2010 and 2020, 117 patients were included. Thirty-nine (33.3%) were treated with raltegravir and 2 nucleoside reverse transcriptase inhibitors (NRTIs), 19 (16.2%) with dolutegravir (and 2 NRTIs) and 59 (50.4%) with efavirenz (and 2 NRTIs). At W48, the primary endpoint was achieved in 24 patients (61.5%) in the raltegravir group, in 12 (63.2%) in the dolutegravir group, and in 41 (69.5%) in the efavirenz group using an Intention-To-Treat analysis ( P = 0.68). Emergence of drug resistance in patients with virological failure, defined as a VL >50 copies/mL, was observed in 3 patients with efavirenz and one patient with raltegravir. Rate of treatment discontinuation for drug-related adverse events was 10.3%, 10.6%, 16.9% for raltegravir, dolutegravir and efavirenz respectively ( P = 0.67).. In this retrospective cohort study, raltegravir and dolutegravir yielded similar efficacy and safety results to efavirenz for the treatment of HIV-1/TB coinfected patients.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Coinfection; Cyclopropanes; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Tuberculosis; Viral Load

Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018.. This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data.. 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs.. This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality.. US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Darunavir; Europe; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; North America; Raltegravir Potassium; Rilpivirine

In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration.. Integrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+ G140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200 bp fragment spanning amino acids 85-150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay.. At least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105-106 pg/mL) for WT and NL4-3-Q148H; by contrast, it was low (102-104 pg/mL) for both F1(BF)-Q148H + G140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (P = 0.05), 9-fold for URTR23-Q148H (P = 0.01) and 16000-fold for ARMA159-Q148H (P = 0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants.. The functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.

Topics: Amino Acids; Catalytic Domain; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium

Although integrase inhibitor (INI)-based regimens are now the first-line choice for all people living with HIV, experience among children and adolescents is still scarce. We describe the characteristics and outcomes of a paediatric/adolescent cohort on INI-based ART.. Retrospective analysis of HIV-infected patients below 18 years of age who started an INI-based regimen from 2007 to 2019, enrolled in the Spanish National Adult (CoRIS) and Paediatric (CoRISpe) cohorts. Resistance mutations were identified by the Stanford HIV Drug Resistance Database.. Overall, 318 INI-based regimens were implemented in 288 patients [53.8% female; median age at start of 14.3 years (IQR 12.0-16.3)]. Most were born in Spain (69.1%), vertically infected (87.7%) and treatment-experienced (92.7%). The most frequently prescribed INI was dolutegravir (134; 42.1%), followed by raltegravir (110; 34.6%) and elvitegravir (73; 23.0%). The median exposure was 2.0 years (IQR 1.1-3.0). The main reasons to start an INI-based therapy were treatment simplification (54.4%) and virological failure (34.3%). In total, 103 (32.4%) patients interrupted their regimen: 14.5% for simplification and 8.5% due to virological failure. Most subjects who received dolutegravir (85.8%) and elvitegravir (83.6%) did not interrupt their regimen and maintained undetectable viral load. There were only five virological failures with dolutegravir and three with elvitegravir. There were no interruptions related to adverse events. Seven patients with virological failure presented major resistance mutations to INIs; none of them were on dolutegravir.. INI-based regimens were effective and safe for HIV treatment in children and adolescents. Dolutegravir and elvitegravir presented an excellent profile, and most patients achieved and maintained viral suppression.

Topics: Adolescent; Adult; Anti-HIV Agents; Child; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Oxazines; Pyridones; Raltegravir Potassium; Retrospective Studies

This study was aimed at assessing the adherence and incorrect drug intake associated with changes in the dosing schedule of raltegravir, the first integrase strand transfer inhibitor, from 400 mg twice a day (BID) to 600 mg × 2 tablets once a day (QD) in human immunodeficiency virus (HIV)-infected patients. Medication adherence over 1 month was evaluated in 25 male patients using the 100-mm visual analog scale (VAS) at the 3-day recall pill count and during pharmacist counseling after the first post-change visit. VAS scores before and after the raltegravir formulation change were compared. Medication adherence increased from 96 ± 4.3 mm (BID) to 100 ± 0.3 mm (QD) (P < 0.05). The patients exhibited improved medication adherence; however, three patients incorrectly took the drug when the formulation changed. This discovery can be used to facilitate the treatment of HIV-infected patients to increase treatment suitability and safety.

Topics: Drug Administration Schedule; HIV Infections; Humans; Integrases; Male; Medication Adherence; Medication Errors; Raltegravir Potassium; Tablets

Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited.. We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results.. Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar.. Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Cohort Studies; Darunavir; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant, Newborn; Oxazines; Piperazines; Pregnancy; Premature Birth; Pyridones; Quinolones; Raltegravir Potassium; Rilpivirine; Ritonavir; United States

In 2020, Zimbabwe adopted the WHO's recommendation to use raltegravir (RAL) granule-based regimens for treatment of neonates identified with HIV at the time of birth testing. This study explores the acceptability of RAL granules by caregivers and healthcare workers (HCWs).. Interviews were conducted with 15 caregivers and 12 HCWs from 8 health facilities in Zimbabwe participating in the introductory pilot of RAL granules treatment for newborns. Eligible caregivers included those who had administered RAL to their infant and attended either 8th or 28th day of life appointments. Caregivers of neonates recently initiated on RAL were selected through convenience sampling. Eligible HCWs who provided RAL preparation, administration instructions and support to caregivers of neonates on RAL for at least 3 months were recruited from the same facilities as the caregivers. Interview transcripts were coded and thematically analysed.. Caregivers reported that their babies looked healthier after RAL initiation, with improved skin appearance and weight gain. Some caregivers wanted their child to remain on RAL beyond 28 days instead of switching regimens, as recommended by national guidelines. HCWs observed that RAL granules improved health outcomes compared with other regimens. HCWs reported challenges with caregivers understanding dosing instructions, measuring with a syringe, swirling and not shaking the medicine, discarding unused medication and following the changes in the dosing schedule and amount when RAL was initiated a few days after birth. HCWs stated that adequate counselling and repeat demonstrations were crucial to ensure that caregivers clearly understood RAL dosing and administration instructions. HCWs requested more standardised training targeting nurses with guidance on handling missed doses and clarification on mixing RAL granules with water and not breastmilk.. While feedback from caregivers and HCWs on RAL implementation was positive, barriers were also noted. Adequate training and sufficient instruction and support for caregivers would help to ensure that RAL granules are prepared, dosed and administered correctly.

Topics: Caregivers; Counseling; Health Personnel; HIV Infections; Humans; Infant; Infant, Newborn; Raltegravir Potassium

We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained subtherapeutic and viral load increased during concurrent rifampicin therapy despite using double-dosed raltegravir. Even after rifampicin therapy, a higher dose was needed. This highlights the importance of therapeutic drug monitoring and dose adjustments of raltegravir in infants with rifampicin as comedication.

Topics: Anti-HIV Agents; HIV Infections; Humans; Infant; Raltegravir Potassium; Rifampin; Viral Load

Each year, approximately 1.1 million children are exposed in utero to human immunodeficiency virus antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase strand transfer inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental.. The effects of InSTIs on 2 human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. In addition, fetal resorptions after exposure to InSTIs from conception were analyzed in pregnant mice.. At subtherapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts and pluripotency and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. It is notable that first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested.. Exposure to some InSTIs, even at subtherapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety after in utero exposure.

Topics: Animals; Drug Resistance, Viral; Female; Fetal Resorption; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; Human Embryonic Stem Cells; Humans; Infant, Newborn; Maternal Exposure; Mice; Pregnancy; Pyridones; Raltegravir Potassium

Previous clinical data have shown that raltegravir-based antiretroviral therapy (ART) with fewer drug-drug interactions (DDIs) and adverse events (AEs) is a good regimen in patients with HIV infection who need cancer chemotherapy. There are currently few data on ART regimens that include Integrase inhibitors (INSTIs) other than RAL among this patient subgroup.. We evaluated the safety and efficacy of different kinds of INSTI-based regimens among patients with HIV and concomitant colorectal cancer (CRC) who received antineoplastic agents.. From January 2020 to November 2021, 66 patients were enrolled. The patients were divided into three groups: 20 patients treated with dolutegravir (DTG)/lamivudine (3TC)/tenofovir (TDF) (group I), 24 patients treated with DTG/albuvirtide (ABT) (group II), and 22 patients treated with bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (group III). The majority of AEs during treatment were of grade 1-2. Treatment-related AEs of grade 3-4 occurred in 6 patients (9.09%), and no grade 5 AEs occurred. The most common AEs were nausea (100%) and neutrophils (84.85%) attributed to anticancer agents, and there was no significant difference in the incidence of these AEs among the three groups (P > 0.05). Viral load rebound was not observed among pretreated patients during chemotherapy. The viral load of untreated patients who started their ART concomitant with chemotherapy almost decreased to the lower limit of detection 6 months after ART initiation (only one patient in group III had a viral load of 102 copies/ml). At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05). However, the change in CD4 count was not significant in group II (P = 0.457) or group III (P = 0.748).. DTG- or BIC-containing regimens are good options for patients with HIV and concomitant CRC.

Topics: Amides; Anti-HIV Agents; Colorectal Neoplasms; Emtricitabine; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Integrase Inhibitors; Lamivudine; Piperazines; Pyridones; Raltegravir Potassium; Tenofovir

In 2018, Switzerland changed its guidelines to support women living with HIV wishing to breastfeed. The exposure of antiretroviral drugs (ARVs) in breastmilk and the ingested daily dose by the breastfed infant are understudied, notably for newer ARVs. This study aimed to quantify ARV concentrations in maternal plasma and breastmilk to determine the milk/plasma ratio, to estimate daily infant ARV dose from breastfeeding and to measure ARV concentrations in infants.. All women wishing to breastfeed were included, regardless of their ARV treatment. Breastmilk and maternal plasma samples were mostly collected at mid-dosing interval.. Twenty-one mother/child pairs were enrolled; of those several were on newer ARVs including 10 raltegravir, 1 bictegravir, 2 rilpivirine, 2 darunavir/ritonavir and 3 tenofovir alafenamide. No vertical HIV transmission was detected (one infant still breastfed). The median milk/plasma ratios were 0.96/0.39 for raltegravir once/twice daily, 0.01 for bictegravir, 1.08 for rilpivirine, 0.12 for darunavir/ritonavir and 4.09 for tenofovir alafenamide. The median estimated infant daily dose (mg/kg) from breastfeeding was 0.02/0.25 for raltegravir once/twice daily, 0.01 for bictegravir, 0.02 for rilpivirine, 0.05 for darunavir/ritonavir and 0.007 for tenofovir alafenamide, resulting in relative infant dose <10% exposure index for all ARVs.. ARVs were transferred to a variable extent in breastmilk. Nevertheless, the estimated daily ARV dose from breastfeeding remained low. Differential ARV exposure was observed in breastfed infants with some ARVs being below/above their effective concentrations raising the concern of resistance development if HIV infection occurs. More data on this potential risk are warranted to better support breastfeeding.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Cohort Studies; Darunavir; Female; HIV Infections; Humans; Infant; Milk, Human; Mothers; Prospective Studies; Raltegravir Potassium; Rilpivirine; Ritonavir; Switzerland

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.

Topics: Anti-HIV Agents; beta-Lactams; Drug Resistance, Viral; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; HIV-1; HIV-2; Humans; Raltegravir Potassium

Integrase inhibitors appear to increase body weight, but paradoxically some data indicate that raltegravir (RAL) may decrease liver fat. Our objective was to study the effects of switching from a protease inhibitor (PI) or efavirenz (EFV) to RAL on liver fat, body composition, and metabolic parameters among people living with HIV (PLWH) with high risk for nonalcoholic fatty liver disease (NAFLD). We randomized overweight PLWH with signs of metabolic syndrome to switch a PI or EFV to RAL (

Topics: Adipose Tissue; Alkynes; Benzoxazines; Body Composition; Cyclopropanes; HIV Infections; Humans; Liver; Protease Inhibitors; Raltegravir Potassium

To investigate the durability of the first integrase inhibitor-based regimen in a HIV geriatric multicentric prospective cohort and to explore the reasons of regimen discontinuation.. This is an analysis conducted on the Geriatric Patients Living with HIV/AIDS (GEPPO) cohort, an Italian prospective observational multicentre cohort of people living with HIV with 65 years of age or more.. The analysis was performed using R (version 4.0.2). The tests performed were two sided assuming a 5% significance level (Kruskal-Wallis test, Chi-squared test, log-rank test and a Cox Proportional Hazard model). The proportion of participants discontinuing the three regimens was displayed using cumulative curves.. Among 1531 patients enrolled between 2017 and 2019 in the GEPPO cohort, we included 822 participants in this analysis. At baseline, median age was 69.8, the immunovirological profile good, multimorbidity was present in 42.3% of participants, while 27.4% were on polypharmacy. Overall, 483, 243 and 96 participants received DTG, RAL and EVG/c respectively as first InSTI. At the end of the follow up 6.4%, 21.1% and 22.9% participants discontinued DTG, RAL and EVG/c respectively. Using a log-rank test, EVG showed a significantly lower durability than DTG (p<0.001) or RAL (p 0.05) or both, DTG and RAL (p<0.001). Among participants who discontinued their regimen we found 0 virological failure and 56.7% simplification/deprescription.. The three integrase inhibitors considered showed a good durability and no virological failures in geriatric patients such as those enrolled in the GEPPO cohort when used in a two or three drug regimen.

Topics: Aged; Amides; Anti-Retroviral Agents; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Longitudinal Studies; Male; Medication Adherence; Oxazines; Piperazines; Polypharmacy; Proportional Hazards Models; Prospective Studies; Pyridones; Quinolones; Raltegravir Potassium; Treatment Outcome

As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a "start/switch" to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P's < 0.05). Switching to EVG improved symptoms of avoidance (P = 0.01). Starting RAL improved arousal subscale symptoms (P = 0.03); however, switching to RAL worsened re-experiencing subscale symptoms (P < 0.005). Starting DTG worsened avoidance subscale symptoms (P = 0.03), whereas switching to DTG did not change subscale or overall PTSD symptoms (P's > 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Stress Disorders, Post-Traumatic

HIV-1 integrase (IN) is a primary target for combination antiretroviral therapy. Only a limited number of studies report on the emergence of resistance-associated mutations (RAMs) in Cameroon. We observed that 1.4% of sequence from treatment-naive patients had IN strand transfer inhibitor (INSTI) RAMs. These mutations confer resistance to raltegravir and elvitegravir. We also observed that 10.1% of the sequences have INSTI accessory RAMs. HIV-1 CRF02_AG was the predominant subtype (44.7%) in this study analyses. The occurrence of INSTI RAMs among the sequences at baseline needs to be monitored carefully.

Topics: Cameroon; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Raltegravir Potassium

Regardless of adherence to combined antiretroviral therapy, white matter and myelin pathologies persist in patients with HIV-associated neurocognitive disorders, a spectrum of cognitive, motor, and behavioral impairments. We hypothesized that antiretroviral therapy alters the maturation of oligodendrocytes which synthesize myelin. We tested whether specific frontline integrase strand transfer inhibitors would alter oligodendrocyte differentiation and myelination. To model the effect of antiretrovirals on oligodendrocytes, we stimulated primary rat oligodendrocyte precursor cells to differentiate into mature oligodendrocytes in vitro in the presence of therapeutically relevant concentrations of elvitegravir or raltegravir and then assessed differentiation with lineage specific markers. To examine the effect of antiretrovirals on myelination, we treated mice with the demyelinating compound cuprizone, for 5 weeks. This was followed by 3 weeks of recovery in absence of cuprizone, during which time some mice received a daily intrajugular injection of elvitegravir. Brains were harvested, sectioned and processed by immunohistochemistry to examine oligodendrocyte maturation and myelination. Elvitegravir inhibited oligodendrocyte differentiation in vitro in a concentration-dependent manner, while raltegravir had no effect. Following cuprizone demyelination, administration of elvitegravir to adult mice reduced remyelination compared with control animals. Elvitegravir treatment activated the integrated stress response in oligodendrocytes in vitro, an effect which was completely blocked by pretreatment with the integrated stress response inhibitor Trans-ISRIB, preventing elvitegravir-mediated inhibition of oligodendrocyte maturation. These studies demonstrate that elvitegravir impairs oligodendrocyte maturation and remyelination and that the integrated stress response mediates this effect and may be a possible therapeutic target.

Topics: Animals; Cell Differentiation; Cuprizone; HIV Infections; Humans; Integrases; Mice; Mice, Inbred C57BL; Myelin Sheath; Oligodendroglia; Quinolones; Raltegravir Potassium; Rats

Nucleoside reverse transcriptase inhibitor (NRTI) transmitted drug resistance mutations (TDRMs) could increase the risk of virological failure (VF) of first-line integrase strand transfer inhibitor (InSTI)-based regimens.. Patients starting two NRTIs (lamivudine/emtricitabine plus abacavir/tenofovir) plus raltegravir or dolutegravir were selected from the EuResist cohort. The role of NRTI genotypic susceptibility score and of specific TDRMs in VF (i.e. two consecutive viral loads > 50 HIV-1 RNA copies/mL or a single viral load ≥ 200 copies/mL after 3 months from antiretroviral therapy start) was evaluated in the overall population and according to the InSTI employed.. From 2008 to 2017, 1095 patients were eligible for the analysis (55.5% men, median age 39 years). In all, 207 VFs occurred over 1023 patient-years of follow-up. The genotypic susceptibility score (GSS) had no effect on the risk of VF in the overall population. However, the presence of M184V/I independently predicted VF of raltegravir- but not dolutegravir-based therapy when compared with a fully-active backbone [adjusted hazard ratio (aHR) = 3.09, P = 0.035], particularly when associated with other non-thymidine analogue mutations (aHR = 27.62, P = 0.004). Higher-zenith HIV-RNA and lower nadir CD4 counts independently predicted VF.. NRTI backbone TDRMs increased the risk of VF with raltegravir-based but not dolutegravir-based regimens.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Female; HIV Infections; Humans; Integrase Inhibitors; Male; Raltegravir Potassium; Viral Load

Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or other adverse pregnancy outcomes.. In the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery.. Among 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment,  P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir.. We found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV.

Topics: Abnormalities, Drug-Induced; Congenital Abnormalities; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Infant, Newborn; Integrases; Oxazines; Piperazines; Pregnancy; Premature Birth; Prospective Studies; Pyridones; Raltegravir Potassium

Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; Humans; Post-Exposure Prophylaxis; Pre-Exposure Prophylaxis; Raltegravir Potassium; Tenofovir

There are generic fixed-dose combinations (FDCs) of ritonavir-boosted darunavir (DRV/r) available in Argentina. Experiences with these FDCs in dual therapy remain limited in clinical practice. We aimed to describe clinical and virologic outcomes in patients exposed to FDC DRV/r + raltegravir (RAL) 400 mg every 12 h in a real-life setting.. Retrospective analysis of electronic medical records of HIV-infected patients under FDC DRV/r + RAL in an HIV clinic in Argentina (2014-2018). Individuals were classified as "switch group" (SG, undetectable viral load [VL] with any toxicity/comorbidity) and "virologic group· (VG, detectable viremia and infection by multidrug-resistant HIV).. Of 7,380 patients on ART, 116 (1.5%) received FDC DRV/r + RAL, being 58% in SG. Sixty percent received DRV/r 800/100 mg dose (rest, 600/100 mg). The median (IQR) age and CD4+ T-cell count were: 52 (42-58) years, and 373 cell/µL (202-642). Ninety-eight percent were ART-experienced with a median of 3 (IQR 2-5) prior treatments. Main reasons for switch (SG) were renal (57%), cardiovascular (54%) and bone (14%) comorbidities. Median exposure to DRV/r + RAL was 18 months. Among patients in SG, 98% and 96% had undetectable VL at 6 and 12 months; in the VG, 89% and 87% had undetectable VL at 6 and 12 months. No patient required suspension due to toxicity/ intolerance.. In this cohort of mostly experienced HIV-infected patients, FDC DRV/r + RAL was effective and safe. Such therapy may be considered an option for patients with comorbid conditions and/or with multidrug-resistant HIV.

Topics: Anti-HIV Agents; Argentina; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Raltegravir Potassium; Retrospective Studies; Ritonavir; Viral Load

Topics: Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin; Lamivudine; Menopause; Nitriles; Oxazines; Piperazines; Pyridones; Pyrimidines; Raltegravir Potassium; Waist Circumference; Weight Gain

Integrase strand transfer inhibitors (INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive symptoms in women with HIV (WWH).. Women's Interagency HIV Study, a multisite, prospective, cohort study.. WWH who started or switched to INSTI-based antiretroviral therapy (ART) and completed neuropsychological testing and the Center for Epidemiological Studies-Depression (CES-D) scale before and after INSTI start/switch were included in the analyses. Primary outcomes were demographically corrected cognitive domain T-scores. Linear mixed-effects models adjusted for relevant covariates were used to examine effects of start/switch of any INSTI and individual INSTI drugs on cognition and CES-D scores.. Six hundred thirty-nine WWH, median age 49 (interquartile range 12) years, 66% Black non-Hispanic, had neuropsychological and CES-D scale data before and after INSTI start/switch. Although 14% started INSTI-based ART, the remainder switched to INSTI-based ART from another regimen. Overall, any INSTI use was associated with poorer learning post-INSTI. Specifically, use of dolutegravir and elvitegravir, but not raltegravir, was associated with poorer learning. In analyses restricted to INSTI switch, any INSTI use, and dolutegravir use, was associated with poorer learning. Among those switching from a PI-based regimen, INSTIs overall and dolutegravir remained associated with poorer learning; switching from a nonnucleoside reverse transcriptase inhibitor to dolutegravir was also associated with poorer learning. INSTI start/switch was not related to depressive symptom changes.. INSTI use was associated with poorer learning among WWH. These changes were mainly observed in elvitegravir and dolutegravir users, indicating that the impact of INSTI on cognition in WWH may not be a class effect.

Topics: Adult; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Integrases; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Quinolones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; United States

Moderate-to-severe hepatic steatosis in people living with human immunodeficiency virus (HIV) without viral hepatitis or excessive alcohol intake was associated with cumulative exposure to stavudine, elvitegravir, and raltegravir. Prospective trials are required to establish a causal association. Clinical Trials Registration. NCT02382822.

Topics: HIV Infections; Humans; Prospective Studies; Quinolones; Raltegravir Potassium

Topics: Adipose Tissue; Anti-HIV Agents; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Raltegravir Potassium

Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies.. Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay.. All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro.. This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Cell Death; Cell Line; Drug Compounding; Drug Liberation; Drug Synergism; Female; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Lectins; Nanoparticles; Particle Size; Plant Lectins; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrimidines; Raltegravir Potassium; Recombinant Proteins; Tenofovir

Topics: Alkynes; Benzoxazines; Coinfection; Cyclopropanes; HIV Infections; Humans; Raltegravir Potassium; Tuberculosis

To evaluate the effect on anthropometric, metabolic and adipose tissue parameters of switching ART-controlled persons living with HIV (PLWH) from a protease inhibitor regimen to raltegravir/maraviroc.. Sub-study of the ANRS157 ROCnRAL study with the investigation of subcutaneous abdominal adipose tissue (SCAT) biopsy at inclusion and study end.. We performed lipoaspiration of paired SCAT samples, histology on fresh/fixed samples and examined the transcriptomic profile analyzed using Illumina microarrays after RNA extraction. Statistical analyses used the Wilcoxon-paired test.. The patients (n = 8) were mainly male (7/8), aged (mean ± standard error of the mean) 54.9 ± 1.2 years, BMI 26.1 ± 1.2 kg/m2, CD4+ 699 ± 56 cells/mm3, all viral load (VL) <50 copies/ml. After a follow-up of 6 ± 0.5 months, all PLWH remained with VL <50 copies/ml. BMI, trunk and limb fat amounts were unchanged yet systemic insulin resistance increased. Adipose tissue histology was unchanged except for borderline increased adipocyte diameter (P = 0.1). Among the 16 094 RNA transcripts, 458 genes were up-regulated and 244 were down-regulated. Analyses of the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases, evaluating modifications in the main functional pathways, revealed that genes related to immune recognition/function were less expressed as were genes encoding T-cell receptor and receptor signaling pathways. The gene expression profiles indicated decreased inflammation but genes involved in adipogenesis and insulin resistance were overexpressed.. After 6 months of raltegravir/maraviroc, adipogenesis-related gene profile was enhanced in SCAT, in agreement with a tendency for increased adipocyte size. Enhanced SCAT insulin resistance-related profile was concordant with higher systemic insulin resistance. However, the immune activation/inflammation profile was globally lowered. We propose that raltegravir/maraviroc might favor SCAT gain but reduce inflammation/immune activation.

Topics: Adipose Tissue; Anti-HIV Agents; HIV Infections; Humans; Male; Maraviroc; Raltegravir Potassium; Subcutaneous Fat

Successful 2-drug regimens (2DRs) for HIV were made possible by the availability of drugs combining potency and tolerability with a high genetic barrier to resistance. How these deal with resistance development/re-emergence, compared with 3DRs, is thus of paramount importance.. A national survey including patients who were either naive or experienced with any 2DR or 3DR but failing integrase strand transfer inhibitor (INSTI)-containing regimens [two consecutive plasma viral load (VL) values >50 copies/mL] was conducted between 2014 and 2019. Genotypic resistance tests were interpreted with the v28 ANRS algorithm.. Overall, 1104 patients failing any INSTI-containing regimen (2DRs, n = 207; 3DRs, n = 897) were analysed. Five hundred and seventy-seven (52.3%) patients were infected with a B subtype and 527 (47.3%) with non-B subtypes. Overall, 644 (58%) patients showed no known integrase resistance mutations at failure. In multivariate analysis, factors associated with the emergence of at least one integrase mutation were: high VL at failure (OR = 1.24 per 1 log10 copies/mL increase); non-B versus B subtype (OR = 1.75); low genotypic sensitivity score (GSS) (OR = 0.10 for GSS = 2 versus GSS = 0-0.5); and dolutegravir versus raltegravir (OR = 0.46). Although 3DRs versus 2DRs reached statistical significance in univariate analysis (OR = 0.59, P = 0.007), the variable is not retained in the final model.. This study is one of the largest studies characterizing integrase resistance in patients failing any INSTI-containing 2DR or 3DR in routine clinical care and reveals factors associated with emergence of integrase resistance that should be taken into consideration in clinical management. No difference was evidenced between patients receiving a 2DR or a 3DR.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyridones; Raltegravir Potassium

Integrase strand-transfer inhibitors (INSTI) are the latest class of antiretrovirals registered in Mexico. They include raltegravir (RAL), elvitegravir/cobicistat (EVG/c), dolutegravir (DTG) and bictegravir (BIC). Along with international guidelines, Mexico adopted the use of INSTI about two years ago as initial antiretroviral therapy (ART). This is partially due to the increase in the pre-treatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI), mainly efavirenz (EFV). Furthermore, INSTI depict greater efficacy, safety and less drug-drug interactions than NNRTI and protease inhibitors (PI). DTG is a second generation INSTI with a high barrier to resistance. It is recommended in international and national guidelines in a wide variety of clinical scenarios for persons living with human immunodeficiency virus (HIV) (PLWHIV), including treatment-naïve, first-line NNRTI treatment failure, simplification switch in suppressed patients, pregnancy, women with childbearing potential, adolescents and children over 6 years of age. DTG is mostly metabolized by the liver UDP-glucuronosyltransferase, and exhibits low drug-drug interactions overall; on the other hand, it has an extremely low renal elimination, therefore may be used in PLWHIV with advanced kidney disease without dose modification. Tuberculosis is a common coinfection in Mexico that requires rifampin-based anti-tuberculosis therapy, which requires increasing DTG to double dosing (50 mg BID). In Mexico, DTG-based regimens are likely to be cost-effective in many scenarios, given its acquisition costs and the particularities of the HIV population and associated clinical conditions, including a relatively high proportion of the following: i) new HIV diagnoses presenting at acquired immunodeficiency syndrome (AIDS) stage; ii) high rate of tuberculosis coinfection; iii) frequent first-line NNRTI treatment failures; and iv) relatively high proportion of infected children and adolescents.

Topics: Adolescent; Costs and Cost Analysis; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mexico; Oxazines; Piperazines; Pyridones; Raltegravir Potassium

INSTIs have become a pillar of first-line ART. Real-world data are needed to assess their effectiveness in routine care.. We analysed ART-naive patients who started INSTI-based regimens in 2012-19 whose data were collected by INTEGRATE, a European collaborative study including seven national cohorts.. Kaplan-Meier analyses assessed time to virological failure (VF), defined as one viral load (VL) ≥1000 copies/mL, two consecutive VLs ≥50 copies/mL, or one VL ≥50 copies/mL followed by treatment change after ≥24 weeks of follow-up, and time to INSTIs discontinuation (INSTI-DC) for any reason. Factors associated with VF and INSTI-DC were explored by logistic regression analysis.. Of 2976 regimens started, 1901 (63.9%) contained dolutegravir, 631 (21.2%) elvitegravir and 444 (14.9%) raltegravir. The 1 year estimated probabilities of VF and INSTI-DC were 5.6% (95% CI 4.5-6.7) and 16.2% (95% CI 14.9-17.6), respectively, and were higher for raltegravir versus both elvitegravir and dolutegravir. A baseline VL ≥100 000 copies/mL [adjusted HR (aHR) 2.17, 95% CI 1.55-3.04, P < 0.001] increased the risk of VF, while a pre-treatment CD4 count ≥200 cells/mm3 reduced the risk (aHR 0.52, 95% CI 0.37-0.74, P < 0.001). Predictors of INSTI-DC included use of raltegravir versus dolutegravir (aHR 3.03, 95% CI 2.34-3.92, P < 0.001), use of >3 drugs versus 3 drugs (aHR 2.73, 95% CI 1.55-4.79, P < 0.001) and starting ART following availability of dolutegravir (aHR 0.64, 95% CI 0.48-0.83, P = 0.001). Major INSTI mutations indicative of transmitted drug resistance occurred in 2/1114 (0.2%) individuals.. This large multi-cohort study indicates high effectiveness of elvitegravir- or dolutegravir-based first-line ART in routine practice across Europe.

Topics: Cohort Studies; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Integrases; Oxazines; Pyridones; Raltegravir Potassium

We explored associations of inflammatory and immune activation biomarkers at baseline and percentage gain in peripheral and trunk fat and lean mass over 96 weeks in patients with confirmed virological failure initiating lopinavir-anchored second-line antiretroviral therapy (ART) regimens.. We measured baseline plasma concentration of interleukin (IL)-6, tumour necrosis factor (TNF), neopterin, IL-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, soluble cluster of differentiation 14 (sCD14), and soluble CD163 in 123 participants of the SECOND-LINE body composition substudy. Linear regression assessed the association between biomarkers and percentage gain in limb/trunk fat and lean mass, adjusting for age, nucleoside or nucleotide reverse transcriptase inhibitor (N(t)RTI) use, body mass index, ethnicity, smoking, viral load, CD4+ T-cell counts, smoking, duration of ART use, and cholesterol.. Mean (standard deviation) age was 38 (7.3) years, CD4+ T-cell count was 252 (185.9) cells/μl, human immunodeficiency virus viral load was 4.2 (0.9) log10 copies/ml, 47% (58/123) were in the N(t)RTI arm (vs. raltegravir [RAL] arm in 53%); 56.1% (69/123) were females. In adjusted analyses, for every log10 increase in baseline levels of IL-6, neopterin, and D-dimer, the percentage gain in peripheral fat over 96 weeks was 11.8% (95% confidence interval [CI]: 0.9-22.6, P = 0.033); neopterin, 11.2% (95% CI: 3.2-19.2, P = 0.007); D-dimer 9.6% (95% CI: 3.1-15.9, P = 0.004), respectively. The associations remained significant when analysis was stratified by N(t)RTI vs. RAL and included only patients with viral suppression at week 48. A significant gradient in lean mass gain was seen across quartiles of IL-6, TNF, neopterin, hsCRP, D-dimer, and sCD14.. Inflammatory biomarkers provide important mechanistic insights into the pathogenesis of limb fat and lean mass changes independently of ART.

Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Biomarkers; CD4 Lymphocyte Count; Female; HIV Infections; Humans; Raltegravir Potassium; Viral Load

The aim of the present study was to compare the efficacy and durability of treatment switch to two-drug (2DR) vs. three-drug (3DR) integrase inhibitor (InSTI)-based regimens in a real-life setting.. Within the ODOACRE cohort, we selected adult patients with HIV RNA < 50 copies/mL switching to an InSTI-based 2DR or 3DR. Survival analyses were performed to estimate the probability of virological failure (VF, defined as one HIV RNA > 1000 copies/mL or two consecutive HIV RNA > 50 copies/mL) and treatment discontinuation (TD, defined as any modification, intensification or interruption of the regimen), and to evaluate their predictors.. Overall, 1666 patients were included, of whom 1334 (80%) were treated with a 3DR (19.9%, 25.0% and 55.1% elvitegravir-, raltegravir- and dolutegravir-based, respectively) and 332 (20%) with a 2DR (79.2% dolutegravir + lamivudine and 20.8% dolutegravir + rilpivirine). Over a median (interquartile range) follow-up of 100 (52-150) weeks, 52 (3.1%) patients experienced VF with an incidence of 1.5/100 person-year of follow-up (PYFU). The estimated 96-week probability of VF was similar for the 2DR and 3DR groups (2.3% vs. 2.8%, P = 0.53), but it was higher for elvitegravir (4.9%) and raltegravir (5.0%) than for dolutegravir (1.5%) (P = 0.04). Four hundred (24%) patients discontinued their InSTI-based regimen, with an incidence of 11.3/100 PYFU. At 96 weeks, 3DRs showed a higher probability of TD for any reason (20.6% vs. 11.2%, P < 0.001) and TD for toxicity (9.0% vs. 6.6%, P = 0.02) when compared with 2DRs. A higher risk of TD for central nervous system toxicity was observed for dolutegravir than for elvitegravir and raltegravir (4.0% vs. 2.5% vs. 0.6%, P = 0.005).. In virologically suppressed HIV-infected patients, 2DRs showed an efficacy similar to 3DRs but with better tolerability.

Topics: Adult; Cohort Studies; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Lamivudine; Oxazines; Raltegravir Potassium; Viral Load

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Topics: Adult; Anti-Retroviral Agents; Atazanavir Sulfate; Chi-Square Distribution; Darunavir; Female; HIV Infections; Humans; Lipidomics; Lipids; Male; Mass Spectrometry; Middle Aged; Plasma; Raltegravir Potassium; Tenofovir

The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs.. HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells.. HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug.. Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.

Topics: Amides; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Piperazines; Pyridones; Raltegravir Potassium

Raltegravir (RAL) is a HIV-integrase inhibitor recommended for treatment of HIV type 1 infection during pregnancy. The elimination of RAL to RAL glucuronide (RAL GLU) is mediated primarily by UDP glucuronosyltransferase 1A1 (UGT1A1). The present study shows the development and validation of 4 different methods for the analysis of RAL and RAL GLU in plasma and in urine samples. The methods were applied to evaluate the maternal-fetal pharmacokinetics of RAL and RAL GLU in a HIV-infected pregnant woman receiving RAL 400 mg twice daily. The sample preparation for RAL and RAL GLU analysis in 25 μL plasma and 100 μL diluted urine (10-fold with water containing 0.1% formic acid) were carried out by protein precipitation procedure. RAL and RAL GLU generate similar product mass fragments and require separation in the chromatographic system, so a suitable resolution was achieved for unchanged RAL and RAL GLU employing Ascentis Express C18 (75 × 4.6 mm, 2.7 μm) for both plasma and urine samples. The methods showed linearities at the ranges of 0.1-13.5 μg/mL RAL and 0.15-19.5 μg/mL RAL GLU in urine and 10-2000 ng/mL RAL and 2.5-800 RAL GLU in plasma. Precise and accurate evaluation showed coefficients of variation and relative errors ≤ 15%. The methods have been successfully applied in a maternal-fetal pharmacokinetic study.

Topics: Brazil; Chromatography, High Pressure Liquid; Female; Glucuronides; HIV Infections; HIV Integrase Inhibitors; Humans; Infant, Newborn; Maternal-Fetal Exchange; Permeability; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Raltegravir Potassium; Tandem Mass Spectrometry; Umbilical Cord

Patients with HIV infection represent a high-risk group for medication overdose because of the high frequency of complicating psychiatric disorders. Raltegravir is well-known for its low frequency of adverse effects. We herein report a 42-year-old Japanese man with HIV infection who was hospitalized 6 hours after overdosing with 24,000 mg of raltegravir in a suicide attempt. No serious adverse events occurred, although the plasma concentration of raltegravir at 18 hours after the overdose was 79,871.1 ng/mL. Raltegravir may be well-indicated for HIV patients at risk of overdosing.

Topics: Adult; Anti-HIV Agents; Drug Overdose; HIV Infections; Humans; Male; Raltegravir Potassium

Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy.. Retrospective single-centre cohort.. Adults who switched to RAL or DTG before or between January 2015 and October 2017 were identified. Virologically suppressed, treatment-experienced (≥2 years) individuals, at least 6 months on INSTI, with weight measurements 2 years or less pre and postswitch were included. Our analysis used a random effects model with linear slope pre and post-INSTI with adjustment for age, sex, ethnicity, preswitch-regimen (protease inhibitor vs. nonprotease inhibitor), and RAL vs. DTG use.. A total of 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and BMI at switch of 76.6 kg and 25.3 kg/m, respectively, were included. Weight increased by an average of 0.63 kg/year (95% confidence interval 0.17-1.09) preswitch with no overall change in rate of weight gain postswitch [+0.05 kg/year (-0.61-0.71, P = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain postswitch was isolated to older individuals though this lacked statistical significance [e.g., +1.59 kg/year (-0.26-3.45) if aged 65 years]. Our findings did not differ by sex, ethnicity, preswitch regimen, or RAL vs. DTG. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone.. We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically suppressed individuals.

Topics: Adult; Aged; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Retrospective Studies; Sustained Virologic Response; Treatment Outcome; Weight Gain; Young Adult

The use of combination anti-retroviral therapy (cART) correlates with longer and healthier life and with nearly normal life expectancy in people living with HIV. However, cART does not completely restore health. Chronic immune activation and inflammation persist in treated patients and have been described as predictors for clinical events and mortality in HIV-infected patients. Limited information is available on the impact of the various cART regimens on inflammation/immunoactivation. The aim of this work was to explore the impact of elvitegravir, dolutegravir, raltegravir (integrase strand transfer inhibitors, INSTIs) and atazanavir (protease inhibitor, PI) on several soluble markers of immune activation and inflammation during the first year of effective combination anti-retroviral therapy (cART). We conducted an observational retrospective cohort study in HIV-infected cART-naïve patients who initiated an INSTI or atazanavir regimen between March 2015 and February 2016 and a serum sample was available at baseline, 6 and 12 months after initiation. We compared the trend of D-Dimer, TNF- α, IL-2, IL-6, IL-7, IL-10, CCL4/MIP1-β, CCL5/RANTES, s-CD14, s-CD163, hs-CRP levels among the 4 arms of treatment. Percentage of variation from baseline was also measured for all markers. A total of 36 patients were included. We observed heterogeneous modifications in inflammation markers among arms. In particular, we noted that EVG have significant negative effect on s-CD14, hs-CRP, IL-6 and D-Dimer in respect to other INSTIs and this different effect occurs mainly during the first 6 months of cART. IL-7 values increased in the three arms with INSTIs (significantly only in EGV, 159.8%, p = 0.0003) and decreased significantly in patients on PI (-48.96%; p = 0.04) over the period. In conclusion, our results provide further data on changes of inflammatory marker levels, especially for the new INSTIs. Our data show that among INSTIs, EVG seems to have a worse impact on inflammation.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Cytokines; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Inflammation; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Raltegravir granules for oral suspension, now recommended by World Health Organization for use in neonates with HIV infection, may be challenging for caregivers because of the multistep preparation required.. We evaluated the acceptability and feasibility of preparing granules for oral suspension in a low-to-middle-income country setting. Thirty-four caregivers and 10 health-care workers were enrolled from an HIV clinic in Durban, South Africa. Health-care workers were provided with pictorial instruction booklet, demonstration kit and guidance on preparation of granules for oral suspension. The health-care workers then trained caregivers on the preparation of granules for oral suspension. Caregivers were evaluated during the preparation process and instructed to practice at home with a sample kit and return to the clinic for repeat evaluation 5-7 days later. Caregivers and health-care workers were interviewed and participated in a focus group discussion regarding their experiences.. The median age of the caregivers was 31 years (interquartile range: 9.7); 70% had received secondary-level education, 37% were employed. The median preparation time was 7.95 minutes (interquartile range: 5.08 minutes) and 7.48 minutes (3.55 minutes) at initial and repeated observation, respectively. Major errors were insufficient mixing time and incorrect suspension volume. The average number of errors between the 2 observation time points was significantly reduced at the repeat session (2.5 vs. 0.87, P = 0.023). Most participants found the preparation difficult at first but gained confidence over time.. Despite the complexity involved in the preparation of the granules for oral suspension, with practice, this formulation was found to be acceptable and feasible to majority of participants in this low-resource setting. As a result, this formulation was included in the 2018 World Health Organization recommendations for first line in neonates living with HIV.

Topics: Caregivers; Developing Countries; Female; Health Personnel; Health Resources; HIV Infections; HIV Integrase Inhibitors; Humans; Infant, Newborn; Male; Patient Acceptance of Health Care; Patient Compliance; Raltegravir Potassium; South Africa

: Integrase strand transfer inhibitor-based antiretroviral therapy can cause weight gain. It is unknown if this is a class effect, with limited data regarding raltegravir. In 37 virologically suppressed adults (36 men, mean age 49 years) who switched from tenofovir disoproxil fumarate to raltegravir 400 mg twice daily, mean weight changes from baseline at weeks 24, 48 and 96 were not significant (maximum 0.8 kg at week 24; all P ≥ 0.16). Weight gain may not occur with all integrase strand transfer inhibitors.

Topics: Adult; Anti-HIV Agents; Body Mass Index; Emtricitabine; HIV Infections; HIV-1; Humans; Male; Middle Aged; Raltegravir Potassium; Tenofovir; Weight Gain

In resource-limited settings, multi-experienced HIV infected patients are often prescribed raltegravir for salvage therapy. Patients failing raltegravir-containing regimens require other drugs including other integrase inhibitors. In this context, real-life data about the resistance and cross-resistance pathways between integrase inhibitors is limited. The aim of this study was to investigate integrase resistance pathways in a cohort of Mexican multi-experienced patients failing of a raltegravir-containing salvage regimen.. Twenty-five plasma samples from subjects failing antiretroviral regimens which included raltegravir were obtained from various healthcare centres from 2009 to 2017 in Mexico. Antiretroviral history and demographics were collected. Samples were processed for integrase resistance genotyping testing by sequencing. The viral sequences were analysed with the Stanford HIV drug resistance database algorithm. Data was analysed with SPSS Statistics software.. Our findings suggest a high occurrence of resistance and cross-resistance to other integrase inhibitors among multi-experienced subjects failing raltegravir. We found a modestly lower proportion of cross-resistance to dolutegravir than data from clinical trials. Likely this drug could be used for salvage therapy. Explanations for the absence of mutations in half of the samples, other than reduced adherence, should be further investigated. Close surveillance is needed.

Topics: Cohort Studies; Cross-Sectional Studies; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV Seropositivity; HIV-1; Humans; Male; Mexico; Raltegravir Potassium; Sequence Analysis, DNA; Treatment Failure; Viral Load

Topics: Anti-HIV Agents; Drug Overdose; HIV Infections; HIV Integrase Inhibitors; Humans; Raltegravir Potassium

Topics: Drug Overdose; HIV Infections; Humans; Raltegravir Potassium; Therapeutic Irrigation

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Female; Follow-Up Studies; HIV Infections; Humans; Lipid Metabolism; Male; Middle Aged; Platelet Count; Raltegravir Potassium; Treatment Outcome; Viral Load

Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate.. HIV-1 drug resistance genotyping was performed in 30 HIV-1-infected individuals undergoing virological failure to raltegravir. Drug resistance mutations (DRMs) and HIV-1 subtype were characterized using Stanford HIVdb and phylogenetic analyses.. Of the 30 integrase (IN) sequences, 14 were characterized as subtype F (47%), 8 as subtype B (27%), 7 as BF recombinants (23%) and 1 as a putative CRF05_DF (3%). In 25 cases (83%), protease and reverse transcriptase (PR-RT) sequences from the same individuals confirmed the presence of different BF recombinants. Stanford HIVdb genotyping was concordant with phylogenetic inference in 70% of IN and 60% of PR-RT sequences. INI DRMs differed between B and F IN subtypes, with Q148K/R/H, G140S and E138K/A being more prevalent in subtype B (63% versus 0%, P = 0.0021; 50% versus 0%, P = 0.0096; and 50% versus 0%, P = 0.0096, respectively). These differences were independent of the time on raltegravir therapy or viral load at the time of genotyping. INI DRMs in subtype F IN genomes predicted a lower level of resistance to raltegravir and no cross-resistance to second-generation INIs.. Alternative resistance pathways to raltegravir develop in subtypes B and F IN genomes, with implications for clinical practice. Evaluating the role of HIV-1 subtype in development and persistence of mutations that confer resistance to INIs will be important to improve algorithms for resistance testing and optimize the use of INIs.

Topics: Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV-1; Humans; Mutation; Phylogeny; Raltegravir Potassium

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Coinfection; Comorbidity; Darunavir; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Middle Aged; Raltegravir Potassium; Retrospective Studies; Spain; Treatment Outcome; Viral Load

Although some integrase strand transfer inhibitors (INSTIs) promote peripheral and central adipose tissue/weight gain in people with human immunodeficiency virus (PHIV), the underlying mechanism has not been identified. Here, we used human and simian models to assess the impact of INSTIs on adipose tissue phenotype and function.. Adipocyte size and fibrosis were determined in biopsies of subcutaneous and visceral adipose tissue (SCAT and VAT, respectively) from 14 noninfected macaques and 19 PHIV treated or not treated with an INSTI. Fibrosis, adipogenesis, oxidative stress, mitochondrial function, and insulin sensitivity were assessed in human proliferating or adipocyte-differentiated adipose stem cells after long-term exposure to dolutegravir or raltegravir.. We observed elevated fibrosis, adipocyte size, and adipogenic marker expression in SCAT and VAT from INSTI-treated noninfected macaques. Adiponectin expression was low in SCAT. Accordingly, SCAT and VAT samples from INSTI-exposed patients displayed higher levels of fibrosis than those from nonexposed patients. In vitro, dolutegravir and, to a lesser extent, raltegravir were associated with greater extracellular matrix production and lipid accumulation in adipose stem cells and/or adipocytes as observed in vivo. Despite the INSTIs' proadipogenic and prolipogenic effects, these drugs promoted oxidative stress, mitochondrial dysfunction, and insulin resistance.. Dolutegravir and raltegravir can directly impact adipocytes and adipose tissue. These INSTIs induced adipogenesis, lipogenesis, oxidative stress, fibrosis, and insulin resistance. The present study is the first to shed light on the fat modifications observed in INSTI-treated PHIV.

Topics: Adipocytes; Adipose Tissue; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Insulin Resistance; Integrase Inhibitors; Oxazines; Piperazines; Pyridones; Raltegravir Potassium

Most HIV-infected cells during antiretroviral therapy (ART) persist in lymphoid tissues. Studies disagree on whether suboptimal tissue ART concentrations contribute to ongoing HIV replication during viral suppression.. We performed a cross-sectional study in virally-suppressed HIV+ participants measuring lymphoid tissue ART [darunavir (DRV), atazanavir (ATV), and raltegravir (RAL)] concentrations by LC-MS/MS assay. Tissue and plasma ART concentrations were used to estimate TPRs and drug-specific tissue:inhibitory concentration ratios (TICs). HIV DNA and sequentially produced HIV RNA transcripts were quantified from rectal biopsies using droplet digital PCR (ddPCR) assays.. Tissue samples were collected in duplicate from 19 participants: 38 rectal, 8 ileal (4 RAL, 2 DRV, 2 ATV), and 6 lymph node (4 RAL, 2 DRV) samples. Overall, median TICs were higher for RAL than DRV or ATV (both P = 0.006). Median TICs were lower in lymph nodes vs. ileum (0.49 vs. 143, P = 0.028) or rectum (33, P = 0.019), and all ART levels were below target concentrations. Higher rectal TICs were associated with lower HIV RNA transcripts (read-through, long LTR, and Nef, P all < 0.026) and a lower long LTR RNA/long LTR DNA ratio (P = 0.021).. We observed higher tissue ART concentrations in ileum and rectum compared with lymph nodes. We observed higher HIV transcription in participants with lower rectal ART concentrations. These findings add to the limited data supporting the idea that viral transcription may be influenced by ART concentrations in lymphoid tissues. Further exploration of tissue pharmacokinetics is needed in future HIV eradication strategies.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Biopsy; CD4-Positive T-Lymphocytes; Cross-Sectional Studies; Darunavir; Female; Gastrointestinal Tract; HIV Infections; HIV-1; Humans; Ileum; Lymph Nodes; Male; Raltegravir Potassium; Real-Time Polymerase Chain Reaction; San Francisco; Virus Replication

Several antiretroviral therapy (ART) classes have been associated with increased myocardial infarction (MI) risk. Cardiovascular disease in people living with HIV (PLWH) on integrase strand transfer inhibitors (INSTI) has not been examined. Here we aim to examine this.. Retrospective cohort design study.. We used the IBMMarketScan databases for U.S. commercially insured and Medicaid covered adults to identify PLWH newly initiated on ART between January 1, 2008 and December 30, 2015. Major adverse cardiac event (MACE), a composite of acute MI, ischemic stroke, coronary artery bypass grafting, and percutaneous coronary intervention was the primary outcome. We used calendar time-specific probability-weighted Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for the association between INSTI use and MACE. We used propensity score weighting methods to account for potential confounding.. Twenty thousand two hundred forty-two new ART initiators were identified. 5069 (25%) PLWH initiated INSTI-based regimens. 203 MACE events occurred; acute MI 16 (0.32%) vs 66 (0.43%), stroke 24 (0.47%) vs 54 (0.36), coronary artery bypass grafting 2 (0.04%) vs 9 (0.06%), percutaneous coronary intervention 7 (0.14%) vs 25 (0.16%) of INSTI users vs non-users. INSTI-based ART was associated with significantly lower risk of MACE events (hazard ratios 0.79; 95% confidence intervals: 0.64 to 0.96) compared with non-INSTI-based regimens.. In this cohort, INSTI-based regimens were associated with a 21% decreased risk of incident cardiovascular disease. These finding require validation in other cohorts and with longer follow-up.

Topics: Adult; Anti-Retroviral Agents; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Ischemic Stroke; Male; Middle Aged; Myocardial Infarction; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies

Topics: Anti-HIV Agents; HIV Infections; Humans; Nitriles; Pyridazines; Pyrimidines; Raltegravir Potassium

Resistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility. This was further supported by weaker non-bonded pairwise interaction energy and binding free energy values between the drug DTG and E92Q, Y143R and G140S mutants suggesting reduced binding affinity, as indicated by interaction analysis in comparison to the WT. Our findings suggest the G140S mutant has the strongest effect on the HIV-1C IN protein structure and Dolutegravir binding. To the best of our knowledge, this is the first study that uses the consensus wild type HIV-1C IN sequence to build an accurate 3D model to understand the effect of three known mutations on DTG drug binding in a South Africa context.

Topics: Amino Acid Sequence; Catalytic Domain; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Dynamics Simulation; Mutation; Oxazines; Piperazines; Protein Binding; Protein Stability; Pyridones; Quinolones; Raltegravir Potassium; South Africa; Virus Replication

Topics: Alkynes; Anti-Retroviral Agents; Benzoxazines; Cyclopropanes; Female; HIV Infections; Humans; National Institute of Child Health and Human Development (U.S.); Pregnancy; Raltegravir Potassium; United States

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir.

Topics: Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Imidazoles; Mutation; Pyrrolidinones; Quinolones; Raltegravir Potassium; Structure-Activity Relationship

The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6-66], DTG 6.3 (IQR 0.8->186), EVG >164 (IQR 2.6->164) and RAL >188 (IQR 2.7->197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.

Topics: Amides; Drug Resistance, Multiple, Viral; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Treatment Outcome

Predicting drug pharmacokinetics in pregnant women including placental drug transfer remains challenging. This study aimed to develop and evaluate maternal-fetal physiologically based pharmacokinetic models for two antiretroviral drugs, dolutegravir and raltegravir.

Topics: Female; Fetus; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Maternal Exposure; Oxazines; Piperazines; Placenta; Pregnancy; Pyridones; Raltegravir Potassium

We assessed changes in functional connectivity by fMRI (functional magnetic resonance imaging) and cognitive measures in otherwise neurologically asymptomatic people with HIV (PWH) switching combination antiretroviral therapy (cART). In a prospective study (baseline and follow-up after at least 4 months), virologically suppressed PWH switched non-nuclease reverse-transcriptase inhibitors (NNRTI; tenofovir-DF/emtricitabine with efavirenz to rilpivirine) and integrase-strand-transfer inhibitors (INSTI; tenofovir-DF/emtricitabine with raltegravir to dolutegravir). PWH were assessed by resting-state fMRI and stop-signal reaction time (SSRT) task fMRI as well as with a cognitive battery (CogState™) at baseline and follow-up. Switching from efavirenz to rilpivirine (n = 10) was associated with increased functional connectivity in the dorsal attention network (DAN) and a reduction in SSRTs (p = 0.025) that positively correlated with the time previously on efavirenz (mean = 4.8 years, p = 0.02). Switching from raltegravir to dolutegravir (n = 12) was associated with increased connectivity in the left DAN and bilateral sensory-motor and associative visual networks. In the NNRTI study, significant improvements in the cognitive domains of executive function, working memory and speed of visual processing were observed, whereas no significant changes in cognitive function were observed in the INSTI study. Changes in fMRI are evident in PWH without perceived neuropsychiatric complaints switching cART. fMRI may be a useful tool in assisting to elucidate the underlying pathogenic mechanisms of cART-related neuropsychiatric effects.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Asymptomatic Diseases; Benzoxazines; Cognitive Dysfunction; Connectome; Cyclopropanes; Drug Substitution; Emtricitabine; Executive Function; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Magnetic Resonance Imaging; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Oxazines; Piperazines; Prospective Studies; Pyridones; Raltegravir Potassium; Rilpivirine; Tenofovir

Topics: Anti-Bacterial Agents; Anti-HIV Agents; Asthma; Betacoronavirus; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Testing; Diagnosis, Differential; DNA, Bacterial; Emtricitabine; Glucocorticoids; HIV Infections; Humans; Lung; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Oxygen Inhalation Therapy; Pandemics; Pneumocystis carinii; Pneumonia, Pneumocystis; Pneumonia, Viral; Prednisolone; Raltegravir Potassium; Real-Time Polymerase Chain Reaction; RNA, Viral; SARS-CoV-2; Tenofovir; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination; Viral Load

Understanding the viral-host cell interface during HIV-1 infection is a prerequisite for the development of innovative antiviral therapies. Here we show that the suppressor of G2 allele of skp1 (SUGT1) is a permissive factor for human immunodeficiency virus (HIV)-1 infection. Expression of SUGT1 increases in infected cells on human brain sections and in permissive host cells. We found that SUGT1 determines the permissiveness to infection of lymphocytes and macrophages by modulating the nuclear import of the viral genome. More importantly, SUGT1 stabilizes the microtubule plus-ends (+MTs) of host cells (through the modulation of microtubule acetylation and the formation of end-binding protein 1 (EB1) comets). This effect on microtubules favors HIV-1 retrograde trafficking and replication. SUGT1 depletion impairs the replication of HIV-1 patient primary isolates and mutant virus that is resistant to raltegravir antiretroviral agent. Altogether our results identify SUGT1 as a cellular factor involved in the post-entry steps of HIV-1 infection that may be targeted for new therapeutic approaches.

Topics: Acetylation; Active Transport, Cell Nucleus; Anti-HIV Agents; Cell Cycle Proteins; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Microtubule-Associated Proteins; Microtubules; Raltegravir Potassium; Virus Replication

We assessed whether changes at week 12 in markers of bone turnover, inflammation, and immune activation were associated with clinically important (≥ 5%) bone mineral density (BMD) loss from baseline to week 48 at the proximal femur (hip) and lumbar spine in the SECOND-LINE study.. We measured concentrations of procollagen type 1 pro-peptide (P1NP), carboxyl-terminal collagen crosslinks (CTX), high-sensitivity C-reactive protein (hs-CRP), D-dimer, interleukin (IL)-6, tumor necrosis factor (TNF), neopterin, and soluble CD14 and 163 at weeks 0, 12, and 48 in 123 SECOND-LINE dual-energy X-ray absorptiometry (DXA) substudy participants. Linear regression was used to compare changes in biomarkers. Predictors of ≥ 5% BMD loss were examined using multivariable regression.. The mean age was 38 years, the mean CD4 T-cell count was 252 cells/µL and the mean viral load was 4.2 log HIV-1 RNA copies/mL; 56% of participants were female and 47% were randomized to receive a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI]-based regimen [91% (53/58) were randomized to receive a tenofovir disoproxil fumarate (TDF)-containing regimen]. Over 48 weeks, 71% in the N(t)RTI arm experienced ≥ 5% hip BMD loss vs. 29% in the raltegravir arm (P = 0.001). Week 12 changes in P1NP and CTX were significantly greater among patients experiencing ≥ 5% hip BMD loss, patients randomized to N(t)RTI, and male patients. Predictors of ≥ 5% hip BMD loss at week 48 were P1NP increase [odds ratio (OR) 5.0; 95% confidence interval (CI) 1.1-27; P < 0.043]; N(t)RTI randomization (OR 6.7; 95% CI 2.0-27.1; P < 0.003), being African, higher baseline CD4 T cell count , and smoking.. In a diverse cohort of viraemic HIV-infected patients, switching to second-line antiretroviral therapy (ART) was associated with clinically significant BMD loss, which was correlated with an early increase in P1NP. Measurement of P1NP may facilitate timely interventions to reduce rapid BMD loss among at-risk patients.

Topics: Absorptiometry, Photon; Adult; Biomarkers; Bone Density; C-Reactive Protein; CD4 Lymphocyte Count; Female; Hip; HIV Infections; HIV-1; Humans; Interleukin-6; Male; Middle Aged; Neopterin; Peptide Fragments; Procollagen; Raltegravir Potassium; Random Allocation; Reverse Transcriptase Inhibitors; Spine; Tenofovir; Treatment Failure; Treatment Outcome; Tumor Necrosis Factor-alpha; Viral Load

A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration (

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Raltegravir Potassium

Topics: Female; HIV Infections; HIV Integrase Inhibitors; Humans; Milk, Human; Pyrrolidinones; Raltegravir Potassium

Human immunodeficiency virus (HIV) viral load (VL) during pregnancy is a critical determinant of the risk of HIV mother-to-child transmission (MTCT). Prior studies suggest that VL suppression is influenced by antiretroviral regimen. In this study, using secondary real-life data from the Ministry of Health of Brazil, we compared VL suppression at 60-180 days after the first antiretroviral therapy (ART) prescription during pregnancy and time to undetectable VL among pregnant women under treatment with double nucleoside/nucleotide regimens combined with efavirenz, boosted lopinavir, boosted atazanavir, or raltegravir, with adjustment for potential confounders in multivariable models. A total of 18,997 pregnant women living with HIV were included in the study. Compared to regimens containing lopinavir, we found that atazanavir-, efavirenz-, and raltegravir-based regimens were superior in achieving both outcomes after adjustment for age, social vulnerability index, time under ART, baseline CD4+ cell count, and baseline HIV VL. Raltegravir-containing regimens had the highest adjusted odds/rates of VL suppression compared to patients with other regimens. Elimination of HIV MTCT is still a critical public health issue in many countries. Our findings suggest that raltegravir-based regimens were superior when compared to efavirenz-, lopinavir-, and atazanavir-based antiretroviral regimens in achieving suppression of HIV VL.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Brazil; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Treatment Outcome; Viral Load

As integrase inhibitors become available in low- and middle-income countries (LMICs), they offer the potential to expand extremely limited treatment options available to children and adolescents. In LMICs, only small numbers have used raltegravir, primarily as part of third-line regimens. Using data from the IeDEA global consortium, we aimed to describe the characteristics of children on raltegravir-containing regimens and their outcomes.. We included data from 1994 to 2017 from children (age <18 years), from East and Southern Africa, Asia and South America, who received cART regimens containing raltegravir for ≥90 days. We describe their characteristics at raltegravir start, and their immunological and virological outcomes.. In total, 62 children were included, with median age at raltegravir initiation of 14.3 years (IQR 11.2 to 15.8) and median CD4 count of 276 cells/µL (IQR 68 to 494). Among 40 (65%) with drug resistance testing prior to raltegravir, 71% were resistant to at least one protease inhibitor (PI), and 32% had high-level resistance to at least one drug class. Most (n = 50; 81%) received raltegravir as part of third-line cART following PI-based regimens, and were on regimens containing four or more drugs (n = 47, 76%). By database closure, median duration on raltegravir was 2.0 years (IQR 0.8 to 3.0), 1 (1.6%) patient had died, 6 (9.7%) were lost to follow-up and 21 (34%) had discontinued raltegravir. Among 15 patients reporting reasons for stopping raltegravir, six discontinued because it was no longer available. Within one year of starting raltegravir, among 53 patients with VL measures, 40 (75%) had VL < 1000 copies/mL, and among 54 with a reported CD4 count, 45 (83%) and 36 (67%) were ≥350 and ≥500 cells/µL, respectively, with median CD4 count increasing to 517.5 cells/µL (IQR 288 to 810).. Among children in LMICs, the initial use of raltegravir has been primarily for post PI-based cART. We found good virological and immunological outcomes despite frequent prior triple-class failure and high levels of drug resistance. Both access to raltegravir and long-term adherence to regimens with large pill-burdens remain challenging. Policies which promote earlier access to new drugs and simplify daily regimens for children and adolescents in LMICs are needed.

Topics: Adolescent; Africa, Southern; Asia; CD4 Lymphocyte Count; Child; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Poverty; Raltegravir Potassium; South America; Treatment Outcome; Viral Load

Antiretroviral dual regimens including lamivudine and one boosted PI or dolutegravir are warranted in order to optimize combination ART (cART), prevent long-term toxicity and reduce the cost of treatments.. We hypothesized that a maintenance dual regimen of lamivudine plus raltegravir would be effective and as well tolerated as the dual maintenance combination of lamivudine plus dolutegravir.. We performed an observational, retrospective study of HIV-infected patients on suppressive ART who switched to a dual regimen containing lamivudine 300 mg once daily plus raltegravir 1200 mg once daily or dolutegravir 50 mg once daily.. In total, 109 patients (79 men; mean age 46.4 years; mean CD4+ T lymphocyte count 605 cells/mm3) were enrolled. Overall, 50 subjects switched to lamivudine plus raltegravir (Group A) and 59 to lamivudine plus dolutegravir (Group B). After 12 months, 45 patients (90%) in Group A and 52 (88.1%) in Group B had HIV RNA <20 copies/mL. No patients had severe adverse effects in either group, and the percentages of patients with mild adverse effects were comparable, except for a higher incidence of headache and sleeping disturbances in Group B than in Group A (30.5% versus 14%, P < 0.001). A comparable and non-significant weight increase was reported in both groups (+1.91 kg in Group A and +2.28 kg in Group B).. In our study, dual therapies containing lamivudine plus raltegravir or dolutegravir in virologically suppressed patients showed high and comparable efficacy, as well as good tolerability.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Retrospective Studies; Viral Load

Virological response and resistance profile were evaluated in drug-naïve patients starting their first-line integrase inhibitors (INIs)-based regimen in a clinical setting.. Virological success (VS) and virological rebound (VR) after therapy start were assessed by survival analyses. Drug-resistance was evaluated at baseline and at virological failure.. Among 798 patients analysed, 38.6 %, 27.1 % and 34.3 % received raltegravir, elvitegravir and dolutegravir, respectively. Baseline resistance to NRTIs, NNRTIs, PIs and INIs was: 3.9 %, 13.9 %, 1.6 % and 0.5 %, respectively. Overall, by 12 months of treatment, the probability of VS was 95 %, while the probability of VR by 36 months after VS was 13.1 %. No significant differences in the virological response were found according to the INI used. The higher pre-therapy viremia strata was (<100,000 vs. 100,000-500,000 vs. > 500,000 copies/mL), lower was the probability of VS (96.0 % vs. 95.2 % vs. 91.1 %, respectively, P < 0.001), and higher the probability of VR (10.2 % vs. 15.8 % vs. 16.6 %, respectively, P = 0.010). CD4 cell count <200 cell/mm. Our findings confirm that patients receiving an INI-based first-line regimen achieve and maintain very high rates of VS in clinical practice.

Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium; Viral Load

: Fat gain is reported in integrase strand transfer inhibitors exposed persons living with HIV. We investigated in 165 persons living with HIV (117 men/48 women), included in the 96-week ANRS-163-ETRAL trial and switched to raltegravir/etravirine, the impact of sex, menopausal status and ovarian reserve (detectable anti-Müllerian hormone). From baseline to 48/96 weeks, women with ovarian reserve were protected from raltegravir/etravirine-induced weight/fat gain and associated insulin-resistance while peri/postmenopausal women increased weight, fat and insulin resistance as did men. The functional ovarian status could protect against raltegravir/etravirine-induced weight gain.

Topics: Anti-HIV Agents; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Nitriles; Pyrimidines; Raltegravir Potassium

Sub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation integrase strand-transfer inhibitors (INSTI) such as raltegravir. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART).. We report a 65 years old Cameroonian, previously exposed to raltegravir, and failing on third-line treatment with multi-drug resistance to darunavir/r and dolutegravir. Genotypic resistance testing (GRT) and viral tropism were performed during monitoring time points. The patient initiated ART in August 2007. At the time point of the first (29.04.2010), second (01.12.2017) and third (08.08.2019) GRT, prior ART exposure included 3TC, d4T, NVP and EFV; additionally TDF, DRV/r and RAL; and additionally ABC and DTG respectively. First GRT revealed mutations associated with resistance only to first-generation Non-nucleoside reverse transcriptase inhibitors (NNRTI). Second GRT revealed mutations associated with high-level resistance to all NRTIs, first generation NNRTIs, all ritonavir boosted protease inhibitors (PI/r), and all INSTI, while viral tropism (using geno2pheno) revealed a CCR5-tropic virus with a false positive rate (FPR) of 60.9% suggesting effectiveness of maraviroc (MRV). The third GRT showed high-level resistance to NRTI, NNRTI, all PI and all INSTI, with additional mutations (H221HY for NNRTI and S147G for INSTI), and a CCR5-tropic virus with a slightly reduced FPR (57.0%). Without any locally available active therapeutic option, the patient has been on a maintenance therapy with "DRV/r (600mg x 2/day)+TDF+3TC" and patient/family-centered adherence has been reinforced. Since the first viral load (VL) measurement in 2010, the patient has had 12 VL tests with the VL ranging from 4.97 Log to 6.44 Log copies/mL and the CD4 count never exceeded 200 cells/μL.. As African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection (and potential transmission) of dolutegravir-resistance, supporting case surveillance.

Topics: Aged; Anti-HIV Agents; Cameroon; CD4 Lymphocyte Count; Darunavir; Drug Resistance, Multiple, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Viral Load

Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs).. A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman's correlation coefficient was used to determine cross-resistance between INSTIs.. INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT.. In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Uganda

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.

Topics: Amides; Binding Sites; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Linear Models; Models, Molecular; Molecular Docking Simulation; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Sequence Alignment

Participants from the Modena HIV Metabolic Clinic taking RAL, ATV/r, or DRV/r with at least 1 computed tomography (CT) scan were included. CT scans were reanalyzed for area and density of truncal fat and musculature. Multivariate models explored the effect of ART on fat and muscle density.. One hundred six participants were receiving ATV/r, 48 DRV/r, and 141 RAL. In multivariate models (reference ATV/r), only DRV/r was associated with greater subcutaneous (SAT) and visceral adipose tissue (VAT) area, lower lateralis muscle density (more fat), and greater lateralis intermuscular fat area. Compared to ATV/r, RAL was independently associated with less psoas intermuscular fat area. Among all, greater paraspinal muscle density correlated with better physical function. No associations between ART group and physical function were seen among men; DRV/r was associated with stronger grip strength among women.. DRV/r was associated with greater fat area and lower density of both fat and muscle, and RAL with less intermuscular psoas fat. Higher density psoas and paraspinal musculature were associated with better physical function, suggesting potential clinical relevance of these findings.

Topics: Adipose Tissue; Adult; Anti-HIV Agents; Atazanavir Sulfate; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Hospitals, Teaching; Humans; Italy; Male; Middle Aged; Muscles; Raltegravir Potassium; Retrospective Studies; Viral Load

Topics: Adult; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Integrases; Male; Pyridones; Quinolones; Raltegravir Potassium

Topics: Anti-HIV Agents; HIV Infections; Humans; Nitriles; Pyridazines; Pyrimidines; Raltegravir Potassium

Topics: Alleles; Black People; Drug Hypersensitivity Syndrome; Female; Genetic Predisposition to Disease; HIV Infections; HIV-1; HLA-B Antigens; Humans; Male; Raltegravir Potassium

This study evaluated the emergence of mutations associated with integrase strand transfer inhibitors (INSTI) resistance (INSTI-RMs) and the integrase evolution in human immunodeficiency virus type 1 (HIV-1) infected patients treated with this drug class.. The emergence of INSTI-RMs and integrase evolution (estimated as genetic distance between integrase sequences under INSTI treatment and before INSTI treatment) were evaluated in 107 INSTI-naïve patients (19 drug-naïve and 88 drug-experienced) with two plasma genotypic resistance tests: one before INSTI treatment and one under INSTI treatment. A logistic regression analysis was performed to evaluate factors associated with the integrase evolution under INSTI treatment.. The patients were mainly infected by B subtype (72.0%). Eighty-seven patients were treated with raltegravir, 13 with dolutegravir and seven with elvitegravir. Before INSTI treatment one patient harboured the major INSTI-RM R263K and three patients the accessory INSTI-RMs T97A. Under INSTI treatment the emergence of ≥1 INSTI-RM was found in 39 (36.4%) patients. The major INSTI-RMs that more frequently emerged were: N155H (17.8%), G140S (8.4%), Y143R (7.5%), Q148H (6.5%), and Y143C (4.7%). Concerning integrase evolution, a higher genetic distance was found in patients with ≥1 INSTI-RM compared with those without emergence of resistance (0.024 [0.012-0.036] vs. 0.015 [0.009-0.024], P=0.018). This higher integrase evolution was significantly associated with a longer duration of HIV-1 infection, a higher number of past regimens and non-B subtypes.. These findings confirm that major INSTI-RMs very rarely occur in INSTI-naïve patients. Under INSTI treatment, selection of drug-resistance follows the typical drug-resistance pathways; a higher evolution characterises integrase sequences developing drug-resistance compared with those without any resistance.

Topics: Adult; Drug Resistance, Viral; Evolution, Molecular; Female; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Logistic Models; Male; Middle Aged; Mutation; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Compounding; Female; HIV; HIV Infections; Humans; Male; Medication Adherence; Middle Aged; Raltegravir Potassium; RNA, Viral; Treatment Outcome

The decision about whether to switch to third-line antiretroviral therapy (ART) in patients with treatment failure on second-line therapy is difficult in settings with little access to genotypic resistance testing. In this study, we used a standardised algorithm including a wide range of adherence-enhancing interventions followed by a new viral load measurement to decide whether to switch to third-line therapy in this situation. The decision, made on the basis of effectiveness of the adherence reinforcement to drive viral resuppression, did not use genotypic resistance testing.. In this prospective cohort study, adults in four west African countries with treatment failure of a boosted protease inhibitor ART regimen were offered nine adherence reinforcement interventions, and followed up for 64 weeks. We measured viral load at week 12 and used the results to decide ART treatment at week 16: if successful resuppression (plasma HIV-1 RNA <400 copies per mL or had decreased by ≥2 log. Between March 28, 2013, and May 11, 2015, of the 198 eligible participants, five died before week 16. Of the 193 remaining, 130 (67%) reached viral resuppression and continued with second-line ART, and 63 (33%) switched to third-line ART at week 16. Post-study genotypic resistance testing showed that the baseline genotypic susceptibility score was calculable in 166 patients, of whom 57 (34%) had a score less than 2. We retrospectively concluded that the week 16 decision was appropriate in 145 (75%) patients. At week 64, four patients (2%) were lost to follow-up, ten (5%) had died, and 101 (52%) had a viral load less than 50 copies per mL.. Poor adherence is the first problem to tackle in patients for whom second-line ART is failing when resistance tests are not routinely available and is effectively a manageable problem. Lack of access to genotypic resistance testing should not be an obstacle to the prescription of third-line ART in patients who do not achieve viral resuppression after adherence reinforcement.. French Agency for Research on AIDS and Viral Hepatitis.

Topics: Adult; Africa, Western; Algorithms; Clinical Decision-Making; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Medication Adherence; Middle Aged; Prospective Studies; Raltegravir Potassium; Ritonavir; Treatment Failure; Treatment Outcome; Viral Load

For HIV cure strategies like "kick and kill" to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of six ARVs in three preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some, but not all, ARVs. These results have implications for interpreting HIV treatment, prevention, or cure interventions between preclinical and clinical models.

Topics: Animals; Anti-HIV Agents; Anti-Retroviral Agents; Atazanavir Sulfate; Emtricitabine; Female; HIV Infections; Humans; In Vitro Techniques; Maraviroc; Mice; Raltegravir Potassium; Tenofovir

Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC, and CAB demonstrated a comparable activity on a panel of INSTI-resistant strains isolated from patients exposed to RAL, EVG, and/or DTG, with a significantly reduced susceptibility only with the pathway Q148H/K/R plus one to two additional INSTI mutations.

Topics: Amides; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates.. P1110 is an international, multicenter trial to determine safe and effective raltegravir doses in neonates at risk for HIV infection.. P1110 used a 2-cohort adaptive design incorporating population pharmacokinetic modeling and simulations. An initial cohort of neonates received 2 single oral doses of raltegravir with standard-of-care therapy for prevention of perinatal transmission-one within 48 hours of birth and a second at 7-10 days of life. Raltegravir concentration data after administration of these doses were combined with data from a previous study of infants aged 4 weeks to 2 years. The combined database was used for population pharmacokinetic modeling and simulations to select a daily dosing regimen for investigation in a second cohort of neonates.. Raltegravir concentration data from 6 neonates were combined with data from infants aged 4 weeks to 2 years receiving raltegravir twice daily. The combined data set allowed for successful development of a population pharmacokinetic model with reasonable precision of parameter estimates. Monte Carlo simulations were run to evaluate potential daily dosing regimens from birth to 6 weeks of age, allowing for selection of a regimen to be evaluated in a subsequent cohort of neonates receiving chronic raltegravir dosing.. An adaptive design incorporating population pharmacokinetic modeling and simulations was used to select a developmentally appropriate neonatal raltegravir dosing regimen in the first 6 weeks of life.

Topics: Adolescent; Adult; Anti-HIV Agents; Child; Drug Administration Schedule; Female; HIV Infections; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Models, Biological; Monte Carlo Method; Raltegravir Potassium; Young Adult

The impact of switching antiretroviral therapy (ART) regimen for dyslipidemia management in HIV-infected (HIV+) patients has not been reported in Chile.. To assess effectiveness and safety at 12 months after switching to raltegravir-based regimen for dyslipidemia management.. Retrospective cohort of HIV+ patients receiving ART at Arriaran Foundation, with dyslipidemia switched to raltegravir-based regimen for lipid management.. 73 patients were included, receiving ART based in nonnucleoside reverse transcriptase inhibitor (NNRTI; 50,7%) or protease inhibitor (PI; 49,3%), with mixed dyslipidemia (42,5%) or isolated hypertriglyceridemia (57,5%). At baseline, median total cholesterol (TC) and triglycerides (TG) were 228 mg/dl and 420 mg/dl, respectively; undetectable viral load (VL) was present in 94,5% of patients. Backbone ART was switched in 58,4% and lipid-lowering therapy was used by 89,1% of them. At 12 months, there was a significant decrease in TG (-43,6%) and TC (-19,3%). No cases of virologic failure were observed, although 10,9% of patients had detectable VL at 12 months, mostly transient.. Switching ART to raltegravir-based regimen in dyslipidemic patients receiving NNRTI or PI is associated with a significative decrease in TG and TC at 12 months. This strategy is safe, but VL can be increased temporarily.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Dyslipidemias; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Raltegravir Potassium; Retrospective Studies; Viral Load

The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)-experienced HIV-1-infected patients and its predictors.. We selected HIV-1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI-experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ. We included 462 genotypes from INSTI-exposed individuals: 356 'INSTI-failing' patients and 106 'previously INSTI-exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17-110 weeks]). Overall, at least low-level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non-B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008-2009.. The results support integrase resistance testing in INSTI-experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation.

Topics: Adult; Drug Resistance, Viral; Female; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Italy; Logistic Models; Male; Middle Aged; Mutation; Oxazines; Piperazines; Prevalence; Pyridones; Quinolones; Raltegravir Potassium

The indisputable benefits of antiretroviral therapy (ART) in the reduction of mother-to-child-transmission of HIV have to be carefully balanced with the risks of embryo-fetal toxicities due to fetal exposure to maternal ART. The recent report of a potential safety signal with dolutegravir use in pregnancy and potential increased rate of neural tube defects has raised the question of a potential class effect for integrase strand inhibitors. To contribute real-world evidence, we evaluated data on pregnant women receiving raltegravir (RAL) or elvitegravir (EVG) in the United Kingdom and Ireland.. The National Study of HIV in Pregnancy and Childhood is a comprehensive population-based surveillance study collecting data on all HIV-positive pregnant women and their children. We collected data on all pregnancies exposed to an ART regimen containing RAL or EVG resulting in live birth, stillbirth, and induced abortion with an expected date of delivery between September 2008 and April 2018. Pregnancies were stratified into 3 groups of earliest exposure.. A total of 908 pregnancies were exposed to a RAL- or EVG-based regimen (875 to RAL and 33 to EVG). There were 886 live-born infants exposed to RAL, 8 pregnancies ended in stillbirth, and 9 in induced abortions. Among the 886 live-born infants, there were 23 (2.59%, 95% confidence interval: 1.65 to 3.86) reported congenital anomalies, 2 nervous system defects but no reported neural tube defects. Of the 33 pregnancies exposed to EVG, 31 resulted in live-born infants with no congenital anomaly and the remaining 2 pregnancies ended in induced abortion.. The prevalence of congenital anomalies is consistent with national population estimates for 2008-2016 in the United Kingdom. More data are needed on safety of RAL and EVG in pregnancy.

Topics: Abnormalities, Drug-Induced; Adult; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Ireland; Pregnancy; Pregnancy Complications, Infectious; Quinolones; Raltegravir Potassium; Stillbirth; United Kingdom

To analyse the frequency and causes of treatment discontinuation in patients who were treated with an integrase strand transfer inhibitor (INSTI), with a focus on neuropsychiatric adverse events (NPAEs).. Patients in 18 HIV reference centres in France were prospectively included in the Dat'AIDS cohort. Data were collected from all patients starting an INSTI-containing regimen between 1 January 2006 and 31 December 2016. All causes of INSTI-containing regimen discontinuations were analysed, and patients' characteristics related to discontinuation due to NPAEs were sought.. INSTIs were prescribed to 21315 patients: 6274 received dolutegravir, 3421 received elvitegravir boosted by cobicistat, and 11620 received raltegravir. Discontinuation was observed in 12.5%, 20.2% and 50.9% of the dolutegravir-, elvitegravir- and raltegravir-treated patients, respectively (P < 0.001). Discontinuation for NPAEs occurred in 2.7%, 1.3% and 1.7% of the dolutegravir-, elvitegravir-, and raltegravir-treated patients, respectively (P < 0.001). In the multivariate analysis, discontinuation for NPAEs was related to dolutegravir versus elvitegravir (HR = 2.27; 95% CI 1.63-3.17; P < 0.0001) and versus raltegravir (HR = 2.46; 95% CI 2.00-3.40; P < 0.0001), but neither gender (HR for women = 1.19; 95% CI 0.97-1.46; P = 0.09) nor age (P = 0.12) was related. The association with abacavir was not retained in the final model.. Although discontinuation for side effects was less frequent with dolutegravir than with boosted elvitegravir, discontinuation for NPAEs, although rare (2.7%), was more frequent with dolutegravir. No patient characteristic was found to be associated with these side effects in this very large population.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Female; France; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Mental Disorders; Nervous System Diseases; Oxazines; Piperazines; Prospective Studies; Public Health Surveillance; Pyridones; Quinolones; Raltegravir Potassium; Viral Load

An observational, prospective, cohort study was performed to assess changes in insulin sensitivity and serum leptin level after a switch from a ritonavir-boosted PI (PI/r) to raltegravir or dolutegravir in HIV-infected adults on stable combination ART (cART).. Non-diabetic HIV-infected patients receiving suppressive cART including tenofovir disoproxil fumarate/emtricitabine plus one PI/r, who underwent a switch from the PI/r to raltegravir (group A) or dolutegravir (group B), were enrolled in the study. Serum levels of insulin, leptin and the homeostasis model assessment of insulin resistance (HOMA) index were evaluated during a 12 month follow-up.. Overall, 86 patients were enrolled: 45 patients were included in group A and 41 were included in group B. The mean age was 45.7 years and 74 (86%) patients were male. After 12 months of follow-up, a significant reduction in the mean concentration of leptin and insulin was reported both in group A [-0.61 ng/mL (P < 0.001) and -2.5 mIU/L (P = 0.008), respectively] and in group B [-0.54 ng/mL (P = 0.005) and -2.1 mIU/L (P = 0.017), respectively], without a significant difference between the groups. A significant and comparable reduction in the mean HOMA index was reported both in group A [-0.55 (P = 0.004)] and in group B [-0.49 (P < 0.001)], as well as a significant decrease in lipid levels.. In HIV-positive subjects on suppressive cART, the switch from a PI/r to raltegravir or dolutegravir led to a significant and comparable reduction in both HOMA index and serum leptin level, reflecting a similar and significant improvement in insulin sensitivity.

Topics: Adult; Antiretroviral Therapy, Highly Active; Biomarkers; Coinfection; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Raltegravir Potassium; Risk Factors; Ritonavir; Treatment Outcome; Viral Load

Integrase strand transfer inhibitors (INSTIs), dolutegravir, elvitegravir, and raltegravir, have become integral in the treatment of HIV, with close monitoring of continued efficacy and tolerability. As side effect occurrence varies among subjects receiving these drugs, we sought to perform an exploratory analysis examining the role of several single-nucleotide polymorphisms (SNPs) on drug concentration changes, selected clinical outcomes, and the occurrence of subject-reported adverse events.. Adults (aged ≥ 18 years) receiving INSTI-based regimens for treatment of HIV were recruited and genotyped with an iPLEX ADME PGx Pro v1.0 Panel. Multiple linear or logistic regression with covariates [age, sex, BMI, regimen (in the across-regimen group), regimen duration, and baseline variables (for continuous parameters)] was used to detect significant (p < 0.05) association of selected clinical data with genetic variants within the study population.. In a sample (n = 88) with a median age of 52.5 years (IQR 45.7-57.2) being predominately Caucasian (88.6%) and male (86.4%), this exploratory study discovered several associations between variables and SNPs, when using INSTIs. Abnormal dream occurrence was statistically different (p = 0.028) between regimens. Additionally, several SNPs were found to be associated with adverse event profiles primarily when all regimens were grouped together.. The associations found in this study point to a need for further assessment, within the population living with HIV, of factors contributing to unfavorable subject outcomes. These exploratory findings require confirmation in larger studies, which then may investigate pharmacogenetic mechanisms.

Topics: Adult; Female; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Pharmacogenetics; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Antiretroviral agents are approved in Japan based on non-clinical and clinical data reported from overseas. Neither the long-term tolerability nor the effectiveness of raltegravir or other integrase strand transfer inhibitors in Japan is known. This study reports on the long-term tolerability and effectiveness of raltegravir in Japanese clinical practice using data collected through approximately 9 years of post-marketing surveillance. This observational survey used data on human immunodeficiency virus (HIV) infected patients initiated treatment with raltegravir between 2008 and 2017 in the HIV-related drug (HRD) cooperative survey to assess the safety and effectiveness of raltegravir in real world clinical practice. There were totally 1,303 patients prescribed raltegravir across 30 institutions; 1,293 patients and 1,178 patients were included for the safety and effectiveness analyses, respectively. The overall risk of adverse drug reaction was 17.25%, with abnormal hepatic function and hyperlipidaemia (<1.5%) having the highest proportion. Median HIV-1 RNA viral loads rapidly decreased below 40 copies/mL after 3 months of raltegravir use in treatment-naïve patients, and consistently sustained below 40 copies/mL after the start of raltegravir use in treatment-experienced patients. Among the patients who were treated for 7 years, 92.00% (95% CI: 73.97-99.02) maintained HIV-1 RNA viral load below 50 copies/mL. Additionally, CD4+ cell counts exceeded >500 cells/μL in treatment-naïve and treatment-experienced patients after 3 years and 4 years of treatment, respectively. In Japanese HIV patients, long-term treatment with raltegravir is well-tolerated and effective at viral suppression as measured by HIV-1 RNA levels and subsequent change in CD4+ cell counts. Such benefits can be expected for not only treatment-naïve but also treatment-experienced patients.

Topics: Adolescent; Adult; Aged; CD4 Lymphocyte Count; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Japan; Male; Middle Aged; Product Surveillance, Postmarketing; Raltegravir Potassium; RNA, Viral; Safety; Time Factors; Treatment Outcome; Viral Load; Young Adult

The aim of the study was to assess the rates of discontinuation of integrase inhibitor regimens because of any neuropsychiatric adverse event (NPAE) and the factors associated with discontinuation.. A population-based, prospective, multicentre cohort study was carried out. Treatment-naïve subjects starting therapy with a regimen containing integrase inhibitors, or those switching to such a regimen, with plasma HIV-1 RNA < 50 HIV-1 RNA copies/mL in 14 hospitals in Catalonia or the Balearic Islands (Spain) were included in the study. Every discontinuation because of adverse events (AEs) was double-checked directly with treating physicians. Multivariable Cox models identified factors correlated with discontinuation.. A total of 4165 subjects (37% treatment-naïve) started regimens containing dolutegravir (n = 1650; 91% with abacavir), raltegravir (n = 930) or elvitegravir/cobicistat (n = 1585). There were no significant differences among regimens in the rate of discontinuation because of any AE. Rates of discontinuation because of NPAEs were low but higher for dolutegravir/abacavir/lamivudine [2.1%; 2.9 (95% confidence interval (CI) 2.0, 4.2) discontinuations/100 patients/year] versus elvitegravir/cobicistat (0.5%; 0.8 (95% CI 0.3, 1.5) discontinuations/100 patients/year], with significant differences among centres for dolutegravir/abacavir/lamivudine and NPAEs (P = 0.003). We identified an association of female gender and lower CD4 count with increased risk of discontinuation because of any AE [Incidence ratio (IR) 2.3 (95% CI 1.4, 4.0) and 1.8 (95% CI 1.1, 2.8), respectively]. Female gender, age > 60 years and abacavir use were not associated with NPAE discontinuations. NPAEs were commonly grade 1-2, and had been present before and improved after drug withdrawal.. In this large prospective cohort study, patients receiving dolutegravir, raltegravir or elvitegravir/cobicistat did not show significant differences in the rate of discontinuation because of any toxicity. The rate of discontinuations because of NPAEs was low, but was significantly higher for dolutegravir than for elvitegravir/cobicistat, with significant differences among centres, suggesting that greater predisposition to believe that a given adverse event is caused by a given drug of some treating physicians might play a role in the discordance seen between cohorts.

Topics: Adult; CD4 Lymphocyte Count; Cobicistat; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Male; Middle Aged; Oxazines; Piperazines; Proportional Hazards Models; Prospective Studies; Pyridones; Quinolones; Raltegravir Potassium; Spain

High rates of clinical acute rejection after kidney transplantation have been reported in people living with HIV (PLHIV), probably as a consequence of drug interactions. We therefore investigated the incidence of acute rejection within 6 months of transplantation in HIV-infected recipients treated with a protease-inhibitor-free raltegravir-based regimen.. The Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) 153 TREVE (NCT01453192) study was a prospective multicentre single-arm trial in adult PLHIV awaiting kidney transplantation, with viral load < 50 HIV-1 RNA copies/mL, CD4 T-cell count > 200 cells/μL, and HIV-1 strains sensitive to raltegravir, aiming to demonstrate 6-month clinical acute rejection rates < 30%. Time to transplantation was compared with that for uninfected subjects matched for age, sex and registration date.. In total, 61 participants were enrolled in the study, and 26 underwent kidney transplantation. Two participants experienced clinical acute rejection, corresponding to an estimated clinical acute rejection rate of 8% [95% confidence interval (CI) 2-24%] at 6 and 12 months post-transplantation. HIV infection remained under control in all but one participant, who temporarily stopped antiretroviral treatment. Median time to transplantation was longer in PLHIV than in controls (4.3 versus 2.8 years, respectively; P = 0.002) and was not influenced by blood group.. Acute rejection rates were low after kidney transplantation in PLHIV treated with a raltegravir-based regimen. However, PLHIV have poorer access to transplantation than HIV-uninfected individuals after registration on the waiting list.

Topics: Adult; Anti-HIV Agents; Female; Graft Rejection; HIV Infections; HIV-1; Humans; Incidence; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Raltegravir Potassium; Viral Load

To evaluate the durability of three integrase strand transfer inhibitors (INSTIs) and two NRTIs in ART-naive individuals.. The study design was observational. Patients were HIV-positive, ART-naive subjects starting raltegravir, elvitegravir/cobicistat or dolutegravir with two NRTIs. The primary endpoint was time to treatment failure, i.e. occurrence of virological failure (first of two consecutive plasma HIV RNAs  ≥200 copies/mL after 24 weeks) or INSTI discontinuation for any reason apart from simplification. Secondary endpoints were INSTI discontinuation due to toxicity/intolerance and CD4 count response. Survival analysis was done using Kaplan-Meier and Cox regression.. Two thousand and sixteen patients were included: 310 (15.4%) started raltegravir-based regimens, 994 (49.3%) started dolutegravir-based regimens and 712 (35.3%) started elvitegravir/cobicistat-based regimens. Over a median of 11 months, 167 patients experienced treatment failure; the 1 year probability of treatment failure was 6.5% for raltegravir, 5.4% for dolutegravir and 6.7% for elvitegravir/cobicistat (P = 0.001). Sixty-eight patients (3.4%) discontinued INSTIs owing to toxicity/intolerance. By multivariable analysis, patients starting raltegravir had a 2.03-fold (95% CI = 1.2-3.2) higher risk and patients on elvitegravir/cobicistat a 1.88-fold (95% CI = 1.2-2.9) higher risk of treatment failure versus dolutegravir; there was no difference in risk of discontinuation due to toxicity/intolerance when comparing dolutegravir and raltegravir and marginal evidence for a difference when comparing elvitegravir/cobicistat and dolutegravir (adjusted relative hazard = 1.94 for elvitegravir/cobicistat versus dolutegravir, 95% CI = 1.00-3.76, P = 0.05).. In our real-life setting, INSTI-based regimens showed high potency and durability. Among regimens currently recommended in Europe, those including dolutegravir are associated with a lower risk of treatment failure.

Topics: Adult; CD4 Lymphocyte Count; Cobicistat; Cohort Studies; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV Seropositivity; Humans; Italy; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Regression Analysis; Survival Analysis; Treatment Failure

We report a case of darunavir-induced cholestatic hepatitis in a human immunodeficiency virus (HIV)-infected patient in the third year of his combined antiretroviral therapy. During the patient's monthly follow-up with regard to his HIV infection, elevated transaminase levels were detected. The patient was subsequently hospitalised at the AIDS and gastroenterology departments. All tested viral hepatitis markers were negative. A diagnosis of autoimmune hepatitis was also ruled out. The liver biopsy revealed cholestatic hepatitis. Darunavir withdrawal resulted in a progressive decrease in liver enzyme levels. We highlight the importance of recognising late development of liver injury secondary to the use of darunavir, and the importance of monitoring liver function in patients undergoing prolonged treatment involving darunavir.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Cholestasis, Intrahepatic; Darunavir; HIV Infections; HIV Protease Inhibitors; Homosexuality, Male; Humans; Male; Raltegravir Potassium; Treatment Outcome; Viral Load

Our case was a 70-year-old male (height: 168 cm, weight: 74.3 kg) with polypharmacy (total 15 drugs including 10 tablets) who was treated for HIV infection. His dosing schedule of raltegravir was changed from BID (a 400 mg tablet, twice) to QD (2x600 mg tablet, once). After a month, we found that he miss-took raltegravir for 1x600 mg tablet at once. His HIV-1 RNA increased from undetectable levels to < 20 copies per mL. Pharmaceutical companies should therefore carefully consider swallowing difficulties in old patients, such as by reformulating medications so that only one dosing is required per day and decreasing the size of tablets to 7-8 mm in diameter or orally distinguish tablet.

Topics: Aged; Anti-HIV Agents; Deglutition Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; HIV Infections; Humans; Male; Polypharmacy; Raltegravir Potassium; RNA, Viral; Tablets

Characterize virologic and immunologic outcomes of INSTI-based antiretroviral therapy (ART) in experienced patients with and without virologic failure.. Prospective clinical cohort.. ART-experienced, INSTI-naive participants in the University of North Carolina Center for AIDS Research HIV Clinical Cohort (UCHCC) initiating an INSTI-containing regimen 2007-2016 were followed from INSTI initiation (baseline) to the earliest of: outcome of interest, loss to follow-up (LTFU, 1 year without clinical visit), or death. Outcomes of interest were virologic failure (first of two consecutive viral loads at least 200 copies/ml more than 2 weeks apart, or one viral load ≥200 before LTFU) and immune recovery (first CD4 ≥500 cells/μl). Patients with baseline viral load at least 50 copies/ml were given 24 weeks before meeting virologic failure criteria. Kaplan-Meier curves and Cox proportional hazards models compared INSTI regimens and patient characteristics.. Of 773 patients, 32% were women, 59% African-American, and 42% had a viral load at least 50 copies/ml at INSTI initiation. After 2 years, 5% of patients with baseline viral load less than 50 copies/ml experienced virologic failure, compared with 35% of patients with baseline viral load at least 50 copies/ml (P < 0.01). Among patients with baseline viral load less than 50 copies/ml, dolutegravir/NRTIs was associated with longer time to virologic failure [adjusted hazard ratio (aHR) 0.11, 95% confidence interval (CI) 0.01-0.80], whereas among patients with baseline viral load at least 50 copies/ml, raltegravir/NRTIs was associated with longer time to virologic failure (aHR 0.35, 95% CI 0.18-0.68), both compared with elvitegravir/NRTIs. After 5 years suppressed, irrespective of baseline viral load, 61% of patients experienced immune recovery.. In this cohort, INSTI-containing regimens led to low virologic failure rates in patients switching ART while suppressed. Viremic patients initiating INSTIs were at high risk of virologic failure during follow-up.

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Kaplan-Meier Estimate; Male; Middle Aged; North Carolina; Oxazines; Piperazines; Proportional Hazards Models; Prospective Studies; Pyridones; Raltegravir Potassium; Treatment Failure; Viral Load

The recent approval of raltegravir granules for suspension in the newborn population offers a new option for the antiretroviral prophylaxis of newborns for the prevention of perinatal transmission. However, there are little data on its use in preterm infants, nor on outcomes following its use as empiric HIV therapy for newborns subsequently found to be infected. We describe here the use of RAL granules for suspension in these cases.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemoprevention; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Post-Exposure Prophylaxis; Raltegravir Potassium; Young Adult

To evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy.. Exposures to raltegravir during pregnancy reported cumulatively through May 31, 2018, to the company safety database were reviewed to identify cases of NTDs. This database includes all reports of pregnancy from Merck-sponsored clinical trials, spontaneous postmarketing reports, and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (before knowledge of pregnancy outcome) or retrospective (after knowledge of pregnancy outcome). We also reviewed data from 2 ongoing pregnancy cohorts.. A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, 3 NTD cases per APR criteria were identified (anencephaly, and 2 meningomyelocele), of which only one (meningomyelocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate.. Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. The current data support the updated DHHS and EACS treatment guidelines for use of raltegravir as a preferred integrase inhibitor in all stages of pregnancy.

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Neural Tube Defects; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Raltegravir Potassium; Retrospective Studies

Integrase strand transfer inhibitors (INSTIs) have become the preferred first-line antiretroviral therapy in adults. There is paucity of published data on their use in children outside of clinical trials, particularly long-term safety and tolerability. This study aimed to describe INSTI use including the number of, and reasons for INSTI discontinuation.. We conducted a retrospective cohort analysis by database and electronic record review of children aged under 18 years with perinatally acquired human immunodeficiency virus who started INSTI-based antiretroviral therapy between May 2009 and March 2018, in a single tertiary centre.. Fifty-six INSTI-based regimens were prescribed in 54 children, 64.9% from 2015 onwards. Twenty-one of 56 (37.5%) regimens commenced with raltegravir, 29 (51.8%) with dolutegravir and six (10.7%) with elvitegravir. The median age at the start of treatment was 15 years (interquartile range 13.5-16.4) with a median duration of INSTI-antiretroviral therapy of 1.65 years (range 0.01-8.8). Twenty-four children had a detectable viral load at the start INSTI therapy; 20 (83%) achieving viral suppression in a median of 26 days (interquartile range 19.5-34.5). There were 26 discontinuations of INSTI-based antiretroviral therapy after a median of 183 days; 9/26 because of adverse events. Four of nine adverse events were attributed to INSTI use, all in patients taking dolutegravir and the adverse events were neuropsychiatric and gastrointestinal in nature.. INSTI-based regimens were generally efficacious and well tolerated in this paediatric cohort, with 4/26 discontinuations due to INSTI-attributed adverse events. Further post-marketing surveillance of INSTI use in children is warranted.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies; Viral Load

Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults living with human immunodeficiency virus (HIV), due to its high virological efficacy and good tolerability profile. To date, limited data are available on the use of RAL with abacavir/lamivudine (ABC/3TC). We investigated retrospectively 62 HIV-1 infected patients managed by three Italian Infectious Diseases Outpatient Departments, including 57 treatment-experienced patients and 5 treatment-naïve patients, treated with ABC/3TC plus RAL. In all five naïve patients (100%), virological suppression was achieved and maintained , while 55 experienced patients (96.5%) maintained viral suppression at the most recent review. In the treatment-experienced patients, we observed a significant decrease in triglyceride levels (p < 0.01), while liver transaminases, renal function and cholesterol levels remained substantially stable. In the 34 treatment-experienced patients who switched from a protease inhibitor (PI)-based regimen, we observed a significant improvement of total cholesterol (p=0.03) and triglyceride (p < 0.01) levels. No significant alterations were found on renal and liver function and serum lipid profile of treatment-naïve patients. Despite the small number of participants, results support the efficacy and safety of ABC/3TC plus RAL, either in treatment-naïve or treatment-experienced patients.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cholesterol; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Kidney Function Tests; Lamivudine; Liver Function Tests; Male; Middle Aged; Raltegravir Potassium; Treatment Outcome; Triglycerides

Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and middle-income countries, because of a high resistance barrier and a good safety profile. Very recently, a World Health Organization safety signal has been raised regarding neural tube defects after the first-trimester exposure. Furthermore, to date, the experience is limited regarding the use of the other InSTI drugs (raltegravir and elvitegravir) during pregnancy. Our objective is to analyze the safety of InSTI drugs in pregnant women.. Nation-wide database cohort analysis.. We evaluated the risk of major birth defects according to EUROCAT classification in pregnant women, which had had a first-trimester exposure to dolutegravir, raltegravir, or elvitegravir.. We found a major birth defect rate of 1.9% in the general population between 2012 and 2016. As InSTI drugs are not used as first-line therapy in pregnant women, we found a very low exposure in this population. Among 49, 240, and 70 pregnancy outcomes exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester, there were 2, 3, and 1 major birth defects, respectively. There was no case of neural tube defect.. Drug exposure to InSTI is limited in our nation-wide database. Nevertheless, our data do not support a pharmacovigilance signal on neural tube defects in women exposed to dolutegravir, raltegravir or elvitegravir during pregnancy. Owing to a small number of pregnancy outcomes, these results need to be confirmed with further studies.

Topics: Adult; Anti-Retroviral Agents; Cohort Studies; Congenital Abnormalities; Drug Resistance, Viral; Female; France; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Neural Tube Defects; Oxazines; Pharmacovigilance; Piperazines; Pregnancy; Pyridones; Quinolones; Raltegravir Potassium; Treatment Outcome; Young Adult

No data on resistance to HIV integrase strand transfer inhibitors (InSTIs) in Argentina are available as access to these drugs and to integrase genotypic resistance test is limited. We aimed to evaluate the clinical profile of patients who underwent an integrase genotypic resistance test, prevalence of InSTI resistance mutations and predicted efficacy of raltegravir, elvitegravir and dolutegravir in our country.. Retrospective multicentric pilot survey from January 2011 to November 2017 of InSTI-failing patients assisted at two private and one public healthcare institutions located in Buenos Aires city, Argentina.. Sixty seven patients were included. Patients had a median of 5 (4-7) prior treatments. All patients had InSTI-containing regimens (median exposure of 22.5 months); 94% were under raltegravir therapy and 71.9% had InSTI-resistance mutations. Predominant major mutations were N155H (35.1%), Q148H/R (15.8%) and G140A/S (14%). Considering Stanford HIVdb program, extremely low and identical activity of raltegravir and elvitegravir was described while dolutegravir remained either partially or fully active in 97.7% of patients.. Integrase resistance test was prescribed almost exclusively in heavily pretrated raltegravir-exposed patients. The three main mutational pathways were described, with a predominance of N155H. Despite almost null susceptibility and extensive cross resistance was shown among raltegravir and elvitegravir, dolutegravir remains active in the majority of patients.

Topics: Adult; Argentina; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Pilot Projects; Piperazines; Prevalence; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies; Surveys and Questionnaires; Urban Population; Viral Load; Young Adult

Integrase strand-transfer inhibitor (InSTI)-based regimens are the preferred combinations for naïve HIV-infected individuals. Polymorphic substitutions that reduce InSTIs activity have been described, with E157Q being one of the most frequently found. This study aimed to evaluate the prevalence of E157Q substitution in newly diagnosed acute/recent HIV cases and the presence of transmission clusters.. Prospective cohort study in patients with acute/recent HIV infection.. Genotypic drug resistance tests were performed in all consecutive patients prospectively enrolled with a documented infection of less than 6 months from May 2015 to May 2017. Sequences were obtained by ultra-deep sequencing. Phylogenetic inferences were performed using maximum likelihood trees constructed with Mega 6.06. Bootstrap values of 75% or greater were defined for cluster assignment. Follow-up was, at least, 1 year.. In six out of 67 consecutive patients (8.95%, 95% confidence interval 4.17-18.19) with acute/recent HIV infection, strains carrying the E157Q InSTI substitution were detected. All cases were MSM patients infected with subtype B strains. No other resistance substitutions were detected in these cases. Median viral load was 5.33 (interquartile range: 4.54-5.71) log10 copies/ml and, in all cases, the mutational viral load was high (>95%). Three cases were included in transmission clusters. Three cases responded to dolutegravir-based regimens; nonnucleoside reverse transcriptase inhibitor-based regimens were used for the other case(s).. E157Q substitution, reducing raltegravir and elvitegravir activity, was frequently found in acute/recent HIV cases. All cases were infected with subtype B, and some were included in clusters. Cases treated with dolutegravir-based regimens had good virological response.

Topics: Adult; Amino Acid Substitution; Disease Transmission, Infectious; Drug Resistance, Viral; Female; Gene Frequency; Genotype; Genotyping Techniques; High-Throughput Nucleotide Sequencing; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Male; Molecular Epidemiology; Mutation, Missense; Phylogeny; Prevalence; Prospective Studies; Quinolones; Raltegravir Potassium; Sexual and Gender Minorities; Viral Load

HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy is started, plasma viremia decays in 2 phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay, and we speculated this may be due to higher intracellular concentration (IC) of RAL in LT. We have previously measured suboptimal ICs of antiretroviral therapy agents in LT, which were associated with slower decay of both vRNA+ cells and the follicular dendritic cell network pool.. Outpatient clinic at the Joint Clinical Research Center in Kampala, Uganda.. We compared the rate of decay in LT in people starting RAL with those starting efavirenz (EFV).. There was no difference in the rate of virus decay in LT. The ratio of the ICs of RAL and EFV in lymph node to the concentration of drug that inhibits 95% of virus in blood was 1 log lower in lymph node for EFV and >3 logs lower for RAL.. These data further highlight the challenges of drug delivery to LT in HIV infection and demonstrate that RAL is not superior to EFV as judged by direct measurements of the source of virus in LT.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dendritic Cells, Follicular; Female; HIV Infections; HIV Integrase Inhibitors; Humans; In Situ Hybridization; Lymph Nodes; Lymphoid Tissue; Male; Raltegravir Potassium; Viral Load; Viremia; Young Adult

Raltegravir readily crosses the placenta to the fetus with maternal use during pregnancy. After birth, neonatal raltegravir elimination is highly variable and often extremely prolonged, with some neonates demonstrating rising profiles after birth despite removal from the source of extrinsic raltegravir. To establish an appropriate dosing regimen, an integrated maternal-neonatal pharmacokinetics model was built to predict raltegravir plasma concentrations in neonates with in utero raltegravir exposure. Postnatal age and body weight were used as structural covariates. The model predicted rising or decreasing neonatal elimination profiles based on the time of maternal drug administration relative to time of birth and degree of in utero drug disposition into the central and peripheral compartments. Based on this model, it is recommended to delay the first oral dose of raltegravir until 1-2 days of age in those neonates born to mothers who received raltegravir during pregnancy, labor, and delivery.

Topics: Anti-HIV Agents; Case-Control Studies; Drug Dosage Calculations; Female; HIV Infections; Humans; Infant, Newborn; Maternal-Fetal Exchange; Models, Theoretical; Pregnancy; Raltegravir Potassium

Dual therapy combining integrase inhibitors and NNRTIs represents a promising regimen in ageing HIV-infected individuals with long exposure to nucleoside analogues and PIs.. The ANRS 163 ETRAL trial (NCT02212379) was a 96 week, multicentre, single-arm study evaluating the efficacy and safety of raltegravir (400 mg twice daily)/etravirine (200 mg twice daily) in individuals >45 years, on a PI-containing regimen who were integrase inhibitor and etravirine naive. The primary endpoint was the proportion of participants with virological success, defined by the absence of virological failure up to week 48. Main secondary outcomes included evolution of metabolic parameters, CD4/CD8 count, bone mineral density and inflammatory markers. The study was designed to show an efficacy >90%, assuming a success rate ≥95%, with a power of 80% and a 5% type-1 error.. One hundred and sixty-five participants (median age 52 years, duration of ART 16.9 years, viral suppression 6.9 years and CD4 count 700 cells/mm3) were enrolled. By ITT analysis, viral suppression was maintained in 99.4% of participants (95% CI = 95.6%-99.9%) at week 48 and 98.7% (95% CI = 95.0%-99.7%) at week 96. Two virological failures occurred (week 24 and week 64) without emergence of integrase inhibitor resistance. Eight participants discontinued raltegravir/etravirine for adverse events, leading to a strategy success rate of 95.1% (95% CI = 90.5%-97.5%) at week 48 and 92.7% (95% CI = 87.5%-95.8%) at week 96. Over 96 weeks, lipid fractions improved (P < 0.001), CD4/CD8 ratio increased, IFNγ-induced protein 10 (IP-10) decreased (-8.1%), soluble CD14 decreased (-27%, P < 0.001) bone mineral density improved and BMI increased.. Raltegravir plus etravirine dual therapy demonstrated durable efficacy in virologically suppressed ageing patients.

Topics: Antiretroviral Therapy, Highly Active; Biomarkers; CD4 Lymphocyte Count; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Medication Adherence; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Quality of Life; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Time Factors; Treatment Outcome; Viral Load

Integrase inhibitor (INI)-containing regimens are increasingly replacing protease inhibitor(PI)-containing regimens in clinical practice. The aim of this study was to evaluate the determinants of the durability of INI-containing regimens after the switch.. We retrospectively analysed all of the people with HIV infection attending the University of Milan's Infectious Diseases Unit at Luigi Sacco Hospital who were switched from a PI- to an INI-containing regimen between April 2008 and March 2017. The probability of remaining on an INI-containing regimen was estimated using Kaplan-Meier curves, and the baseline clinical predictors of INI-containing regimen durability were assessed using a multivariable Cox proportional hazard regression model.. Switching from a PI- to an INI-containing regimen may be an option for patients under virological control. The patients switched to dolutegravir were less likely to discontinue the INI than those switched to raltegravir. Our findings support this therapeutic strategy and highlight the durability and efficacy of dolutegravir containing-regimens after switching from a PI-containing regimen.

Topics: Anti-HIV Agents; Cohort Studies; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Oxazines; Piperazines; Protease Inhibitors; Pyridones; Raltegravir Potassium; Retrospective Studies

Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Combinations; HIV Infections; HIV-1; Humans; Lamivudine; Middle Aged; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Viral Load

The dose of tenofovir alafenamide is reduced from 25 to 10 mg daily when given with boosting agents. However, such dose reduction has never been adopted for tenofovir disoproxil fumarate (TDF). In this study, we aim to quantify the effect of cobicistat (COBI) both on tenofovir concentrations and TDF durability in real life setting.. HIV-positive patients receiving TDF-containing antiretroviral therapies with at least 1 assessment of tenofovir plasma trough concentrations were included in the study. Univariate and multivariate regression analyses were performed considering tenofovir concentration as the dependent variable and clinical characteristics as independent covariates. Subsequently, survival and Cox analyses were performed considering as the primary outcome TDF discontinuation for any reasons.. Patients were given TDF with protease inhibitors/ritonavir (n = 212), non-nucleoside reverse transcriptase inhibitors (n = 176), integrase inhibitors (dolutegravir or raltegravir, n = 46), or with elvitegravir/COBI (ELV/COBI) (n = 76). By multivariate analysis, concomitant antiretroviral therapies resulted significantly associated with tenofovir levels, with the highest drug concentrations measured in patients given ELV/COBI. By survival analysis, we found that patients given TDF with ELV/COBI had the lowest rate of drug durability. Overall, these patients had a 2.3-fold increased risk to experience TDF discontinuation.. Coadministration with COBI resulted in significantly higher tenofovir concentrations and higher TDF discontinuation compared with other antiretroviral regimens. Accordingly, the possibility that the lack of proper dose adjustment for TDF when given with COBI might have biased the safety comparisons with tenofovir alafenamide during registrative trials cannot be ruled out.

Topics: Adenine; Adult; Aged; Alanine; Anti-HIV Agents; Cobicistat; Drug Combinations; Drug Interactions; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Oxazines; Piperazines; Proportional Hazards Models; Pyridones; Quinolones; Raltegravir Potassium; Ritonavir; Tenofovir; Treatment Outcome

There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association.. The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression.. The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95-1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37-2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84-1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90-1.61) and 0.83 (95% CI 0.70-0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47-1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65-1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53-1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76-1.72 for RALvs. CONC).. We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

Topics: Adult; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Neoplasms; Prospective Studies; Raltegravir Potassium; Risk Assessment; Survival Analysis

To explore the effectiveness of raltegravir-based antiretroviral therapy (ART) on treatment response among ART-naive patients seeking routine clinical care.. Cohort study of adults enrolled in HIV care in the United States.. We compared virologic suppression and CD4 cell count recovery over a 2.5 year period after initiation of an ART regimen containing raltegravir or efavirenz using observational data from a US clinical cohort, generalized to the US population of people with diagnosed HIV. We accounted for nonrandom treatment assignment, informative censoring, and nonrandom selection from the US target population using inverse probability weights.. Of the 2843 patients included in the study, 2476 initiated the efavirenz-containing regimen and 367 initiated the raltegravir-containing regimen. In the weighted intent-to-treat analysis, patients spent an average of 74 (95% confidence interval: 41, 106) additional days alive with a suppressed viral load on the raltegravir regimen than on the efavirenz regimen over the 2.5-year study period. CD4 cell count recovery was also superior under the raltegravir regimen.. Patients receiving raltegravir spent more time alive and suppressed than patients receiving efavirenz, but the probability of viral suppression by 2.5 years after treatment was similar between groups. Optimizing the amount of time spent in a state of viral suppression is important to improve survival among people living with HIV and to reduce onward transmission.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Female; HIV Infections; Humans; Male; Middle Aged; Raltegravir Potassium; Survival Analysis; Time Factors; Treatment Outcome; United States; Viral Load; Young Adult

Data are limited on the selection and sequencing of second-line and third-line pediatric antiretroviral treatment (ART) in resource-limited settings. This study aimed to evaluate characteristics of African pediatric patients initiated on darunavir (DRV) and/or etravirine (ETR) through a specific drug donation program.. This was a cross-sectional study of baseline immunologic, virologic and demographic characteristics of children and adolescents initiating DRV-based and/or ETR-based ART. Descriptive statistics were used.. Study enrolled 48 patients (45.8% women; median age = 15 years [interquartile range 17.7-10.3]) at 9 clinical sites in Zambia, Swaziland, Kenya and Lesotho. The majority (87.5%; n = 42) had received ≥2 prior ART regimens; most (81.2%) had received lopinavir/ritonavir-based ART before switch. All patients had detectable HIV RNA (median = 56,653 copies/mL). Forty seven patients (98.9%) had HIV genotype results: 41 (87.2%) had ≥1 nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistance mutation (RM), predominantly M184V (76.6%; n = 36); 31 (65.9%) had ≥1 non-NRTI-RM, including 27 (57.4%) with ≥1 ETR-RM; 30 (63.8%) had ≥3 protease inhibitor RM, including 20 (42.6%) with ≥1 DRV-RM. For new ART regimens, DRV and raltegravir were most frequently prescribed (83.3%; n = 40 on DRV and raltegravir, each). Eighteen patients (37.5%) were initiated on the NRTI-sparing ART.. In our study, a significant proportion of treatment-experienced African children and adolescents had one or more DRV-RM and ETR-RM. For the new regimen, more than a third of pediatric patients failing second-line ART were prescribed NRTI-sparing regimens. Better understanding of the current approaches to pediatric ART sequencing in resource-limited settings is needed.

Topics: Adolescent; Anti-Retroviral Agents; Child; Child, Preschool; Cross-Sectional Studies; Darunavir; Eswatini; Female; HIV Infections; HIV-1; Humans; Kenya; Lesotho; Lopinavir; Male; Nitriles; Pyridazines; Pyrimidines; Raltegravir Potassium; Ritonavir; RNA, Viral; Viral Load; Young Adult; Zambia

Post-exposure prophylaxis (PEP) is a promising but under-utilized strategy for HIV prevention in high-risk populations. Between March 2010 and June 2011, two community-based clinics in Los Angeles County provided PEP in a pilot program to 267 unique individuals. Courses were primarily dispensed to men who have sex with men (84%) and consisted overwhelmingly of a three-drug antiretroviral therapy regimen containing two nucleoside reverse transcriptase inhibitors and either an integrase inhibitor (raltegravir) or a boosted protease inhibitor (lopinavir/ritonavir). Approximately 64% of all PEP courses were followed for at least 12 weeks, and seven individuals seroconverted. Of the seven seroconversions, six had subsequent re-exposure. The low rate of PEP failure calls for expanded funding for PEP in other jurisdictions.

Topics: Adolescent; Adult; Anti-HIV Agents; Female; HIV Infections; HIV-1; Homosexuality, Male; Humans; Lopinavir; Los Angeles; Male; Medication Adherence; Middle Aged; Pilot Projects; Post-Exposure Prophylaxis; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Young Adult

Emergence of resistance against integrase inhibitor raltegravir in human immunodeficiency virus type 1 (HIV-1) patients is generally associated with selection of one of three signature mutations: Y143C/R, Q148K/H/R or N155H, representing three distinct resistance pathways. The mechanisms that drive selection of a specific pathway are still poorly understood. We investigated the impact of the HIV-1 genetic background and population dynamics on the emergence of raltegravir resistance. Using deep sequencing we analyzed the integrase coding sequence (CDS) in longitudinal samples from five patients who initiated raltegravir plus optimized background therapy at viral loads > 5000 copies/ml. To investigate the role of the HIV-1 genetic background we created recombinant viruses containing the viral integrase coding region from pre-raltegravir samples from two patients in whom raltegravir resistance developed through different pathways. The in vitro selections performed with these recombinant viruses were designed to mimic natural population bottlenecks.. Deep sequencing analysis of the viral integrase CDS revealed that the virological response to raltegravir containing therapy inversely correlated with the relative amount of unique sequence variants that emerged suggesting diversifying selection during drug pressure. In 4/5 patients multiple signature mutations representing different resistance pathways were observed. Interestingly, the resistant population can consist of a single resistant variant that completely dominates the population but also of multiple variants from different resistance pathways that coexist in the viral population. We also found evidence for increased diversification after stronger bottlenecks. In vitro selections with low viral titers, mimicking population bottlenecks, revealed that both recombinant viruses and HXB2 reference virus were able to select mutations from different resistance pathways, although typically only one resistance pathway emerged in each individual culture.. The generation of a specific raltegravir resistant variant is not predisposed in the genetic background of the viral integrase CDS. Typically, in the early phases of therapy failure the sequence space is explored and multiple resistance pathways emerge and then compete for dominance which frequently results in a switch of the dominant population over time towards the fittest variant or even multiple variants of similar fitness that can coexist in the viral population.

Topics: Amino Acid Substitution; Anti-HIV Agents; Biological Evolution; Cell Line; Drug Resistance, Viral; Genetic Background; High-Throughput Nucleotide Sequencing; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Population Density; Raltegravir Potassium; RNA, Viral; Selection, Genetic; Treatment Failure; Viral Load

Topics: Adult; Drug Resistance, Viral; Female; HIV; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; India; Male; Middle Aged; Mutation; Mutation, Missense; Raltegravir Potassium; Retrospective Studies; Tertiary Care Centers; Treatment Failure

To describe and compare integrase strand transfer inhibitor (INSTI) adverse drug reactions (ADRs) for raltegravir, elvitegravir-cobicistat, and dolutegravir.. Population-based, retrospective cohort.. Antiretroviral-experienced and naive persons at least 19 years old were included if they received their first prescription for raltegravir, elvitegravir-cobicistat, or dolutegravir in British Columbia, Canada, in 2012-2014, and were followed for 2 years until 31 December 2016. The primary outcome was an ADR resulting in INSTI discontinuation. ADR rates and 95% confidence intervals (95% CIs) were calculated by Poisson method. Cox proportional-hazards regression estimated the hazard ratio for ADR-related INSTI discontinuation, adjusted for confounders. ADR symptoms were compared across INSTIs.. There were 1344 persons contributing 1464 person-INSTI exposures. The cohort was predominantly male (79%) and antiretroviral therapy-experienced (85%). ADR events and unadjusted ADR rates (95% CI) per 100 person-years were raltegravir 24 of 551 (4.4%), 2.91 (1.95, 4.35); elvitegravir-cobicistat 38 of 394 (9.6%), 5.94 (4.32, 8.16); and dolutegravir 27 of 519 (5.2%), 2.96 (2.03, 4.31). The ADR rate for elvitegravir-cobicistat was double that of dolutegravir (adjusted hazard ratio 2.24, 95% CI 1.13, 4.44), but not significantly different for either dolutegravir or elvitegravir versus raltegravir. Elvitegravir-cobicistat-treated persons had a significantly higher proportion of gastrointestinal and general (fatigue, malaise) ADRs. Neuropsychiatric ADRs were more frequent with dolutegravir, but not significantly different between INSTIs. Among those switching between INSTIs, there was no apparent relationship between experiencing an ADR to one INSTI and subsequent intolerance to another.. This study affirms INSTIs are well tolerated during routine clinical use. Consideration of differences in side effect profiles can inform antiretroviral therapy individualization.

Topics: Adult; British Columbia; Cobicistat; Drug-Related Side Effects and Adverse Reactions; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies

In the SAILING study, dolutegravir demonstrated superior virologic efficacy compared with raltegravir in treatment-experienced, integrase strand transfer inhibitor (INSTI)-naive patients with HIV-1 who harbored resistance to ≥2 antiretroviral drug classes. Significantly fewer dolutegravir-treated patients demonstrated virologic failure with treatment-emergent resistance than raltegravir-treated patients through 48 weeks. Investigator-selected background therapy (ISBT) included at least one fully active agent, selected on the basis of resistance analysis. Genotypic and phenotypic resistance testing were performed on baseline and time-of-failure samples from patients with protocol-defined virologic failure (PDVF). A post hoc analysis of SAILING (N = 715; 354 dolutegravir, 361 raltegravir) assessed efficacy in subpopulations defined by ISBT activity, resistance profiles, and treatment history. When ISBT contained only nucleoside reverse transcriptase inhibitors (NRTIs), PDVF occurred in 0% (0/32) of dolutegravir-treated patients and 21.9% (7/32) of raltegravir-treated patients (p = .005). In patients harboring M184 V whose ISBT contained lamivudine or emtricitabine plus a second NRTI, 0% (0/13) of dolutegravir- and 33.3% (4/12) of raltegravir-treated patients (p = .026) experienced PDVF. Among patients receiving protease inhibitor (PI)-containing ISBT, 6.0% (18/300) of dolutegravir-treated patients versus 11.8% (36/305) of raltegravir-treated patients (p = .012) experienced PDVF. Darunavir/ritonavir was part of ISBT in 130 dolutegravir-treated patients and 145 raltegravir-treated patients; 6 (4.6%) and 12 (8.3%), respectively, experienced PDVF (difference -3.7%; 95% confidence interval: -10.1% to 2.5%; p = .256). There was no or less virologic failure in treatment-experienced, INSTI-naive subjects receiving dolutegravir versus raltegravir, even when the ISBT was suboptimal or NRTI resistance was present at baseline. These findings are not explained by the use of PI/ritonavir-containing ISBT.

Topics: Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Protease Inhibitors; Pyridones; Raltegravir Potassium; Reverse Transcriptase Inhibitors

Antiretroviral drugs, especially protease inhibitors (PI), are known to induce disorders of lipid and glucose metabolism. However, there are only a few reports of these side effects in patients treated with integrase strand transfer inhibitors (INSTI). We encountered the case of a 46-year-old man who had been treated for type 2 diabetes with diet and exercise. He contracted immunodeficiency virus (HIV) infection two years earlier and received highly active antiretroviral therapy (HAART). Three months before the current admission, HAART was switched from a non-nucleic acid reverse transcriptase inhibitor (NNRTI) to an INSTI (raltegravir: 800 mg/day). He developed diabetic ketoacidosis and was admitted for treatment. The state of health prior to admission was not well documented but he showed no clinical signs of acute infection. Accordingly, diabetic ketoacidosis was considered to be associated with INSTI. Diabetic ketoacidosis was treated appropriately and blood glucose level was controlled with medications before discharge from the hospital. Although the present case does not provide direct evidence for raltegravir-induced diabetic ketoacidosis, we caution physicians about the potential of such side effect associated with the use of INSTI.

Topics: Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Raltegravir Potassium

Topics: Anti-Retroviral Agents; DNA, Viral; HIV Infections; HIV-1; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Raltegravir Potassium; Treatment Outcome

The aim of this study was to evaluate the effect of UGT1A1 polymorphisms on Raltegravir (RAL) and its metabolite RAL-glucuronide trough plasma concentrations ([RAL]plasma and [RAL-glu]plasma) and on the metabolic ratio (MR): [RAL-glu]plasma/[RAL]plasma. UGT1A1 genotyping was performed on 96 patients. 44% (n = 42) were homozygous UGT1A1*1/*1 while 50% (n = 48) and 6% (n = 6) were UGT1A1*28 and UGT1A1*36 carriers, respectively. The median concentration and interquartile range (IQR) of [RAL]plasma were 88.5 ng/ml (41.0-236), 168 ng/ml (85.8-318) and 92.5 ng/ml (36.4-316) for UGT1A1*1/*1, UGT1A1*28 and UGT1A1*36 carriers, respectively. Only the difference between UGT1A1*1/*1 and *28 carriers was statistically significant (p = 0.022). The median MR (IQR) were 5.8 (3-10), 2.9 (1.6-5.3) and 3.2 (1.7-5.9) for UGT1A1*1/*1, UGT1A1*28 and UGT1A1*36 carriers, respectively. Only the difference between UGT1A1*1/*1 and *28 carriers was statistically significant (p = 0.004) with an allele-dependent effect: UGT1A1*28 homozygous having lower MR than heterozygous carriers who show lower MR compared to *1/*1. Except for the sensation of fatigue, this PK effect did not correlate with clinical adverse events or biological abnormalities. In Conclusion, we demonstrate that UGT1A1*28 polymorphism has a significant impact on RAL metabolism: UGT1A1*28 carriers being characterized by higher [RAL]plasma and lower MR.

Topics: Alleles; Cohort Studies; Female; Genotype; Glucuronides; Glucuronosyltransferase; HIV Infections; HIV-1; Humans; Male; Middle Aged; Polymorphism, Genetic; Raltegravir Potassium

People with HIV are at for metabolic syndrome (MetS) and fatty liver disease, but the role of Antiretroviral therapy (ART) is poorly understood. MetS and fatty liver disease been associated with changes in adiponectin, soluble ST2 (sST2), chitinase 3-like 1 (Chi3L1), hyaluronic acid (HA), tissue inhibitor of metalloproteinase-1 (TIMP-1), lysyl oxidase-like-2 (LOXL2) and transforming growth factor β (TGF-β) concentrations in HIV-uninfected populations. Protease (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) may contribute to these comorbidities, but the effects of switching from PI- or NNRTI to raltegravir (RAL) on these biomarkers is unknown.. Cryopreserved plasma was obtained from a completed, prospective trial of HIV-infected women with central adiposity on NNRTI- or PI-based ART during which they were randomized to remain on their current ART or switch to a RAL based regimen. Biomarker concentrations were quantified using ELISA and Multiplex assays at baseline and 24 weeks after randomization. Wilcoxon-signed rank test evaluated within-group changes, Spearman and linear regression models evaluated correlations between biomarkers and clinical covariates.. Participants had a median age of 43 years, CD4+ T lymphocyte count 558 cells/mm3 and BMI 32 kg/m2; 35% met criteria for MetS. At baseline, higher adiponectin levels correlated with higher Chi3L1 levels (r = 0.42, p = 0.02), as did declines after 24 weeks (r = 0.40, p = 0.03). Changes in sST2 correlated with changes in Chi3L1 (r = 0.43, p = 0.02) and adiponectin (r = 0.40, p = 0.03). Adiponectin and Chi3L1 levels decreased significantly in women switched to RAL vs continue PI/NNRTI.. In women with HIV and central obesity, the hepatic steatosis/fibrosis marker Chi3L1 and adiponectin decrease in conjunction with sST2 decreases following switch to RAL. Whether switching from NNRTI/PI-based regimens to RAL can improve hepatic steatosis and dysmetabolism requires further study.. Clinicaltrials.gov NCT00656175.

Topics: Adiponectin; Adult; Amino Acid Oxidoreductases; Anti-HIV Agents; Biomarkers; CD4 Lymphocyte Count; Chitinase-3-Like Protein 1; Fatty Liver; Female; HIV Infections; HIV Protease Inhibitors; Humans; Metabolic Syndrome; Middle Aged; Obesity; Prospective Studies; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tissue Inhibitor of Metalloproteinase-1; Viral Load

Objective Lipid management is one of the cornerstones of cardiovascular risk reduction. Treatment of HIV infection with protease inhibitors (PIs) may cause dyslipidaemia, whilst the integrase inhibitor raltegravir (RAL) has a relatively favorable effect on plasma lipids. We examined the effect of switching from PIs to RAL on endothelial function, and its effect on immunological and inflammatory parameters. Methods We performed a 16-week open-label prospective crossover study: 8 weeks intervention (switch PIs to RAL) and 8 weeks control (unchanged cART regimen). Flow-mediated dilatation (FMD), inflammatory plasma, and cellular markers of immune activation were measured at weeks 0, 8, and 16. Results Study participants (n = 22) with a median age of 50 years (IQR 42-60) and known HIV infection of 6.5 years (IQR 5.0-17.3) were on stable cART with undetectable HIV viral loads. After 8 weeks of RAL therapy, a reduction in FMD of -0.81% was seen, compared to +0.54% control (pairwise, p = 0.051), while fasting total cholesterol (-17% versus +10%; p < 0.001), LDL cholesterol (-21% versus -3%; p = 0.026), and triglycerides (-41% versus +18%; p = 0.001) significantly decreased during RAL therapy compared to the control. Furthermore, a relation between the change in percentage of B-1 cells and the change in FMD was found (β 0.40, 95%CI 0.16; 0.64, p = 0.005) during treatment with RAL. Finally, during RAL therapy, 27% of the patients experienced an increased ALT rise. Conclusions We present an overall negative study, where switching from PIs to RAL slightly reduced the endothelial function while decreasing plasma lipids, thus possibly decreasing the CVD risk in the long term. A transient elevation of ALT was seen upon switch to RAL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Cholesterol; Cross-Over Studies; Drug Substitution; Endothelium, Vascular; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Middle Aged; Prospective Studies; Raltegravir Potassium; Treatment Outcome; Triglycerides; Viral Load; Young Adult

In Hamburg, Germany, the initiation of HIV post-exposure prophylaxis (HIV PEP) in cases of sexual violence is often carried out by forensic medical specialists (FMS) using the city's unique Hamburg Model. FMS-provided three-day HIV PEP starter packs include a combination of raltegravir and emtricitabine/tenofovir. This study aimed to investigate the practice of offering HIV PEP, reasons for discontinuing treatment, patient compliance, and whether or not potential perpetrators were tested for HIV. We conducted a retrospective study of forensic clinical examinations carried out by the Hamburg Department of Legal Medicine following incidents of sexual violence from 2009 to 2016. One thousand two hundred eighteen incidents of sexual violence were reviewed. In 18% of these cases, HIV PEP was initially prescribed by the FMS. HIV PEP indication depended on the examination occurring within 24 h after the incident, no/unknown condom use, the occurrence of ejaculation, the presence of any injury, and the perpetrator being from population at high risk for HIV. Half of the HIV PEP recipients returned for a reevaluation of the HIV PEP indication by an infectious disease specialist, and just 16% completed the full month of treatment. Only 131 potential perpetrators were tested for HIV, with one found to be HIV positive. No HIV seroconversion was registered among the study sample. Provision of HIV PEP by an FMS after sexual assault ensures appropriate and prompt care for victims. However, patient compliance and completion rates are low. HIV testing of perpetrators must be carried out much more rigorously.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Child; Child, Preschool; Emtricitabine; Female; Germany; HIV Infections; Humans; Male; Medication Adherence; Middle Aged; Post-Exposure Prophylaxis; Raltegravir Potassium; Retrospective Studies; Sex Offenses; Tenofovir; Young Adult

Long-term combination antiretroviral therapy often results in toxicity/tolerability problems, which are one of the main reasons for switching treatment. Despite the favorable profile of raltegravir (RAL), data on its combination with abacavir/lamivudine (ABC/3TC) are scarce. Based on clinical data, we evaluated this regimen as a switching strategy.. Multicenter, non-controlled, retrospective study including all virologically suppressed HIV-1-infected patients who had switched to RAL+ABC/3TC.. We evaluated effectiveness (defined as maintenance of HIV-1-RNA <50 copies/mL at 48 weeks) safety, tolerability, laboratory data, and CD4+ count at week 48 of this switching strategy.. The study population comprised 467 patients. Median age was 49 years (IQR: 45-53). Males accounted for 75.4%. Median CD4+ count at baseline was 580 cells/μL (IQR, 409). The main reasons for switching were toxicity/tolerability problems (197; 42.2%) and physician's criteria (133; 28.5%). At week 48, HIV-1 RNA remained at <50 copies/mL in 371/380 (97.6%; 95%CI: 96.4-99.0) when non-virological failure was censured. Virological failure was recorded in 1.9% patients and treatment failure in 20.5% of patients (96/467 [95%CI, 16.9-24.2]). The main reasons for treatment failure included switch to fixed-dose combination regimens (31; 6.6%), toxicity/poor tolerability (27; 5.8%), and physician's decision (17; 3.6%). A total of 73 adverse events were detected in 64 patients (13.7%). These resolved in 43 patients (67.2%). Of the 33 cases related or likely related to treatment, 30 were Grade-1 (90.9%). CD4+ count and renal, hepatic, and lipid profiles remained clinically stable over the 48 weeks.. Our findings suggest that RAL+ABC/3TC could be an effective, safe/tolerable, and low-toxicity option for virologically suppressed HIV-1-infected patients.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Raltegravir Potassium; Retrospective Studies; Treatment Outcome

Dolutegravir (DTG) is a next-generation HIV integrase inhibitor (INI) with an increased genetic barrier to resistance with respect to raltegravir (RAL) or elvitegravir (EVG). Few data are available on the durability of DTG-containing regimens.. We aimed at investigating the duration of the DTG-containing regimen, the occurrence of an HIV-1 RNA blip, and factors associated with DTG virological response.. From the Antiviral Response Cohort Analysis database, we selected 89 HIV-1-positive four-class-experienced subjects who started DTG after receiving RAL or EVG. Factors associated with durability and virological response were analysed by logistic regression.. After a median duration of 18.8 [0.4-76.2] months, 79/89 (88.8%) subjects were still on DTG. All subjects remaining on DTG at the end of follow-up had undetectable HIV-1 RNA, compared to 5/10 subjects who discontinued DTG. DTG discontinuation was less frequent in patients who had experienced ≥10 regimens (HR 0.11, p = 0.040). The probability of having an HIV-1 RNA positive value at the last follow-up significantly increased in patients with non-B HIV-1 subtype (HR 5.77, p < .001) and significantly decreased in patients with CD4 nadir >200/μL (HR 0.29, p = 0.038), with more than 10 previous regimens (HR 0.27, p = 0.040), and who harbored virus with IN mutations (HR 0.12, p = 0.023) at DTG start.. After previous exposure to first-generation INIs, treatment with DTG showed long durability and did not show virological rebound after virological suppression. Subjects infected with a non-B HIV-1 subtype had a greater risk of having detectable HIV-1 RNA at the last observation.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug Resistance, Multiple, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies; RNA, Viral; Sustained Virologic Response; Young Adult

Raltegravir is used in many antiretroviral combinations, but its use in treatment-experienced patients without knowledge of baseline resistance is discussed controversially as a number of comparative studies have shown a higher rate of virological failure. However, it has been used frequently for the management of treatment failure, as it was the first integrase inhibitor to become available, and thus offered new options for patients with multiple resistance. The strategic use of raltegravir in this setting is examined in this study.. In order to examine the efficacy of raltegravir in second and later lines of antiretroviral combinations, data for 740 patients from three clinical cohorts were analysed with a focus on the combinations that were used. These were stratified into the combination of two nonnucleoside reverse transcriptase inhibitors and raltegravir (2NRTIs + RAL), the combination of a boosted protease inhibitor and raltegravir (bPI + RAL), and other raltegravir-containing combinations.. The overall rate of virological suppression to < 50 HIV-1 RNA copies/mL was 69.5%. Although the baseline rate of virological suppression was higher for 2NRTIs + RAL than for the other strata, the outcomes were similar for all three groups at weeks 24, 48, 72 and 96.. These data indicate that, in a real-life setting, raltegravir can be used with a high virological success rate in treatment-experienced patients, and that the different combinations analysed (2NRTIs + RAL, bPI + RAL and others) show comparable rates of virological suppression.

Topics: Adult; Aged; Aged, 80 and over; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Prospective Studies; Protease Inhibitors; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Sustained Virologic Response; Treatment Outcome; Viral Load; Young Adult

Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown.. NEAT001/ANRS143 is a randomized trial that showed noninferiority over 96 weeks of ritonavir-boosted darunavir plus raltegravir versus tenofovir disoproxil fumarate/emtricitabine in 805 antiretroviral antiretrovrial-naive HIV-infected adults. We compared changes in whole-blood telomere length measured with quantitative polymerase chain reaction in 201 randomly selected participants (104 raltegravir and 97 tenofovir disoproxil fumarate/emtricitabine). We performed multivariable estimative and predictive linear regression.. At week 96, participants receiving tenofovir disoproxil fumarate/emtricitabine had a statistically significant higher gain in telomere length than participants receiving raltegravir. Difference in mean telomere length change between groups (tenofovir disoproxil fumarate/emtricitabine minus raltegravir) from baseline to week 96 adjusted by baseline telomere length was 0.031 (P = .009). This difference was not significantly confounded by age, gender, known duration of HIV infection, CD4 (baseline/nadir), CD8 cells, CD4/CD8 ratio, HIV viral load (baseline/week 96), tobacco and alcohol consumption, statins, or hepatitis C.. Antiretroviral-naive HIV-infected adults receiving ritonavir-boosted darunavir and tenofovir disoproxil fumarate/emtricitabine had a significant higher gain in blood telomere length than those receiving ritonavir-boosted darunavir and raltegravir, suggesting a better initial recovery from HIV-associated immunosenescence.

Topics: Adult; Analysis of Variance; Anti-HIV Agents; Darunavir; DNA; Emtricitabine; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Raltegravir Potassium; Randomized Controlled Trials as Topic; Ritonavir; Telomere; Tenofovir

To evaluate the cost effectiveness of dolutegravir + abacavir/lamivudine (DTG + ABC/3TC) compared with raltegravir + abacavir/lamivudine (RAL + ABC/3TC) and ritonavir-boosted darunavir + abacavir/lamivudine (DRV/r + ABC/3TC) in HIV-1-infected treatment-naive patients in Russia.. The viral suppression rate among patients receiving DTG + ABC/3TC was 71.7% compared with 65.2% for RAL + ABC/3TC and 59.6% for DRV/r + ABC/3TC. The mean duration of response per patient was 116.6 months for DTG + ABC/3TC, 108.6 months for RAL + ABC/3TC, and 98.9 months for DRV/r + ABC/3TC. Total discounted costs for treatment over patient lifetime were RUB 2.89, 5.32, and 4.38 million for DTG + ABC/3TC, RAL + ABC/3TC, and DRV/r + ABC/3TC, respectively. Lifetime discounted QALYs were 12.73 for patients on DTG + ABC/3TC and 12.72 each for patients on RAL + ABC/3TC and DRV/r + ABC/3TC. DTG + ABC/3TC thus dominated the other two alternatives.. With lower costs, higher response rates, and comparable QALYs, DTG + ABC/3TC can be considered as a cost-effective alternative.

Topics: Adult; Anti-HIV Agents; Cost-Benefit Analysis; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Lamivudine; Male; Oxazines; Piperazines; Pyridones; Quality-Adjusted Life Years; Raltegravir Potassium; Russia

Raltegravir became the first integrase inhibitor to gain FDA approval; but with limited evidence documenting long-term risks in real world care, especially for major health outcomes of interest.. Assess raltegravir safety in clinical practice within an integrated health system.. We conducted a cohort study of HIV-infected adults within Kaiser Permanente California from 2005 to 2013. We compared patients initiating raltegravir during the study period with two groups; a historical cohort (started new antiretroviral regimen [ART] 2005-2007) and a concurrent cohort that did not initiate raltegravir (2007-2013). We used multivariate Cox proportional hazard regression to obtain hazard ratios (HR) for pre-specified incident health outcomes, employing propensity scores to adjust for potential confounding.. The population included 8,219 HIV-infected adults (raltegravir cohort N = 1,757; 4,798 patient-years), with greater years known HIV-infected among raltegravir patients. The raltegravir cohort had increased HR for AIDS-defining (HR 2.69 [1.53-4.71]; HR 1.85 [1.21-2.82]) and non-AIDS-defining malignancies (HR 2.26 [1.29-3.94]; HR 1.88 [1.26-2.78]) relative to both comparison cohorts. Compared to the historical cohort we found no significant difference in all-cause mortality; the raltegravir cohort experienced increased HR for all-cause mortality compared to concurrent (HR 1.53 [1.02-2.31]). Raltegravir appeared protective of lipodystrophy when compared to the historical cohort but associated with increased incidence compared to concurrent. There were no significant differences in the incidence of hepatic, skin, or cardiovascular events.. The potentially elevated risk for malignancy and mortality with raltegravir and residual confounding merits further investigation. We demonstrate the value of observational cohorts for monitoring post-licensure medication safety.

Topics: Anti-HIV Agents; California; Cohort Studies; Delivery of Health Care, Integrated; HIV Infections; Humans; Product Surveillance, Postmarketing; Raltegravir Potassium; Treatment Outcome

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; HIV Infections; HIV-1; Humans; Raltegravir Potassium

Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them.. We compared rates and reasons for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients.. Retrospective analysis of a prospectively followed cohort including all antiretroviral-naive and all virologically suppressed antiretroviral-experienced patients prescribed a first regimen containing raltegravir, elvitegravir or dolutegravir with at least one follow-up visit. Major outcomes were early discontinuation (≤1 year) due to any reason and more specifically due to toxicity. Incidence was calculated as number of episodes per 1000 person-years. Risk factors for discontinuation were assessed by multivariate Cox models.. Early discontinuations due to any reason were 271 (raltegravir), 168 (elvitegravir) and 264 (dolutegravir) per 1000 patient-years ( P  =   0.0821). Early discontinuations due to toxicity were 76 (raltegravir), 103 (elvitegravir) and 81 (dolutegravir) per 1000 patient-years ( P  =   0.6792). Overall, the most common toxicities leading to discontinuation were neuropsychiatric, osteomuscular or digestive. Most frequent neuropsychiatric manifestations reported at discontinuation were insomnia, dizziness, headache and anxiety irrespective of the integrase inhibitor. Among discontinuations due to toxicity, neuropsychiatric effects were more common with dolutegravir than with raltegravir or elvitegravir ( P  =   0.0046). Age (HR 1.04, 95% CI 1.02-1.07, P  =   0.0007) was the only independent risk factor for early discontinuation due to toxicity.. Discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations due to toxicity did not differ among integrase inhibitors. Neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir.

Topics: Adult; Cohort Studies; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Life Style; Male; Medication Adherence; Middle Aged; Oxazines; Piperazines; Proportional Hazards Models; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, severe adverse event during treatment with raltegravir. The occurrence of DRESS syndrome during treatment with other drugs is strongly associated with particular HLA alleles.. We performed HLA testing in 3 of the 5 patients previously reported to have developed raltegravir-induced DRESS syndrome and in 1 previously unreported patient. We then used virtual modeling to visualize interactions between raltegravir and the imputed HLA molecule.. Five of the 6 patients who developed raltegravir-induced DRESS syndrome were African, and 1 was Hispanic. HLA typing was performed in 4 patients, all of whom carried both the HLA-B*53 allele and the HLA-C*04 allele to which it is commonly haplotypic. No other HLA alleles were shared by all of the tested patients. Given the approximate prevalence of HLA-B*53 carriage in African (20%) and Hispanic (6%) populations, the probability of all 4 patients being HLA-B*53 carriers, and 2 of 3 African patients being homozygous for HLA-B*53:01, is approximately 0.00002.. These data implicate the prevalent African allele HLA-B*53:01 in the immunopathogenesis of raltegravir-induced DRESS syndrome. Although the immunopathogenic mechanisms are currently unknown, virtual modeling suggests that raltegravir may bind within the antigen binding cleft of the HLA-B*53:01 molecule, but not within the closely related HLA-B*35:01 molecule. Further studies are necessary to confirm the strength of the association between carriage of the HLA-B*53:01 allele and raltegravir-induced DRESS syndrome, and the potential utility of HLA screening before raltegravir treatment.

Topics: Adolescent; Adult; Alleles; Anti-HIV Agents; Drug Hypersensitivity Syndrome; Female; Genetic Predisposition to Disease; HIV Infections; HLA Antigens; Humans; Male; Middle Aged; Models, Molecular; Protein Binding; Protein Conformation; Raltegravir Potassium

A broader extent of amino acid substitutions in the integrase of HIV-2 compared with HIV-1 might enable greater cross-resistance between raltegravir and dolutegravir in HIV-2 infection. Few studies have examined the virological response to dolutegravir in HIV-2 patients that failed raltegravir.. All patients recorded in the HIV-2 Spanish cohort were examined. The integrase coding region was sequenced in viraemic patients. Changes associated with resistance to raltegravir and dolutegravir in HIV-1 were recorded.. From 319 HIV-2-infected patients recorded in the HIV-2 Spanish cohort, 53 integrase sequences from 30 individuals were obtained (20 raltegravir naive and 10 raltegravir experienced). Only one secondary mutation (E138A) was found in one of the 20 raltegravir-naive HIV-2 patients. For raltegravir-experienced individuals, the resistance mutation profile in 9 of 10 viraemic patients was as follows: N155H + A153G/S (four); Y143G + A153S (two); Q148R + G140A/S (two); and Y143C + Q91R (one). Of note, all patients with Y143G and N155H developed a rare non-polymorphic mutation at codon 153. Rescue therapy with dolutegravir was given to 5 of these 10 patients. After >6 months on dolutegravir therapy, three patients with baseline N155H experienced viral rebound. In two of them N155H was replaced by Q148K/R and in another by G118R.. A wide repertoire of resistance mutations in the integrase gene occur in HIV-2-infected patients failing on raltegravir. Although dolutegravir may allow successful rescue in most HIV-2 raltegravir failures, we report and characterize three cases of dolutegravir resistance in HIV-2 patients, emerging variants Q148K and Q148R and a novel change G118R.

Topics: Adult; Amino Acid Substitution; Anti-HIV Agents; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; HIV-2; Humans; Male; Middle Aged; Mutation; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; RNA, Viral; Treatment Failure; Viremia

Only limited efficacy and tolerability data on raltegravir (RAL) use are currently available. Study objectives were to describe the efficacy and tolerability profile of RAL-based antiretroviral therapy (ART) in routine clinical practice in Germany. The WIP study (WIP = "Wirksamkeit von Isentress unter Praxisbedingungen", Efficacy of Isentress under routine clinical conditions) was a prospective, multi-centre cohort study in Germany. Human immunodeficiency virus (HIV)-infected patients aged ≥ 18 years in whom combinational ART with RAL 400 mg BID was indicated were enrolled. The primary endpoint was virologic response (HIV-RNA <50 copies/mL; non-completion equals failure) after 48 weeks. Of 451 patients, 85.1% (n = 384) were still receiving RAL at week 48. At baseline (BL), the prevalence of concomitant diseases was higher in patients of the age group ≥50 years (94.2% vs. 75.7%) as well as concomitant medications (74.8 % vs. 55.4%). Virologic response at week 48 was 74.7% (overall), 75.0% (naïve at BL), 81.5% (suppressed at BL), 47.1% (interrupted previous treatment at BL) and 64.9% (failing at BL), without significant differences by age group. A significant correlation of achievement of HIV-RNA <50 copies/mL was seen with treatment status at BL (p = 0.004). In addition, 77.3 % of the patients with a CD4 cell count >200 cells/µL at BL achieved HIV-RNA <50 copies/mL (p = 0.029). RAL was well tolerated with 80 adverse events (AEs) in 49 patients (10.9%) and 8 serious AEs (SAEs) in 6 patients (1.3%) reported to be drug related. A total of 22 patients (4.9%) discontinued treatment due to AEs. The WIP study shows that the previously reported efficacy and safety profile of RAL can be achieved in a population with multiple comorbidities and comedications, with no major difference observed in ageing patients (≥50 years) vs. younger patients. RAL is therefore an attractive treatment option in routine medical care in Germany.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Germany; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Raltegravir Potassium; RNA, Viral; Viral Load

We studied the relationships between plasma and saliva concentrations of antiretroviral drugs to explore whether saliva can be used for therapeutic drug monitoring (TDM).. Abacavir (ABC), tenofovir (TFV), darunavir (DRV), and raltegravir (RAL) in plasma and saliva from 30 HIV-1-infected patients were quantified using liquid chromatography-tandem mass spectrometry.. Mean saliva-to-plasma concentration ratios were 0.623 (ABC), 0.024 (TFV), 0.065 (DRV), and 0.0135 (RAL), which agree with the plasma protein binding rates except TFV. Significant correlations were evident between saliva and plasma concentrations of ABC, DRV, and RAL.. This study suggests that plasma concentrations of ABC, DRV, and RAL can be estimated from their saliva concentrations and that the saliva concentration of some antiretroviral drugs reflects the unbound drug concentration in plasma.
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Topics: Adult; Aged; Anti-HIV Agents; Chromatography, Liquid; Darunavir; Dideoxynucleosides; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Protein Binding; Raltegravir Potassium; Saliva; Tandem Mass Spectrometry; Tenofovir

Nucleos(t)ide reverse transcriptase inhibitors (NRTI) toxicity may represent a threat for long-term success of combined antiretroviral therapy. Some studies have suggested a possible improvement of NRTI-related toxicity after switching to NRTI-sparing regimens.. We aimed to explore the efficacy and tolerability of switching to darunavir/ritonavir (DRV/r) plus raltegravir (RAL) while having a viral load (VL) ≤50 copies/mL in the clinical setting.. Treatment-experienced HIV 1-infected patients enrolled in the ICONA Foundation Study cohort were included if they switched their current regimen to DRV/r + RAL with a HIV-RNA ≤50 copies/mL. Different definitions of virological failure (VF) and treatment failure (TF) were employed. Kaplan-Meier curves and Cox regression models were performed to estimate time to event probability.. We included 72 HIV-infected patients, 22 (31%) of these were female, 31 (43%) men who have sex with men (MSM) amd 15 (21%) had hepatitis co-infections. Median age was 44 (IQR: 35-50) years amd CD4 count was 389 (IQR 283-606) cells/mmc. Median follow-up time for TF was 24 (IQR 9-31) months. Twenty-five discontinuations occurred (60% simplifications); only 2 (8%) were toxicity-driven (lipid elevations). The probability of VF (confirmed VL >50 copies/mL) was estimated at 7% [95% confidence interval (CI) 1-13%] by 12 and 9% (95% CI 2-16%) by 24 months. When considering TF, we found a probability of stop/intensification/single VL > 200 copies/mL of 13% (95% CI 1-17%) and 22% (95% CI 11-33%) by 12 and 24 months. Female gender (adjusted relative hazard, ARH = 0.10; 95% CI 0.01-0.74; p = 0.024) and older age (AHR = 0.50 per 10 years older; 95% CI 0.25-0.99; p = 0.045) were associated with a lower risk of TF. A previous PI failure was strongly associated with TF (AHR = 52.6, 95% CI 3.6-779; p = 0.004).. DRV/r + RAL is a valuable NRTI-sparing option, especially in female and older patients, with a relatively low risk of VF and good tolerability after 2 years since start in an ART-experienced population. However, previous PI-failure should be a limiting factor for this strategy.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Italy; Male; Middle Aged; Raltegravir Potassium; Ritonavir; RNA, Viral; Viral Load

The long-term effectiveness of human immunodeficiency virus (HIV) treatments containing integrase inhibitors is unknown.. We use observational data from the Centers for AIDS Research Network of Integrated Clinical Systems and the Centers for Disease Control and Prevention to estimate 4-year risk of AIDS and all-cause mortality among 415 patients starting a raltegravir regimen compared to 2646 starting an efavirenz regimen (both regimens include emtricitabine and tenofovir disoproxil fumarate). We account for confounding and selection bias as well as generalizability by standardization for measured variables, and present both observational intent-to-treat and per-protocol estimates.. At treatment initiation, 12% of patients were female, 36% black, 13% Hispanic; median age was 37 years, CD4 count 321 cells/µL, and viral load 4.5 log10 copies/mL. Two hundred thirty-five patients incurred an AIDS-defining illness or died, and 741 patients left follow-up. After accounting for measured differences, the 4-year risk was similar among those starting both regimens (ie, intent-to treat hazard ratio [HR], 0.96 [95% confidence interval {CI}, .63-1.45]; risk difference, -0.9 [95% CI, -4.5 to 2.7]), as well as among those remaining on regimens (ie, per-protocol HR, 0.95 [95% CI, .59-1.54]; risk difference, -0.5 [95% CI, -3.8 to 2.9]).. Raltegravir and efavirenz-based initial antiretroviral therapy have similar 4-year clinical effects. Vigilance regarding longer-term comparative effectiveness of HIV regimens using observational data is needed because large-scale experimental data are not forthcoming.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Raltegravir Potassium; Reverse Transcriptase Inhibitors; RNA, Viral; Tenofovir; United States; Viral Load; Young Adult

A novel HIV-1 integrase mutation pattern, L74F V75I, which conferred resistance to first-generation integrase strand transfer inhibitors (INSTIs), was identified in a clinical case with virological failure under a raltegravir-based regimen. Addition of L74F V75I to N155H or G140S Q148H increased resistance levels to the second-generation INSTIs dolutegravir (>385- and 100-fold, respectively) and cabotegravir (153- and 197-fold, respectively). These findings are important for the development of an accurate system for interpretation of INSTI resistance and the rational design of next-generation INSTIs.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Raltegravir Potassium

To compare the effectiveness of HIV integrase inhibitor monotherapy between raltegravir and dolutegravir as an approach to simplify therapy.. We evaluated and compared the efficacy of 20 week monotherapy with dolutegravir or raltegravir in humanized mice (HSC-NSG) infected with HIVBaL. Plasma HIV RNA was measured by quantitative RT-PCR (limit of detection of 150 copies/45 μL of plasma) and drug levels by LC-MS/MS. Escape viruses were genotyped and analysed for replication capacity and drug susceptibility in tissue culture.. Drug-untreated control mice maintained constant viraemia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC50 of <8 nM) and dolutegravir (EC50 of <1 nM). Mice treated with raltegravir or dolutegravir had plasma drug levels comparable to those in humans. Monotherapy with raltegravir initially suppressed HIV viraemia, but failed to maintain suppression in 4/4 mice. Viruses from raltegravir failing mice developed mutations G140G/S and Q148H/K, and were resistant to both raltegravir (EC50 values of >100 nM) and dolutegravir (EC50 values ranging from 8.8 to 13.3 nM). Monotherapy with dolutegravir suppressed viraemia in 5/5 of mice, but viraemia rebounded in one animal. The virus from this mouse had mutations E138K, G140S, Q148H, N155H and S230R, was highly resistant to both raltegravir (EC50 of >1000 nM) and dolutegravir (EC50 of 550 nM), and replicated to levels similar to those of control viruses in PBMCs.. Monotherapy with either raltegravir or dolutegravir does not consistently maintain HIV suppression, suggesting that dual therapy may be required in simplification strategies.

Topics: Animals; Anti-HIV Agents; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mice; Mice, Transgenic; Mutation; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; RNA, Viral; Viremia; Virus Replication

The importance of an early reduction of HIV-1 RNA as a marker for positive longer term outcome is still under debate. We investigate whether antiretroviral-experienced patients receiving raltegravir plus etravirine have a higher early reduction of HIV-1 RNA compared with patients receiving raltegravir.. An observational study of treatment-experienced patients.. The objective is to investigate 349 patients included in a raltegravir resistance study. The early outcome is defined as a reduction of HIV-1 RNA at week 8. The crude method defines all measurements below the limit of quantification to be equal to the limit of quantification provides biased estimates. Such a reduction is censored by the limit of quantification and is subject to selection bias in observational studies.. The crude method showed a significant higher reduction in HIV-1 RNA reduction in patients receiving raltegravir plus etravirine compared with patients receiving raltegravir (mean reduction of 2.1 versus 1.8 log10 copies/mL). However, survival methods adjusted for both censoring, due to the limit of quantification, and confounding factors lead to a nonsignificant difference between the 2 treatment groups (mean reduction of 2.8 versus 2.7 log10 copies/mL).. Taking into account censoring and confounding factors, our study did not demonstrate a higher early reduction of HIV-1 RNA in patients receiving raltegravir with versus without etravirine.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; France; Gene Expression Regulation, Viral; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nitriles; Propensity Score; Pyridazines; Pyrimidines; Raltegravir Potassium; RNA, Viral; Viral Load

An observational, prospective, cohort study was performed to compare efficacy and safety of a switch from ritonavir-boosted protease inhibitor (PI/r) to nevirapine or raltegravir with that of rosuvastatin addition to current antiretroviral therapy in HIV-infected patients with hyperlipidaemia.. All HIV-infected patients receiving a stable PI/r-based antiretroviral regimen, with persistently suppressed viremia, naïve to non-nucleoside analogues and to integrase strand transfer inhibitors, with mixed hyperlipidaemia, and who underwent a switch from PI/r to nevirapine (Group A) or raltegravir (Group B) or who started rosuvastatin at 10 mg daily (group C) with unchanged antiretroviral regimen were enrolled into the study.. Overall, 136 patients were enrolled: 43 patients were included in the group A, 46 in the group B, and 47 in the group C. The mean age was 46.6 years, and 108 (79.4%) were males. After 48 weeks of follow-up, a significantly greater reduction in the mean low-density lipoprotein (LDL) cholesterol level was reported in group C (-28.2%) than in group A (-10.2%; p < .001) and B (-12.4%; p = .021), while a significantly greater reduction in the mean concentration of triglycerides was observed in group A (-31.2%) and B (-35.5%) than in group C (-11.9%; p = .034 and p = .004, respectively). The incidence of adverse events was <10% and comparable across the three groups.. In HIV-positive subjects receiving a PI/r, the initiation of rosuvastatin treatment after 48 weeks yielded a greater decline in LDL cholesterol, while the switch from PI/r to nevirapine or raltegravir led to a greater decline in triglycerides.

Topics: Adult; Anti-HIV Agents; Anticholesteremic Agents; Antiretroviral Therapy, Highly Active; Cholesterol, LDL; Cohort Studies; Drug Substitution; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Hyperlipidemias; Male; Middle Aged; Nevirapine; Prospective Studies; Raltegravir Potassium; Ritonavir; Rosuvastatin Calcium; Viral Load; Viremia

To compare the frequency and risk factors of toxicity-related treatment discontinuations between raltegravir and dolutegravir.. Prospective cohort study.. All antiretroviral therapy (ART)-naïve and ART-experienced HIV-infected individuals from the Swiss HIV Cohort Study who initiated raltegravir or dolutegravir between 2006 and 2015 were investigated concerning treatment modification within the first year.. Of 4041 patients initiating ART containing raltegravir (n = 2091) or dolutegravir (n = 1950), 568 patients discontinued ART during the first year, corresponding to a rate of 15.5 [95% confidence interval (CI) 14.5-16.9] discontinuations per 100 patient-years. Only 10 patients on raltegravir (0.5%) and two patients on dolutegravir (0.1%) demonstrated virologic failure. The main reason for ART discontinuation was convenience expressed as patient's wish, physician's decision, or treatment simplification (n = 302). Toxicity occurred in 4.3% of patients treated with raltegravir and 3.6% with dolutegravir, respectively. In multivariable analysis, the only independent risk factor for discontinuing ART because of toxicity was female sex (hazard ratio 1.98, 95% CI 1.45-2.71, P < 0.001).Neuropsychiatric complaints were the most commonly reported toxic adverse events and more frequent in the dolutegravir (n = 33, 1.7%) compared with the raltegravir group (n = 13, 0.6%). Risk of discontinuation for neurotoxicity was lower for raltegravir than for dolutegravir in multivariable analysis (hazard ratio 0.46, 95% CI 0.22-0.96, P = 0.037).. In this, large cohort raltegravir and dolutegravir-containing regimen demonstrated a high virologic efficacy. Drug toxicity was infrequent and discontinuation because of neuropsychiatric events within the first year of treatment was only marginal higher with dolutegravir compared with raltegravir. However, monitoring of neurotoxic side-effects of dolutegravir is important.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Drug-Related Side Effects and Adverse Reactions; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Male; Mental Disorders; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Raltegravir Potassium; Switzerland; Withholding Treatment; Young Adult

: The HIV-1 integrase E157Q natural polymorphism has been reported to cause one case of raltegravir (RAL) and dolutegravir (DTG) failure. Six recombinant viruses were constructed containing integrase from clinical HIV-1 isolates found to harbour E157Q as the only integrase strand inhibitor (INSTI) resistance-related mutation. Phenotypic analysis showed that E157Q results in minimal changes in RAL and DTG susceptibility. Together with data retrieved from the Stanford HIV database, our results indicate that E157Q is not a relevant INSTI resistance mutation per se. The previously reported case of E157Q-based resistance must have resulted from combined as yet unidentified integrase polymorphisms.

Topics: Anti-HIV Agents; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Mutation, Missense; Oxazines; Piperazines; Polymorphism, Genetic; Pyridones; Raltegravir Potassium

To determine natural phenotypic susceptibility of non-group M HIV-1 to integrase strand transfer inhibitors (INSTIs) in a large panel of 39 clinical strains from groups O, N and P and to identify genotypic polymorphisms according to susceptibility levels.. Susceptibility to raltegravir, elvitegravir and dolutegravir was evaluated in 36 HIV-1/O, 2 HIV-1/N and 1 HIV-1/P strains plus an HIV-1/M reference strain. IC50 values were determined after 3 days, and fold changes (FCs) were calculated relative to the HIV-1/M strain. Genotypic polymorphism was determined by amplification of codons 19-263 of the integrase; the natural occurrence of resistance-associated mutations was analysed using the main resistance algorithms and the IAS-USA list. VESPA analysis of the strain sequences was used to determine a signature pattern associated with higher FC.. Similar IC50 results were observed for the three drugs. Based on the value for the HIV-1/M reference strain, the data showed FC values <2.5 for raltegravir and dolutegravir, whereas the distribution for elvitegravir was heterogeneous, with FC > 10 for six strains (15%). Analysis of the non-M integrase sequences showed a high level of polymorphism without a major genotypic impact; it also revealed mutations that may be associated with the highest FC values obtained for elvitegravir.. Our phenotypic data showed that non-M strains are globally susceptible to the three currently used INSTIs, but the impact of the high FC values observed for some strains with elvitegravir needs to be explored. Clinical data are now needed to confirm these phenotypic results.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Inhibitory Concentration 50; Mutation; Oxazines; Phenotype; Phylogeny; Piperazines; Polymorphism, Genetic; Pyridones; Quinolones; Raltegravir Potassium

Topics: Anti-HIV Agents; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium

Resistance to the integrase strand transfer inhibitors raltegravir and elvitegravir is often due to well-identified mutations in the integrase gene. However, the situation is less clear for patients who fail dolutegravir treatment. Furthermore, most

Topics: Amino Acid Substitution; Cell Line; Drug Resistance, Viral; Genes, nef; Heterocyclic Compounds, 3-Ring; High-Throughput Nucleotide Sequencing; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Integration; Virus Replication; Zidovudine

Sub-optimal penetration of antiretroviral drugs in genital compartments might promote local HIV persistence and increase the risk of HIV transmission.. To describe the penetration of maraviroc, raltegravir, raltegravir glucuronide and rilpivirine in seminal plasma and cervico-vaginal secretions (CVS) and to assess local antiretroviral efficacy in HIV-1-positive patients.. This was a prospective, multicentre study. Inclusion criteria were HIV-1 positive, age >18 years, receiving regimens containing maraviroc and/or raltegravir and/or rilpivirine for >1 month, and good self-reported adherence. Paired blood and genital samples were collected 12 h (raltegravir and maraviroc) or 24 h (rilpivirine) post-dose. These concentrations were determined (UPLC-MS/MS) in blood and seminal plasma (total and unbound) and CVS (total, dried spots) and HIV-RNA was quantified in paired blood and genital samples.. Among the 54 enrolled patients, 15 received maraviroc (6 men), 27 received raltegravir (14 men) and 20 received rilpivirine (10 men), corresponding to 54 total and 52 unbound plasma concentrations, 29 total CVS samples and 23 total and 18 unbound seminal plasma samples. Maraviroc and raltegravir displayed a ratio of genital fluids/plasma concentrations >0.5 in both male and female genital tracts. Conversely, rilpivirine displayed a low ratio. Antiretroviral free fractions were consistent with historical data. Nine patients had blood plasma HIV-RNA >50 copies/mL (2/9 had sub-optimal antiretroviral blood plasma exposure) and two other patients had detectable HIV-RNA in genital fluids.. Maraviroc and raltegravir demonstrated good penetration in genital compartments, yielding good local virological response in genital compartments, whereas rilpivirine presented a low penetration profile but good local response.

Topics: Adult; Anti-HIV Agents; Body Fluids; Cervix Uteri; Cyclohexanes; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Prospective Studies; Raltegravir Potassium; Rilpivirine; Semen; Triazoles; Vagina; Viral Load

Raltegravir (RAL) is considered one of the better-tolerated antiretroviral medications, due to limited side effects and minimal drug-drug interactions. Matherials and Methods: We retrospectively evaluated 96 HIV+, over 60 years old, experienced patients who had switched from any antiretroviral drug to raltegravir-based nuc-sparing or standard nucleoside-backbone regimens. A control group with patients aged under 60 years old was included.. The median age of the patients was 66 years (IQR 10.5) (77 M, 19 F); the median time horizon of follow-up was 4 years (IQR 5). HIV-RNA at baseline was undetectable for more than 6 months in most of the patients. Median CD4+ count was 453 cells/mmc (IQR 379). 49 patients had AIDS history. All the patients were assuming concomitant medications. No adverse effect attributed to the use of raltegravir was reported in the medical records. Only 2 patients presented virological failure, whereas viremic blips were observed in 10 patients. After switching to RAL-containing regimens triglycerides values showed a statistically significant reduction from a median value of 172 (IQR 105.5) mg/dl to 129 mg/dl (IQR 73) (p=0,0001). Switching to a standard regimens was associated with a marked reduction of triglycerides. Cholesterol levels were reduced at the time of follow-up (T2) but no significant modifications were observed when patients which had introduced drugs to treat dislypidemia were removed from the analysis; in contrast, triglycerides reduction was also confirmed in this sub-group. Patients presented higher levels of CD4+ at T2 and reduced platelet count [from 230 300/mmc (SD 123 527) to 197 125/mmc (SD 66 377), p=0,04]. Similar trends were observed in younger patients.. RAL-containing regimens are safe and highly effective in the older population. RALtreatment is associated with the reduction of triglycerides and platelets count in the older population.

Topics: Aged; Aged, 80 and over; CD4 Lymphocyte Count; Female; Follow-Up Studies; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Platelet Count; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Triglycerides; Viral Load

The dynamics of latent HIV is linked to infection and clearance of resting memory CD4+ T cells. Infection also resides within activated, non-dividing memory cells and can be impacted by antigen-driven and homeostatic proliferation despite suppressive antiretroviral therapy (ART). We investigated whether plasma viral level (pVL) and HIV DNA dynamics could be explained by HIV's impact on memory CD4+ T cell homeostasis. Median total, 2-LTR and integrated HIV DNA levels per μL of peripheral blood, for 8 primary (PHI) and 8 chronic HIV infected (CHI) individuals enrolled on a raltegravir (RAL) based regimen, exhibited greatest changes over the 1st year of ART. Dynamics slowed over the following 2 years so that total HIV DNA levels were equivalent to reported values for individuals after 10 years of ART. The mathematical model reproduced the multiphasic dynamics of pVL, and levels of total, 2-LTR and integrated HIV DNA in both PHI and CHI over 3 years of ART. Under these simulations, residual viremia originated from reactivated latently infected cells where most of these cells arose from clonal expansion within the resting phenotype. Since virion production from clonally expanded cells will not be affected by antiretroviral drugs, simulations of ART intensification had little impact on pVL. HIV DNA decay over the first year of ART followed the loss of activated memory cells (120 day half-life) while the 5.9 year half-life of total HIV DNA after this point mirrored the slower decay of resting memory cells. Simulations had difficulty reproducing the fast early HIV DNA dynamics, including 2-LTR levels peaking at week 12, and the later slow loss of total and 2-LTR HIV DNA, suggesting some ongoing infection. In summary, our modelling indicates that much of the dynamical behavior of HIV can be explained by its impact on memory CD4+ T cell homeostasis.

Topics: CD4-Positive T-Lymphocytes; Drug Administration Schedule; HIV; HIV Infections; HIV Integrase Inhibitors; Homeostasis; Humans; Immunologic Memory; Raltegravir Potassium; Viral Load

We investigated the effect of combination antiretroviral therapy (cART) on immune recovery, particularly on the percentages of PD-1-positive cells within the major leukocyte subsets. Cryopreserved peripheral blood mononuclear cells and plasma samples collected longitudinally from a subset of 13 children and adolescents (between 9.7 and 18.2 years old) who were enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1066 were used for this study. Immunophenotyping by flow cytometry was performed to determine the effect of raltegravir-containing cART regimen on the distribution of leukocyte populations, on the expression of PD-1 on T cell subpopulations, and on the expression of well-established markers of T cell activation (CD38 and HLA-DR) on CD8 T cells. C reactive protein (CRP), lipopolysaccharide (LPS), IL-6, and soluble CD163 were assayed in plasma samples by an enzyme-linked immunosorbent assay. Plasma viral loads were decreased in all subjects (by an average of 2.9 log units). The cART regimen, including raltegravir, induced changes in CD8 T cell subsets, consistent with an effective antiretroviral outcome and improved immunologic status, including increased percentages of CD8 stem cell memory T cells (Tscm). The percentages of CD8 PD-1-positive cells decreased significantly as compared with baseline levels. Among the proinflammatory markers measured in plasma, sCD163 showed a decline that was associated with cART. cART therapy, including raltegravir, over 48 weeks in children is associated with immune restoration, consistent with effective antiretroviral therapy, namely decreased percentages of PD-1

Topics: Adolescent; ADP-ribosyl Cyclase 1; Aged; Anti-HIV Agents; CD8-Positive T-Lymphocytes; Child; Female; Flow Cytometry; HIV Infections; HLA-DR Antigens; Humans; Immune Reconstitution; Immunophenotyping; Longitudinal Studies; Male; Membrane Glycoproteins; Programmed Cell Death 1 Receptor; Raltegravir Potassium; T-Lymphocyte Subsets; Treatment Outcome; Viral Load

Integrase strand transfer inhibitors (INSTIs) have become integral antiretroviral therapy (ART) agents for treating HIV infection. We report the case of a 44-year-old male with a history of hemophilia A who developed diabetes mellitus four months after switching from abacavir, lamivudine, and efavirenz to abacavir, lamivudine, and raltegravir. Hemoglobin A1C normalized without further need for exogenous insulin after raltegravir was switched back to efavirenz. In this case report, we will review a possible mechanism for INSTI-induced hyperglycemia and/or diabetes mellitus.

Topics: Adult; Diabetes Mellitus; Dideoxynucleosides; Drug Combinations; Glycated Hemoglobin; HIV Infections; HIV Integrase Inhibitors; Humans; Lamivudine; Male; Raltegravir Potassium

Unboosted atazanavir with raltegravir has been investigated at 300mg twice daily showing frequent hyperbilirubinemia and selection of resistance-associated mutations.. Atazanavir 200mg twice daily could increase tolerability and plasma exposure.. Patients on atazanavir/raltegravir (200/400 twice daily), with self-reported adherence >95% and no concomitant interacting drugs were retrospectively evaluated.. Switch to atazanavir/raltegravir was safe and well tolerated allowing optimal drugs' plasma exposure. However, a concerning rate (18.6%) failed with newly selected mutations and stopped ATV/RAL because of DDI and intolerance issues or were lost to follow-up. This regimen might be considered in selected patients, without history of protease inhibitors failure or HBV infection, showing optimal adherence and prolonged suppression.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation, Missense; Plasma; Raltegravir Potassium; Retrospective Studies; Selection, Genetic; Treatment Outcome; Viral Load

Ultra-deep sequencing (UDS) allows detection of minority resistant variants (MRVs) with a threshold of 1% and could be useful to identify variants harbouring single or multiple drug-resistance mutations (DRMs).. We analysed the integrase gene region longitudinally using UDS in an HIV-1-infected child rapidly failing a raltegravir-based regimen.. Longitudinal plasma samples at baseline and weeks 4, 8, 13, 17 and 39 were obtained, as well as the mother's baseline plasma sample. Sanger sequencing and UDS were performed on the integrase gene using Roche 454 GS-Junior. A bioinformatic workflow was developed to identify the major DRMs, accessory mutations and the linkage between mutations.. In Sanger sequencing and UDS, no MRV in the integrase gene was detected at baseline in either the mother or the child. The major DRM N155H conferring resistance to raltegravir and elvitegravir was detected in 4% of the sequences by week 4 using UDS, whereas it was not detected by Sanger sequencing. The double mutant E92Q + N155H, conferring resistance to the entire integrase inhibitor class, including dolutegravir, emerged at week 8 (16%) and became rapidly dominant (57% by week 13). At the last timepoint under raltegravir (week 17), Y143R emerged, leading to different resistance mutation patterns: single mutants N155H (47%) and Y143R (24%) and double mutants E92Q + N155H (13%), Y143R + N155H (2%) and E92Q + Y143R (2%). The polymorphic substitution M50I was preferentially selected on resistant variants, especially on E92Q + N155H variants.. This case study illustrates the usefulness of UDS in detecting early MRVs and determining the dynamics of selected HIV-1 variants in longitudinal analysis.

Topics: Child; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; High-Throughput Nucleotide Sequencing; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; RNA, Viral; Selection, Genetic

Antiretroviral therapy can suppress HIV-1 plasma viral load to below the detection limit but cannot eradicate the virus. Whether residual ongoing viral replication persists during suppressive therapy remains unclear. A few clinical studies showed that treatment intensification with an additional drug led to a lower viral load or an increase in 2-LTR (long terminal repeat), a marker for ongoing viral replication. However, some other studies found no change in the viral load and 2-LTR. In this paper, we developed multi-stage models to evaluate the influence of treatment intensification with the integrase inhibitor raltegravir on viral load and 2-LTR dynamics in HIV patients under suppressive therapy. We analyzed one model and obtained the local and global stability of the steady states. The model and its variation predict that raltegravir intensification induces a very minor decrease in the viral load and a minor increase in 2-LTR. We also compared modeling prediction with the 2-LTR data in a raltegravir intensification study. To achieve the 2-LTR increase observed in some patients, the level of viral replication needs to be substantially high, which is inconsistent with the sustained viral suppression in patients during treatment intensification. These modeling results, together with the theoretical estimate of the upper bound of the 2-LTR increase, suggest that treatment intensification with raltegravir has a minor effect on the plasma viremia and 2-LTR in patients under suppressive therapy. Other treatment strategies have to be developed for the cure or functional control of the infection.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dose-Response Relationship, Drug; HIV Infections; Humans; Male; Middle Aged; Models, Biological; Raltegravir Potassium; Terminal Repeat Sequences; Viral Load; Young Adult

Here we describe a case of an HIV-infected young woman with extensive drug-resistant virus, who was successfully switched from a raltegravir-based regimen to a dolutegravir-based intensified antiretroviral regimen a few days before scheduled caesarean section because of the still detectable viral load. The trough concentrations of all antiretroviral drugs before and after delivery are also described. Our case underlines both the difficult management of young women, HIV-infected at young age with very limited treatment options and the great variability in the pregnancy-related physiological changes affecting the pharmacokinetics of antiretrovirals.

Topics: Adult; Anti-HIV Agents; Biological Availability; Cesarean Section; Drug Administration Schedule; Drug Monitoring; Drug Resistance, Viral; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pregnancy; Pyridones; Raltegravir Potassium; Viral Load

Nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI)-sparing antiretroviral regimens may be useful in selected human immune deficiency virus (HIV)-infected patients with resistance or intolerance to these drug classes. This was an observational prospective study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted PI who switched to a dual regimen containing raltegravir plus etravirine. Patients were required not to have prior virological failure to raltegravir and to have efficacy of etravirine shown through the genotypic resistance assay in case of prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure. As a whole, 38 patients were enrolled. The mean duration of current regimen was 4.3 years, and the reason for simplification was toxicity in 29 patients and resistance to NRTIs in 9 patients. After switching, the percentage of patients with HIV RNA <20 copies/ml at week 48 was 81.6% in the intent-to-treat-exposed analysis. The switch led to a significant reduction in the mean serum triglyceride levels (-81.2 mg/dl), in the mean total cholesterol levels (-44.3 mg/dl), and in the prevalence of tubular proteinuria (-30.2%), with a significant increase in the mean phosphoremia (+0.52 mg/dl) and in both mean lumbar and femoral neck bone mineral density (+6.5% and +4.7%, respectively). Two patients (5.2%) had virological failure due to suboptimal adherence, and five subjects (13.1%) discontinued treatment due to adverse events. In our study, simplification to the dual-therapy raltegravir plus etravirine was associated with a good efficacy and tolerability, in addition to a favorable effect on kidney, bone, and serum lipids.

Topics: Adult; Aged; Anti-HIV Agents; Female; HIV Infections; Humans; Maintenance Chemotherapy; Male; Middle Aged; Nitriles; Prospective Studies; Pyridazines; Pyrimidines; Raltegravir Potassium; Treatment Outcome

We evaluated the effectiveness of a raltegravir (RAL)-containing regimen plus an optimized background regimen in HIV-1 highly treatment-experienced patients.. A retrospective cohort, multicentre study was conducted.. Adult (>16 years old) HIV treatment-experience patients starting therapy with a RAL-containing regimen were included. Effectiveness was evaluated as the percentage of patients with an undetectable HIV-1 RNA viral load (<50 and <200 copies/mL) after 48 weeks, and changes in CD4+ cell counts. We evaluated the risk factors associated with treatment failure.. Of the 107 patients in the cohort, 86% were men, the median age was 45 years [interquartile range (IQR) 40-52] and the median number of previous regimens was six (IQR 4-7). After 48 weeks of treatment, 73% (IQR 63-80%) of patients (n = 78) had a viral load of <50 copies/mL and 85% (IQR 77-90%) (n = 91) had <200 copies/mL. In a logistic regression model, risk factors associated with a virological outcome of HIV-1 RNA of <200 copies/mL were age >40 years [odds ratio (OR) 5.61; 95% confidence interval (CI) 1.61-18.84; P = 0.006] and use of tenofovir in the regimen (OR 0.16; 95% CI 0.03-0.80; P = 0.026).. In this Mexican cohort, RAL achieved high rates of virological suppression and an increase in CD4+ cell count in highly treatment-experienced patients infected with HIV-1. Age >40 years was associated with a good virological outcome, contrary to tenofovir use, which was associated with a poor virological outcome.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Raltegravir Potassium; Retrospective Studies; Risk Factors; Treatment Outcome

Good efficacy and safety of raltegravir in person living with HIV was demonstrated in clinical trials over five years, but real-life data, particularly about quality of life (QoL), are lacking. QoL was evaluated over time in adult patients first treated or switched to regimens containing raltegravir in an observational cohort study.. Patient QoL was evaluated using the Fatigue Impact Scale (FIS) and the HIV Symptom Index (HSI). Data were collected at baseline and at 1, 3, 6, 12, 18, and 24 months. Baseline FIS and HSI subscores were compared with the scores at each visit using the paired Wilcoxon test. The impact of time, sociodemographic and medical variables upon patient-perceived fatigue and symptoms was also assessed using mixed multivariate models.. From baseline, all FIS and HSI subscores improved significantly after one month of treatment. In addition, psychosocial FIS subscores and both the frequency of bothersome symptoms and HSI subscores improved significantly at each visit. Physical FIS subscores also improved significantly, except at month 18, whereas both cognitive and total FIS subscores improved only after 6 months and 24 months, respectively. In multivariate analysis, employment was independently associated over time with improved improvement in both FIS and HSI subscores.. Patient QoL improved significantly over a 24-month period of treatment with a raltegravir-containing regimen. FIS and HSI are sensitive tools to measure the impact of new antiretroviral combinations on a patient's perception of QoL.

Topics: Adolescent; Adult; Anti-HIV Agents; Fatigue; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Quality of Life; Raltegravir Potassium; Risk Factors; Socioeconomic Factors; Surveys and Questionnaires; Time Factors; Treatment Outcome; Young Adult

We report a case of therapeutic drug monitoring guided raltegravir use for the prevention of vertical HIV transmission in a premature neonate born to a woman living with perinatally acquired HIV and documented resistance to multiple HIV drugs. Maternal viral load was above 1,000 copies/ml at delivery. This case demonstrates delayed raltegravir elimination in a neonate born at 33 weeks gestational age and a need for less frequent raltegravir dosing than is used in older infants and children.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Monitoring; Drug Resistance, Viral; Female; HIV Infections; Humans; Infant, Newborn; Infant, Premature; Infectious Disease Transmission, Vertical; Post-Exposure Prophylaxis; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Treatment Outcome; Viral Load

Raltegravir is the first integrase inhibitor antiretroviral agent that has been demonstrated to have antiviral efficacy and safety. However, the US Food and Drug Administration has recommended use with caution in patients with risk factors for rhabdomyolysis, based on four case reports of rhabdomyolysis in patients with identifiable risk factors. We present a 32-year-old Asian man with human immunodeficiency virus (HIV), but without other underlying diseases, who developed rapid-onset, raltegravir-associated rhabdomyolysis and hyperlactatemia. Our patient lacked predisposing factors for rhabdomyolysis, and the rapid onset time of 4 days was the shortest reported. Therefore, clinicians should exercise caution when using raltegravir and closely monitor all patients for the symptoms of muscle pain and weakness. This case has been reported to the National Adverse Drug Reactions Reporting System of the Department of Health in Taiwan.

Topics: Adult; Anti-Retroviral Agents; Asian People; HIV Infections; Humans; Hyperlactatemia; Male; Raltegravir Potassium; Rhabdomyolysis; Taiwan; Time

A potential difficulty in the analysis of biomarker data occurs when data are subject to a detection limit. This detection limit is often defined as the point at which the true values cannot be measured reliably. Multiple, regression-type models designed to analyze such data exist. Studies have compared the bias among such models, but few have compared their statistical power. This simulation study provides a comparison of approaches for analyzing two-group, cross-sectional data with a Gaussian-distributed outcome by exploring statistical power and effect size confidence interval coverage of four models able to be implemented in standard software. We found using a Tobit model fit by maximum likelihood provides the best power and coverage. An example using human immunodeficiency virus type 1 ribonucleic acid data is used to illustrate the inferential differences in these models.

Topics: Anti-HIV Agents; Bias; Cross-Sectional Studies; HIV Infections; HIV-1; Humans; Likelihood Functions; Limit of Detection; Multivariate Analysis; Normal Distribution; Probability; Raltegravir Potassium; RNA, Viral; Software; Viral Load

We report safety and tolerability of raltegravir (RAL) as a forth HIV agent in two highly viraemic newborns. Raltegravir (6 mg/kg) was given orally twice daily. The other antiretrovirals were assumed according to standard dose for newborns. The first baby was born at week 36. An antiretroviral therapy consisting of zidovudine, lamivudine, and lopinavir/ritonavir was started 96 hour after delivery. Raltegravir was added at hour 120, being plasma HIV-1 RNA above 10×10(6) copies/ml. HIV RNA declined to 5·000 copies/ml at day 30. The second baby was born at week 40. He was started on zidovudine, lamivudine, and nevirapine at day 0, while RAL was added at day 3. Plasma HIV-1 RNA declined from 6·6×10(6) at birth to 52 copies/ml at day 28. RAL tolerability was good in both patients, one with gamma-glutamyltransferase increase, which normalized after RAL discontinuation. Raltegravir-based four drug regimen may be effective and well tolerated in highly viraemic HIV neonates up to 4 weeks.

Topics: Adult; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Pregnancy; Pregnancy Complications, Infectious; Raltegravir Potassium; Viremia; Young Adult

Raltegravir was the first licensed integrase inhibitor. Real-life experience is informative and complements trial data. We therefore evaluated raltegravir use in adults in a large HIV treatment centre. From pharmacy and departmental HIV database records, we identified all adults taking ≥1 dose of raltegravir from first availability to the end of November 2012. Data were collected using a standardised case report form. Two hundred and fifteen individuals provided 502 patient-years (median 2.6 years/person) of raltegravir use. Of 215 individuals, 166 (77%) were male, median age 43 years; 189 (88%) were antiretroviral therapy (ART)-experienced and 26 (12%) ART-naive, with median baseline CD4 counts of 324 and 54 cells/µL, respectively. Of ten individuals using once-daily raltegravir, four, with good adherence remained virologically suppressed after a median 28 months, four stopped against medical advice, one stopped to simplify and one failed virologically. In hepatitis co-infection, 35 individuals (92 patient-years) took raltegravir without evidence of hepatotoxicity. Six women started raltegravir during pregnancy for intensification (5/6) or switch for tolerability without complications. Of ten individuals stopping raltegravir after virological failure, 2/4 with successful sequencing showed resistance. Raltegravir appears safe and effective, without evidence of toxicity above that in published trials, including in pregnancy and co-infections. Once-daily dosing seems effective where adherence is good.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Coinfection; Female; Hepatitis, Viral, Human; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Life Change Events; Male; Pregnancy; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Viral Load

Abacavir/lamivudine (ABC/3TC) is a nucleoside reverse transcriptase inhibitor used for treating human immunodeficiency viral (HIV) infections. Hypersensitivity reactions such as skin eruptions caused by ABC are well-known, but rarely occur in Asians. Raltegravir (RAL) is an integrase strand transfer inhibitor, that is now increasingly, used for treating HIV infections because it has few adverse effects. This retrospective analysis assessed the efficacy and safety of combined ABC/3TC and RAL in both treatment-naïve and -experienced Japanese patients with HIV infections. In all 11 treatment-naïve patients (100%), virological suppression to undetectable level was achieved. Liver transaminases, renal function, and serum lipid profiles showed no exacerbations up to 48 weeks of treatment. In 12 patients who were switched from previous regimens to ABC/3TC and RAL, HIV viral load was undetectable in 11 patients (91.6%), but remained detectable in 1 patient with poor adherence. Major reasons for switching regimens to ABC/3TC and RAL were hyperlipidemia and nausea. After switching, these adverse effects improved, and no new adverse effects were observed. Despite the small number of participants in this study, the results support the combination of ABC/3TC and RAL as a possible treatment choice in Japanese individuals with HIV-infection.

Topics: Adult; Anti-HIV Agents; Asian People; Dideoxynucleosides; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Hyperlipidemias; Kidney Function Tests; Lamivudine; Lipids; Liver Function Tests; Male; Middle Aged; Nausea; Pilot Projects; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Viral Load; Young Adult

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepatitis C, Chronic; HIV Infections; Humans; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Proline; Raltegravir Potassium; Ritonavir; Sulfonamides; Uracil; Valine

In comparative effectiveness research, it is often of interest to calibrate treatment effect estimates from a clinical trial to a target population that differs from the study population. One important application is an indirect comparison of a new treatment with a placebo control on the basis of two separate randomized clinical trials: a non-inferiority trial comparing the new treatment with an active control and a historical trial comparing the active control with placebo. The available methods for treatment effect calibration include an outcome regression (OR) method based on a regression model for the outcome and a weighting method based on a propensity score (PS) model. This article proposes new methods for treatment effect calibration: one based on a conditional effect (CE) model and two doubly robust (DR) methods. The first DR method involves a PS model and an OR model, is asymptotically valid if either model is correct, and attains the semiparametric information bound if both models are correct. The second DR method involves a PS model, a CE model, and possibly an OR model, is asymptotically valid under the union of the PS and CE models, and attains the semiparametric information bound if all three models are correct. The various methods are compared in a simulation study and applied to recent clinical trials for treating human immunodeficiency virus infection.

Topics: Anti-HIV Agents; Calibration; Computer Simulation; Data Interpretation, Statistical; HIV Infections; Humans; Models, Statistical; Outcome Assessment, Health Care; Raltegravir Potassium; Randomized Controlled Trials as Topic; Regression Analysis; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome

The antiretroviral regimens including tenofovir and a ritonavir-boosted protease inhibitor (r/PI) have been associated with a reduced bone mineral density (BMD), increased bone turnover markers and renal tubular dysfunction.. An observational, prospective study was performed including HIV-1-infected, virologically suppressed patients treated with tenofovir/emtricitabine plus an r/PI for at least 12 months who switched to raltegravir plus nevirapine. The primary end point was changes after 48 weeks in estimated glomerular filtration rate (eGFR), prevalence of tubular dysfunction, BMD and concentration of two serum markers of bone turnover: collagen type-1 cross-linked C-telopeptide (CTX) and bone-specific alkaline phosphatase (BAP).. A total of 46 patients were enrolled: 78% were male, 96% were Caucasian, the mean age was 45 years and the mean CD4(+) T-lymphocyte count was 681 cells/mm(3). A renal impairment was present in 72% of patients and was the main reason for the switch. After 48 weeks, prevalence of proximal tubular dysfunction decreased significantly (-72%; P<0.001), whereas the mean value of eGFR did not change significantly. At the same time, after 48 weeks a significant increase in both lumbar spine and total hip BMD, T-score and Z-score was reported (+11.5% in lumbar spine T-score; P<0.001), and there was a significant reduction in both CTX and BAP mean serum concentrations (-15% and -13%, respectively; P<0.001). Two (4.3%) patients had virological failure due to suboptimal adherence and one (2.2%) subject discontinued treatment due to a skin rash.. Switching virologically suppressed patients from tenofovir/emtricitabine plus one r/PI to raltegravir plus nevirapine after 48 weeks significantly improved proximal tubular function, increased BMD and reduced serum markers of bone turnover.

Topics: Adult; Anti-HIV Agents; Bone Density; Cohort Studies; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Female; Glomerular Filtration Rate; HIV Infections; Humans; Male; Middle Aged; Nevirapine; Pilot Projects; Raltegravir Potassium; Ritonavir

Tolerability, long-term toxicities and selection of resistant variants limit the use and efficacy of antiretroviral drugs in HIV-positive patients. Novel combinations are needed for mantaining long-term control of HIV replication; nevertheless scarse data are available on protease inhibitor-free dual antiretroviral therapies.. A multi-centric retrospective study was conducted including HIV-1-positive patients on raltegravir/nevirapine dual regimens. Plasma concentrations were measured as therapeutic drug monitoring while a subset of patients underwent intensive 12-hour pharmacokinetic evaluation.. A total of 77 patients switching from successful regimens (76.6% male, median age 52 years) was included; 10 patients on raltegravir plus nevirapine once-daily while 67 subjects on twice-daily schedule. After a median follow-up of 32 months 69 patients (89.6%) were still successfully on treatment. Three patients discontinued for side effects (skin rash or hepatoxicity). Virological failure was observed in five patients (6.5%, 3 on once-daily schedule): in 4 patients (80%) resistance-associated mutations were observed (4 reverse transcriptase, 2 integrase). Triglycerides decreased in patients switching with lipid abnormalities (n=52) and estimated creatinine clearance increased in those with less than 60 ml/min (n=13). Median trough raltegravir and nevirapine concentrations were 83 ng/ml (32-227) and 5460 ng/ml (4037-7221); intensive 12-hours pharmacokinetic parameters (n=7) were similar to published data.. Dual therapy with raltegravir/nevirapine in selected patients was highly effective over a 32-month follow up: virological failure was infrequent (6.5%), most common with once-daily schedule (60%) and often associated with the selection of resistance-associated mutations (80%). Twice-daily raltegravir plus nevirapine deserves further clinical evaluation as an NRTI- and PI-sparing strategy in selected patients.

Topics: Adult; Anti-HIV Agents; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Maintenance Chemotherapy; Male; Middle Aged; Nevirapine; Raltegravir Potassium; Retrospective Studies; Viral Load

Three groups of cytomegalovirus (CMV)-seropositive women (total n = 164) were selected from the Chicago Women's Interagency HIV-1 Study to investigate the association between CMV coinfection and immune activation: (1) HIV-1 viremic, (2) HIV-1 aviremic, and (3) HIV-1 uninfected. Quantitative measures of CMV serum IgG, CMV DNA, and serum biomarkers interleukin (IL)-6, soluble CD163 (sCD163), soluble CD14 (sCD14), and interferon gamma-induced protein (IP10) were obtained. Levels of CMV IgG and the serum biomarkers were significantly higher in the HIV-1 viremic group compared to the aviremic and uninfected groups (p < 0.001). No significant associations with CMV IgG levels were found for HIV-uninfected women. When each of the HIV-infected groups was analyzed, sCD14 levels in the viremic women were significantly associated with CMV IgG levels with p < 0.02 when adjusted for age, CD4 count, and HIV viral load. There was also a modest association (p = 0.036) with IL-6 from plasma and cervical vaginal lavage specimens both unadjusted and adjusted for CD4 count and HIV viral load. The association of CMV IgG level with sCD14 implicates the monocyte as a potential site for interaction of the two viruses, which eventually may lead to non-AIDS-defining pathological conditions.

Topics: Adult; Anti-HIV Agents; Antibodies, Viral; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Coinfection; Cytomegalovirus; Cytomegalovirus Infections; Female; HIV Infections; HIV-1; Humans; Immunoglobulin G; Inflammation; Interferon-gamma; Interleukin-6; Lipopolysaccharide Receptors; Middle Aged; Raltegravir Potassium; Receptors, Cell Surface; Viral Load; Viremia

Raltegravir is one of the standard antiretroviral therapy (ART) options in treatment-experienced and -naïve patients. However, efficacy data from clinical practice are scarce. Therefore, the efficacy of raltegravir-containing ART in clinical practice was investigated retrospectively. In all, 295 treatment-naïve and -experienced patients were analysed using two different cut-offs for virological failure (200 or 50 copies/ml). The response at week 24 and onwards was evaluated as a 'time to loss of virological response' analysis and estimated as a survival function. Additionally, dual therapy regimens (raltegravir plus boosted protease inhibitor) were compared to standard combinations in experienced patients performing a snapshot analysis at weeks 24 and 48, as well as a time to loss of virological response analysis. A total of 86.2% of the 64 treatment-naïve patients maintained virological suppression using a cut-off of 200 copies/ml (c/ml), while 67.7% maintained virological suppression with a 50 copies/ml cut-off from week 24 until the end of observation. Among the 231 treatment-experienced patients, 84.8% maintained virological suppression from week 24 onwards using a cut-off of 200 copies/ml; and 71.0% using 50 copies/ml, respectively. In the subgroup snapshot analysis at week 24, 98.3% (86.7% using a cut-off of 50 copies/ml) and at week 48, 93.3% (80.0%) of patients responded to dual therapy. Patients who were receiving a standard background therapy responded in 88.3% (81.3%) at week 24 and in 86.0% (80.7%) at week 48. Differences were not significant. This study shows again the overall long-term efficacy of raltegravir-based ART and furthermore gives reference for a comparable efficacy of dual and standard nucleos(t)ide reverse transcriptase inhibitor-backbone regimens in experienced patients on raltegravir over a period of 48 weeks in a real-life cohort where patients with severe comorbidities were included.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Raltegravir Potassium; Treatment Outcome; Viral Load

We evaluated variant-associated variability at positions related to resistance to the integrase (IN) inhibitors (INIs) raltegravir, elvitegravir and dolutegravir using HIV-1 IN sequences from naive individuals retrieved from GenBank.. We evaluated the frequency of major, secondary and rare amino acid changes associated with INI resistance (INI-R) in 6706 sequences from 3791 INI-naive individuals carrying a large panel of different HIV-1 variants retrieved from GenBank, including four groups: M (6663), O (24), N (15) and P (4). HIV-1 group M sequences included 4599 sequences from the nine group M subtypes and 2064 recombinants ascribed to 54 circulating recombinant forms (CRFs).. Primary INI-R mutations were rare in INI-naive participants and only present at a low rate in subtypes B, C and D and recombinants CRF01_AE and CRF14_BG, ranging from one to five per variant. Three secondary INI-R changes appeared with variable frequency in INI-naive individuals carrying specific HIV-1 variants: L74M in CRF43_02G (33.3%); T97A in group P (50%), J (33.3%), CRF18_cpx (20%) and F2 (11.5%); and G163RK in CRF44_BF (100%), CRF46_BF (66.7%), CRF17_BF (28.6%), F1 (21.7%), CRF12_BF (16.7%) and CRF29_BF (12.5%). Rare mutations were absent.. Natural variability in INI-R positions across HIV-1 variants should be studied as they may facilitate or delay the emergence of INI-R viruses.

Topics: Amino Acid Substitution; Computational Biology; Drug Resistance, Viral; Genetic Variation; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Darunavir; Hemodynamics; HIV Infections; HIV-1; Humans; Lipid Metabolism; Lipids; Raltegravir Potassium; Ritonavir; Treatment Outcome

Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class.. We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks.. As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (-85.2 mg/dL), in the prevalence of tubular proteinuria (-56%) and in the mean level of interleukin-6 (-0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events.. In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism.

Topics: Adult; Anti-HIV Agents; Darunavir; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Raltegravir Potassium; Ritonavir; RNA, Viral; Viral Load

Liver transplantation (LTx) is considered a safe procedure in selected HIV-infected patients. In this clinical setting raltegravir is the antiretroviral of choice due to its optimal tolerability and its negligible interactions with immunosuppressive drugs. We aimed at providing data on the pharmacokinetics of raltegravir in LTx recipients, on which the available information is inconclusive.. In this retrospective multicentre study we characterized the pharmacokinetics of raltegravir in a consecutive series of HIV-infected LTx recipients referred to our laboratory for therapeutic drug monitoring (TDM) and compared the obtained profiles with those collected from a control group of HIV-infected patients.. Seventeen HIV-infected LTx patients were considered. LTx recipients had significantly higher raltegravir AUC0-12 compared with the control group of HIV-infected patients [14 314 (11 627-19 998) versus 8795 (5218-12 954) ng·h/mL; P < 0.01]. Two LTx patients experienced moderate increments in serum transaminases, nausea and vomiting that improved after raltegravir dose reduction.. High raltegravir exposure and acceptable safety profile were observed in HIV-infected LTx recipients. Our results highlight that some patients may obtain an advantage from TDM-guided raltegravir dose adjustments with potential benefits in terms of drug tolerability.

Topics: Adult; Anti-HIV Agents; Drug Interactions; Female; HIV Infections; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Plasma; Raltegravir Potassium; Retrospective Studies; Transaminases; Transplant Recipients

Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data.

Topics: Animals; Disease Models, Animal; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mice; Mice, Inbred BALB C; Mucous Membrane; Pre-Exposure Prophylaxis; Raltegravir Potassium

Topics: Adult; Anti-HIV Agents; Drug Interactions; Female; HIV Infections; HIV Seropositivity; Humans; Male; Medication Adherence; Post-Exposure Prophylaxis; Raltegravir Potassium

When treating HIV-infected patients with hemophilia, adverse drug reactions and interactions and the effect of treatment on bleeding disorders must be considered. Raltegravir is the first HIV integrase inhibitor, but its use in patients with hemophilia is rarely reported. Nine HIV-positive patients with hemophilia were retrospectively studied with a focus on the virological response, changes in the CD4 count, the tendency to bleed, and the response to replacement therapy before and after raltegravir-based antiretroviral therapy (ART). The nine patients were highly treatment-experienced patients and they received raltegravir-based ART for at least nine months. The patients had their own reasons for changing to raltegravir-based ART. During treatment, the CD4 count increased progressively in four patients, with a median absolute increase of 233 cells/mm(3), while the count stabilized in the remaining five patients. Two previous recipients of lopinavir/ritonavir (LPV/r) who failed to respond to lamivudine (3TC) + zidovudine (ZDV) + efavirenz (EFV) had a viral rebound. Genotyping indicated multidrug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). A pattern of resistance to raltegravir was evident, including the primary mutation N155H and the secondary mutation T97A. In the two patients, the tendency to bleed decreased markedly and monthly usage of clotting factor VIII decreased significantly decreased. In the remaining seven patients, the viral load remained < 40 copies/mL, there was no evidence of an increased tendency to bleed, and no evidence of changes in the response to replacement therapy. All of the patients had a stable condition with no signs of disease progression and no serious adverse reactions. Results indicated that Raltegravir-based therapy offered a safe and well-tolerated option for HIV-positive patients with hemophilia.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Hemophilia A; HIV Infections; Humans; Integrases; Middle Aged; Mutation; Raltegravir Potassium; Treatment Outcome

Topics: Anti-HIV Agents; HIV Infections; Humans; Male; Middle Aged; Raltegravir Potassium; Renal Dialysis; Treatment Outcome

To determine the prevalence and types of clinically significant drug-drug interactions (CSDI) in the drug regimens of HIV-infected patients receiving antiretroviral treatment.. retrospective review of database. Centre: Hospital Universitario Severo Ochoa, Infectious Unit.. one hundred and forty-two participants followed by one of the authors were selected from January 1985 to December 2014.. from their outpatient medical records we reviewed information from the last available visit of the participants, in relation to HIV infection, comorbidities, demographics and the drugs that they were receiving; both antiretroviral drugs and drugs not related to HIV infection. We defined CSDI from the information sheet and/or database on antiretroviral drug interactions of the University of Liverpool (http://www.hiv-druginteractions.org) and we developed a diagnostic tool to predict the possibility of CSDI. By multivariate logistic regression analysis and by estimating the diagnostic performance curve obtained, we identified a quick tool to predict the existence of drug interactions.. Of 142 patients, 39 (29.11%) had some type of CSDI and in 11.2% 2 or more interactions were detected. In only one patient the combination of drugs was contraindicated (this patient was receiving darunavir/r and quetiapine). In multivariate analyses, predictors of CSDI were regimen type (PI or NNRTI) and the use of 3 or more non-antiretroviral drugs (AUC 0.886, 95% CI 0.828 to 0.944; P=.0001). The risk was 18.55 times in those receiving NNRTI and 27,95 times in those receiving IP compared to those taking raltegravir.. Drug interactions, including those defined as clinically significant, are common in HIV-infected patients treated with antiretroviral drugs, and the risk is greater in IP-based regimens. Raltegravir-based prescribing, especially in patients who receive at least 3 non-HIV drugs could avoid interactions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Young Adult

Although different factors have been implicated in the CD4/CD8 T-cell ratio recovery in HIV-infected patients who receive effective antiretroviral therapy (ART), limited information exists on the influence of the regimen composition. A longitudinal study carried out in a prospective, single-center cohort of HIV-infected patients. ART regimens including non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), or integrase strand transfer inhibitors (INSTI) from patients who achieved long-term (≥6-month duration) virological suppression (HIV-RNA < 400 copies/mL) from January 1998 to June 2014 were analyzed. The impact of ART composition on the changes of the CD4/CD8 T-cell ratio was modeled using a mixed linear approach with adjustment for possible confounders. A total of 1068 ART regimens from 570 patients were analyzed. Mean (SD) age of the patients was 42.15 (10.68) years and 276 (48.42%) had hepatitis C virus (HCV) coinfection. Five hundred fifty-eight (52.25%) regimens were PI-based, 439 (40.10%) NNRTI-based, and 71 (6.65%) INSTI-based; 487 (45.60%) were initial regimens, 476 (44.57%) simplification, and 105 (9.83%) salvage regimens. Median (IQR) number of regimens was 1 (1-2) per patient, of 29 (14-58) months duration, and 4 (3-7) CD4/CD8 measurements per regimen. The median baseline CD4/CD8 ratio was 0.42, 0.50, and 0.54, respectively, with the PI-, NNRTI-, and INSTI-based regimens (P = 0.0073). Overall median (IQR) increase of CD4/CD8 ratio was 0.0245 (-0.0352-0.0690) per year, and a CD4/CD8 ratio ≥1 was achieved in 19.35% of the cases with PI-based, 25.97% with NNRTI-based, and 22.54% with INSTI-based regimens (P = 0.1406). In the adjusted model, the mean CD4/CD8 T-cell ratio increase was higher with NNRTI-based regimens compared for PI-based (estimated coefficient for PI [95% CI], -0.0912 [-0.1604 to -0.0219], P = 0.009). Also, a higher CD4/CD8 baseline ratio was associated with higher CD4/CD8 increase in the adjusted model (P = 0.001); by contrast, higher age (P = 0.020) and simplification of ART regimen (P = 0.003) had a negative impact on the CD4/CD8 ratio. Antiretroviral regimen composition has a differential impact on the CD4/CD8 T-cell ratio; NNRTI-based regimens are associated with enhanced CD4/CD8 T-cell ratio recovery compared to PI-based antiretroviral regimens.

Topics: Adult; Age Factors; Alkynes; Atazanavir Sulfate; Benzoxazines; CD4-CD8 Ratio; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Interferon Type I; Male; Middle Aged; Oligopeptides; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ribavirin; Ritonavir

Genotyping tests were developed to attenuate the impact of viral resistance. Information about the efficacy in genotype base antiretroviral therapy in children is rare and even more in low- and middle-income countries.. Sixteen children with antiretroviral therapy (ART) failure and triple-class drug-resistant viruses were included in this study. Protease and retrotranscriptase genotypes were available for all patients. Switch of ART regimen was guided by genotyping data. The primary end point was virological suppression (<50 copies/ml) and immunological improvement after 48 wk of treatment with the new ART regimen.. The median age of the patients was 14.5 y (interquartile range (IQR) 11-16.5). Median HIV-1 RNA viral load was 4.2 log10 (IQR: 3.4-4.8). The primary end point was found in 11 children (69%), and 13 children (81%) had an HIV-1 RNA viral load <200 copies/ml. Median (IQR) for the baseline CD4(+) cell count was 382 cells/μl (281-686 cells/μl), whereas after 48 wk of treatment with the new ART regimen, it was 640 cells/μl (361-936 cells/μl) (P < 0.001).. Darunavir/ritonavir, raltegravir, and etravirine were well tolerated in the present pediatric population. These drugs provide good options for children exposed to extensive ART. Regimens guided by genotyping data were effective for children who had ART failure and multidrug-resistant HIV-1 infection.

Topics: Adolescent; Anti-Retroviral Agents; CD4 Lymphocyte Count; Child; Darunavir; Drug Resistance, Multiple, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Nitriles; Poverty; Pyridazines; Pyrimidines; Raltegravir Potassium; Retrospective Studies; Ritonavir; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission.. Long-acting raltegravir was administered subcutaneously to BALB/c, NSG (NOD-scid-gamma) and humanized BLT (bone marrow-liver-thymus) mice and rhesus macaques. Raltegravir concentration in peripheral blood and tissue was analysed. Suppression of HIV replication was assessed in infected BLT mice. Two high-dose HIV vaginal challenges were used to evaluate protection from HIV transmission in BLT mice.. Two weeks after a single subcutaneous injection of long-acting raltegravir in BLT mice (7.5 mg) and rhesus macaques (160 mg), the plasma concentration of raltegravir was comparable to 400 mg orally, twice daily in humans. Serum collected from mice 3 weeks post-administration of long-acting raltegravir efficiently blocked HIV infection of TZM-bl indicator cells in vitro. Administration of long-acting raltegravir suppressed viral RNA in plasma and cervico-vaginal fluids of infected BLT mice, demonstrating penetration of active raltegravir into the female reproductive tract. Using transmitted/founder HIV we observed that BLT mice administered a single subcutaneous dose of long-acting raltegravir were protected from two high-dose HIV vaginal challenges 1 week and 4 weeks after drug administration.. These preclinical results demonstrated the efficacy of long-acting raltegravir in preventing vaginal HIV transmission.

Topics: Animals; Anti-HIV Agents; Chemoprevention; Delayed-Action Preparations; Disease Transmission, Infectious; Female; HIV Infections; Injections, Subcutaneous; Macaca mulatta; Mice, Inbred BALB C; Mice, SCID; Pre-Exposure Prophylaxis; Raltegravir Potassium; Treatment Outcome; Vagina

Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Male; Raltegravir Potassium; Semen; Treatment Outcome; Virus Shedding

Raltegravir was recently identified to be a substrate of ATP-binding cassette transporter B1 (ABCB1) and G2 (ABCG2), which are efflux transporters and expressed in the intestines. We analyzed the relations between plasma raltegravir concentrations and single nucleotide polymorphism of ABCB1 and ABCG2 genes. The peak plasma concentration of raltegravir was significantly higher in the patients with ABCB1 4036 AG/GG and ABCG2 421 CA/AA than in other genotype holders (P = 0.0052), though no difference was identified in trough raltegravir concentrations, which may be explained by reduced expression of efflux transporters in intestine by these genetic variants.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Japan; Male; Middle Aged; Neoplasm Proteins; Polymorphism, Single Nucleotide; Raltegravir Potassium; Reverse Transcriptase Inhibitors

In our study, we have hypothesized that proviral DNA may show the history of mutations that emerged at previous failures to a Raltegravir containing regimen, in patients who are currently undetectable and candidates to simplification to a Dolutegravir containing regimen, in order to decide on once a day or twice a day dosing.. We have performed a pilot, observational, retrospective, non interventional study, including 7 patients infected by HIV-1, all with a history of previous failure to a RAL containing regimen, that were successfully salvaged and had reached viral suppression. A genotypic viral Integrase region study was available for each patient at the moment of RAL failure. After an average (IQR) time of 48 months (29-53) Integrase resistance mutations in proviral DNA were studied.. All the patients were infected by HIV-1 B subtypes, with a mean age of 55 (range 43 to 56), originating from Spain, and 4 were women. Median viral load (log) and CD4 count at the moment of the study on proviral DNA was of 1.3 log cp/ml (range 0-1.47) and 765.5 cells/μL (range; 436.75-1023.75). The median time (IQR) between previous failure to RAL and the study on proviral DNA was 48 (29-53) months. At Raltegravir failure, N155H was detected in four patients, and other secondary mutations were detected in five patients (71.4 %). In proviral DNA, N155H was detected by population sequencing in three patients (42.8 %), and UDS demonstrated a 9.77 % relative abundance of N155H in the remaining patient. Sanger sequencing correctly identified all the secondary mutations.. This is a pilot study that demonstrates the possibility of properly identifying N155H and some secondary mutations 29-53 months after failure.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Drug Resistance, Viral; Female; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation; Oxazines; Pilot Projects; Piperazines; Pyridones; Raltegravir Potassium; Retrospective Studies; Salvage Therapy; Treatment Failure; Viral Load

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; HIV Infections; Humans; Raltegravir Potassium; Viral Load

Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.

Topics: Cell Line; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Models, Molecular; Oxazines; Piperazines; Pyridones; Pyrimidinones; Raltegravir Potassium; Ribonuclease H

To evaluate the role of P-glycoprotein (P-gp) and multidrug-resistant-protein 1 (MRP1) on raltegravir intracellular drug disposition in CD4+ T cells, investigate the effect of HIV-1 infection on P-gp expression and correlate HIV-1 viraemia with P-gp activity in primary CD4+ T cell subsets.. The cellular accumulation ratio of [(3)H]raltegravir was quantified in CD4+ T cell lines overexpressing either P-gp (CEM-P-gp) or MRP1 (CEM-MRP1) and in primary CD3+CD4+ T cells with high (P-gp(high)) and low P-gp activity (P-gp(low)); inhibition of efflux transporters was confirmed by the intracellular retention of calcein-AM. The correlation of P-gp activity with HIV-1 viraemia was assessed in naive and memory T cell subsets from 21 HIV-1-infected treatment-naive subjects.. [(3)H]Raltegravir cellular accumulation ratio decreased in CEM-P-gp cells (P < 0.0001). XR9051 (a P-gp inhibitor) and HIV-1 PIs reversed this phenomenon. Primary CD4+P-gp(high) cells accumulated less raltegravir (38.4% ± 9.6%) than P-gp(low) cells, whereas XR9051 also reversed this effect. In vitro HIV-1 infection of PBMCs and stimulation of CD4+ T cells increased P-gp mRNA and P-gp activity, respectively, while primary CD4+P-gp(high) T cells sustained a higher HIV-1 replication than P-gp(low) cells. A significant correlation between HIV-1 viraemia and P-gp activity was found in different CD4+ T cell subsets, particularly memory CD4+ T cells (r = 0.792, P < 0.0001).. Raltegravir is a substrate of P-gp in CD4+ T cells. Primary CD4+P-gp(high) T cells eliminate intracellular raltegravir more readily than P-gp(low) cells and HIV-1 viraemia correlates with P-gp overall activity. Specific CD4+P-gp(high) T cell subsets could facilitate the persistence of viral replication in vivo and ultimately promote the appearance of drug resistance.

Topics: Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B; Benzylidene Compounds; CD4-Positive T-Lymphocytes; Cell Line; Cells, Cultured; Fluoresceins; Healthy Volunteers; HIV Infections; HIV-1; Humans; Immunologic Memory; Raltegravir Potassium; Ritonavir; Tetrahydroisoquinolines; Viral Load; Viremia; Virus Replication

It is unclear whether differential roles of CD4(+) versus CD8(+) T-cell senescence/exhaustion and effects of antiretroviral therapy (ART) on these processes may contribute to morbidity in treated human immunodeficiency virus type 1 (HIV) infection. In a prospective 96-week trial, 328 HIV-infected ART-naive participants were randomly assigned to receive tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. Markers of CD4(+) T-cell senescence (ie, the percentage of CD28(-)CD57(+) cells among CD4(+) T cells ) and CD4(+)/CD8(+) T-cell exhaustion (ie, the percentage of PD-1(+) cells among CD4(+)/CD8(+) T cells) decreased after ART. There were no changes in markers of CD8(+) T-cell senescence after ART and no differential changes in all markers in ART groups. Senescent CD4(+) and CD8(+) T cells may have differential roles in HIV pathogenesis.

Topics: Adult; Anti-HIV Agents; Antigens, CD; Atazanavir Sulfate; Darunavir; Female; HIV Infections; Humans; Immunophenotyping; Male; Prospective Studies; Raltegravir Potassium; T-Lymphocyte Subsets

Topics: Cyclohexanes; HIV Infections; Humans; Maraviroc; Raltegravir Potassium; Triazoles

Aim of the study was to assess predictors of discontinuation/toxicity of boosted PI-based (PI/r) dual therapy (DT).. Observational, retrospective switch study in patients successfully treated with triple drugs regimen. Patients switched to PI/r based DT [darunavir (DRV/r), lopinavir (LPV/r) or atazanavir (ATV/r)] plus a second drug: [raltegravir (RAL), maraviroc (MVC) etravirine (ETR), lamivudine (3TC) or tenofovir (TDF)] between 2009 and 2014 were included. The effect of each drug as well as other clinical and virological cofactors over treatment discontinuation (TD) was assessed using survival analysis.. Overall, 376 patients were included with mean follow-up of 73 weeks. The most commonly used drugs in DT were DRV/r (63.0 %) and RAL (53.7 %). TD was observed in 77 (20,4 %) patients: 38 (10,1 %) virological failure, 35 (9,3 %) toxicity/intolerance (4 deaths) and 4 (1 %) interruptions for patients decision. At Cox Model, adjusted by demographic and laboratory variables, DRV/r and ATV/r significantly reduced the likelihood of TD and longer treatment was associated with lower risk, while low CD4 count at baseline and number of previous regimens with a higher risk. Moreover, RAL and 3TC use were significantly associated with lower TD by toxicity.. In our clinical practice experience, switching virologically suppressed patients to PI/r based DT showed adequate safety and efficacy, so that it may be used in selected patients with specific medical needs.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Darunavir; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Male; Medication Adherence; Middle Aged; Proportional Hazards Models; Raltegravir Potassium; Retrospective Studies; Risk; Tenofovir

Phenotypic resistance analysis is an indispensable method for determination of HIV-1 resistance and cross-resistance to novel drug compounds. Since integrase inhibitors are essential components of recent antiretroviral combination therapies, phenotypic resistance data, in conjunction with the corresponding genotypes, are needed for improving rules-based and data-driven tools for resistance prediction, such as HIV-Grade and geno2pheno

Topics: Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Phenotype; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Antiretroviral therapy containing an integrase strand transfer inhibitor (INSTI) plus two NRTIs has become the recommended treatment for antiretroviral-naive HIV-1-infected patients in the updated guidelines. We aimed to determine the prevalence of INSTI-related mutations in Taiwan. Genotypic resistance assays were performed on plasma from ARV-naïve patients (N = 948), ARV-experienced but INSTI-naive patients (N = 359), and raltegravir-experienced patients (N = 63) from 2006 to 2015. Major INSTI mutations were defined according to the IAS-USA list and other substitutions with a Stanford HIVdb score ≧ 10 to at least one INSTI were defined as minor mutations. Of 1307 HIV-1 samples from patients never exposed to INSTIs, the overall prevalence of major resistance mutations to INSTIs was 0.9% (n = 12), with an increase to 1.2% in 2013. Of these 12 sequences, 11 harboured Q148H/K/R, one Y143R, and none N155H. Of 30 sequences (47.6%) with INSTI-resistant mutations from raltegravir-experienced patients, 17 harboured Q148H/K/R, 8 N155H, and 6 Y143C/R. Other than these major mutations, the prevalence of minor mutations were 5.3% and 38.1%, respectively, in ARV-naive and raltegravir-experienced patients. The overall prevalence of INSTI mutations remains low in Taiwan. Surveillance of INSTI resistance is warranted due to circulation of polymorphisms contributing to INSTI resistance and expected increasing use of INSTIs.

Topics: Adult; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Mutation; Phylogeny; Prevalence; Raltegravir Potassium; Taiwan

To understand the persistence of latently HIV-1 infected cells in virally suppressed infected patients, a number of in vitro models of HIV latency have been developed. In an attempt to mimic the in vivo situation as closely as possible, several models use primary cells and replication-competent viruses in combination with antiretroviral compounds to prevent ongoing replication. Latency is subsequently measured by HIV RNA and/or protein production after cellular activation. To discriminate between pre- and post-integration latency, integrase inhibitors are routinely used, preventing novel integrations upon cellular activation. Here, we show that this choice of antiretrovirals may still cause a bias of pre-integration latency in these models, as unintegrated HIV DNA can form and directly contribute to the levels of HIV RNA and protein production. We further show that the addition of reverse transcriptase inhibitors effectively suppresses the levels of episomal HIV DNA (as measured by 2-LTR circles) and decreases the levels of HIV transcription. Consequently, we show that latency levels described in models that only use integrase inhibitors may be overestimated. The inclusion of additional control conditions, such as 2-LTR quantification and the addition of reverse transcriptase inhibitors, is crucial to fully elucidate the actual levels of post-integration latency.

Topics: Alkynes; Benzoxazines; CD4-Positive T-Lymphocytes; Cyclopropanes; DNA, Viral; Genes, Reporter; Green Fluorescent Proteins; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Lymphocyte Activation; Models, Biological; Nevirapine; Primary Cell Culture; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Viral Proteins; Virus Integration; Virus Latency; Virus Replication

US guidelines recommend genotyping for persons newly diagnosed with HIV infection to identify transmitted drug resistance mutations associated with decreased susceptibility to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. To date, testing for integrase strand transfer inhibitor (INSTI) mutations has not been routinely recommended. We aimed to evaluate the prevalence of transmitted INSTI mutations among persons with primary HIV-1 infection in Seattle, WA, USA.. Persons with primary HIV-1 infection have enrolled in an observational cohort at the University of Washington Primary Infection Clinic since 1992. We performed a retrospective analysis of plasma specimens collected prospectively from the 82 antiretroviral-naive subjects who were enrolled from 2007-2013, after FDA-approval of the first INSTI. Resistance testing was performed by consensus sequencing.. Specimens for analysis had been obtained a median of 24 (IQR 18-41, range 8-108) days after the estimated date of HIV-1 infection. All subjects were infected with HIV-1 subtype B except for one subject infected with subtype C. Consensus sequencing identified no subjects with major INSTI mutations (T66I, E92Q, G140S, Y143C/H/R, S147G, Q148H/K/R, N155H). Using exact binomial CIs, the upper bound of the 95% CI was 4.4%.. Although our sample size was small, this study does not support the need at this time to evaluate integrase mutations as part of routine consensus sequencing among persons newly diagnosed with HIV-1 infection. However, it is likely that the prevalence of transmitted INSTI mutations may increase with the recent commercial introduction of additional INSTIs and presumably greater INSTI use among persons living with HIV-1.

Topics: Adult; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Mutation; Quinolones; Raltegravir Potassium; Retrospective Studies; Sequence Analysis, RNA

GSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. The in vitro antiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50 relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50 for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

Topics: Anti-HIV Agents; Cell Line; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity.. Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm.. Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load.. Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Female; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation, Missense; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sequence Analysis, DNA; Treatment Failure; Young Adult

Dolutegravir (DTG) has been studied in three trials in HIV treatment-naive participants, showing noninferiority compared with raltegravir (RAL), and superiority compared with efavirenz and ritonavir-boosted darunavir. We explored factors that predicted treatment success, the consistency of observed treatment differences across subgroups and the impact of NRTI backbone on treatment outcome.. Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO.. We examined the efficacy of DTG in HIV-infected participants with respect to relevant demographic and HIV-1-related baseline characteristics using the primary efficacy endpoint from the studies (FDA snapshot) and secondary endpoints that examine specific elements of treatment response. Regression models were used to analyze pooled data from all three studies.. Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4⁺ cell count, and HIV-1 RNA and by third agent. Differences between DTG and other third agents were generally consistent across these subgroups. There was no evidence of a difference in snapshot response between abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) overall [ABC/3TC 86%, TDF/FTC 85%, difference 1.1%, confidence interval (CI) -1.8, 4.0 percentage points, P = 0.61] or at high viral loads (difference -2.5, 95% CI -8.9, 3.8 percentage points, P = 0.42).. DTG is a once-daily, unboosted integrase inhibitor that is effective in combination with either ABC/3TC or TDF/FTC for first-line antiretroviral therapy in HIV-positive individuals with a variety of baseline characteristics.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials, Phase III as Topic; Coinfection; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Organophosphonates; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Regression Analysis; Retrospective Studies; Ritonavir; Tenofovir; Treatment Outcome; Viral Load

Strand transfer inhibitors (raltegravir, elvitegravir and dolutegravir) are now commonly used to inhibit HIV-1 integration. To date, three main pathways conferring raltegravir/elvitegravir resistance, involving residues Y143, Q148 and N155, have been described. However, no pathway has been clearly described for dolutegravir resistance. The aim of this study was to characterize the susceptibility of two mutations, F121Y and G118R, originally described in patients failing raltegravir-containing regimens, to dolutegravir and raltegravir, and then to compare the resistance of these mutations with that of other well-known mutations involved in raltegravir resistance.. Both the F121Y and G118R mutations were introduced by site-directed mutagenesis into the pNL4.3 backbone and studied in cell-based and in vitro assays. The effects of the mutations were characterized at the different steps of infection by quantitative PCR.. Results obtained with in vitro and ex vivo assays consistently showed that both mutations impaired the catalytic properties of integrase, especially at the integration step. Moreover, both mutations conferred an intermediate level of resistance to dolutegravir. Interestingly, the F121Y mutation, but not the G118R mutation, displayed differential resistance to raltegravir and dolutegravir. Indeed, the F121Y mutation was more resistant to raltegravir than to dolutegravir.. Mutations at G118 and F121, which have been described in patients failing raltegravir-containing regimens, must be included in drug-resistance-testing algorithms.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Mutagenesis, Site-Directed; Mutation, Missense; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; Real-Time Polymerase Chain Reaction; RNA, Viral

Novel combination antiretroviral regimens may be needed for selected HIV-infected patients with toxicity or resistance. We evaluated prospectively 25 virologically suppressed patients, largely pretreated (15.6 years on therapy) with antiretroviral drug toxicity (n=19) or interactions (n=9, mainly with chemotherapy against non-Hodgkin lymphoma or anti-HCV therapy), who switched to a dual therapy with etravirine (ETR) plus raltegravir (RAL). Patients were required not to have prior virological failure or resistance to both drugs. After a median follow up of 722 days (473-1088: 53.3 patients-year), there were no cases of transient virological replication or failure. Only 1 patient left therapy at day 10 due to a grade 2 rash, and therefore efficacy by intent-to-treat analysis was 96% at 48 weeks. There were no cases of liver toxicity grade 3-4, and total cholesterol (TC) and triglycerides (TG) levels decrease significantly after initiation (TC, -17 mg/dl; p=0.01; TG, -42 mg/dl; p=0.01), as well as the TC/High density lipoprotein-cholesterol ratio (from 4.35 to 4.28). Geometric mean plasma trough level of RAL was 166 ng/ml (IQR, 40-249), well above the inhibitory concentration 90 (IC(90)). In conclusion, a novel dual therapy with ETR plus RAL is effective and well tolerated, and it could be an option to maintain durable viral suppression in hard-to-treat HIV-infected patients.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; Follow-Up Studies; HIV; HIV Infections; Humans; Male; Middle Aged; Nitriles; Prospective Studies; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Viral Load

Muscle alterations ranging from asymptomatic creatine phosphokinase (CPK) increases to rhabdomyolysis and central nervous system (CNS) symptoms have been reported in patients receiving raltegravir. Muscle symptoms and CPK increases were investigated in a cohort of HIV-infected patients receiving raltegravir-based antiretroviral therapy, and possible associated predictors were evaluated. The SCOLTA Project is a prospective, observational, multicentre study created to assess the incidence of adverse events in patients receiving new antiretroviral drugs in clinical practice. In total, 496 HIV-infected patients were enrolled [333 (67.1%) male]. CDC stage was C in 196 patients (39.5%). Mean age at enrolment was 45.9 ± 9.3 years. Median follow-up was 21 months. Twenty-six patients (5.2%) reported muscle symptoms (16 muscle pain and 17 weakness; 7 had both). Of 342 patients with normal baseline CPK values, 72 (21.1%) had a CPK increase. Seven patients (1.4%) discontinued raltegravir because of muscular events (three for muscle pain/weakness and four CPK increases). No cases of rhabdomyolysis were observed. Patients with muscle symptoms were more frequently receiving in their regimen than those not receiving atazanavir (P=0.04) and were more likely to also report CNS symptoms (P<0.0001). Significant predictors of muscle symptoms were CNS symptoms and use of atazanavir. Female sex was associated with a reduced risk of CPK increase. In conclusion, muscle symptoms and CPK elevations occurred frequently and caused most discontinuations due to adverse events. Their monitoring in patients receiving raltegravir should be considered, especially when co-administered with atazanavir or when CNS symptoms are also present.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Creatine Kinase; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Muscle Weakness; Myalgia; Oligopeptides; Prospective Studies; Pyridines; Pyrrolidinones; Raltegravir Potassium

The objectives of this study were to determine the prevalence and patterns of resistance to integrase strand transfer inhibitors (INSTIs) in patients experiencing virological failure on raltegravir-based ART and the impact on susceptibility to INSTIs (raltegravir, elvitegravir and dolutegravir).. Data were collected from 502 treatment-experienced patients failing a raltegravir-containing regimen in a multicentre study. Reverse transcriptase, protease and integrase were sequenced at failure for each patient. INSTI resistance-associated mutations investigated were those included in the last ANRS genotypic algorithm (v23).. Among the 502 patients, at failure, median baseline HIV-1 RNA (viral load) was 2.9 log10 copies/mL. Patients had been previously exposed to a median of five NRTIs, one NNRTI and three PIs. Seventy-one percent harboured HIV-1 subtype B and the most frequent non-B subtype was CRF02_AG (13.3%). The most frequent mutations observed were N155H/S (19.1%), Q148G/H/K/R (15.4%) and Y143C/G/H/R/S (6.7%). At failure, viruses were considered as fully susceptible to all INSTIs in 61.0% of cases, whilst 38.6% were considered as resistant to raltegravir, 34.9% to elvitegravir and 13.9% to dolutegravir. In the case of resistance to raltegravir, viruses were considered as susceptible to elvitegravir in 11% and to dolutegravir in 64% of cases. High HIV-1 viral load at failure (P < 0.001) and low genotypic sensitivity score of the associated treatment with raltegravir (P < 0.001) were associated with the presence of raltegravir-associated mutations at failure. Q148 mutations were selected more frequently in B subtypes versus non-B subtypes (P = 0.004).. This study shows that a high proportion of viruses remain susceptible to dolutegravir in the case of failure on a raltegravir-containing regimen.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Female; France; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Male; Middle Aged; Mutant Proteins; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Sequence Analysis, DNA

Topics: Anti-HIV Agents; DNA, Viral; HIV; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium; Viral Load; Viremia

The relationship between hepatic tolerance and hepatitis C virus (HCV) co-infection has not been extensively studied in clinical practice. We assessed the efficacy and safety of raltegravir-based therapy in an Italian cohort of HIV/HCV co-infected patients. One hundred and forty patients with HIV/HCV co-infection initiating raltegravir from SCOLTA project (Surveillance Cohort Long-Term Toxicity Antiretrovirals) were examined. Of them, 43 were women, with mean age of 45.4±6.4years; 65 (46%) had undetectable HIV-RNA<50copies/mL and 75 (54%) HIV-RNA≥50copies/mL. According to CDC classification, 49 (35%) were in stage C. Based on Fib4 score at the time of starting raltegravir, patients were classified in class I in 41 cases, class II in 68 and in class III in 31 cases. Globally, the Fib4 score slightly decreased during 24months follow-up, from 2.2 to a value of 1.8. Hepatic adverse events of any grade were observed in 67 patients, of which only 2 cases (3%) had severe liver toxicity (grade 3-4). Only one patient had to discontinue the therapy because of adverse events. According to univariate analysis, being in CDC stage C represented a risk for the development of liver toxicity, with a hazard ratio (HR) of 2.27 (95% CI 1.06-4.84, P=0.033). None of the other variables considered (age, sex, years since detection of HIV and HCV-RNA detectable, years of previous HIV therapy, concomitant therapy with PI or NRTI, CD4+ cell count, Fib4, and transaminases level at baseline) resulted statistically correlated to the outcome. In conclusion, raltegravir-based regimens can be safely used in HCV infected patients; in this study, the hepatic toxicity has been found to be more frequent in patients with an advanced HIV disease (CDC stage C), independently of HIV-RNA suppression at raltegravir initiation.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Cohort Studies; Coinfection; Demography; Female; Follow-Up Studies; Hepatitis C; HIV Infections; Humans; Liver; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral

Immunovirological consequences of a switch to a maraviroc/raltegravir dual therapy were analyzed in 16 HIV-infected patients with persistent viral load below 50 copies/ml. At 26-week postswitch, the CD4/CD8 ratio decreased and the CD8 T-cell activation increased. A decrease in classical monocytes was associated with a shift toward a proinflammatory monocyte profile and negatively correlated with ultrasensitive viral load. Thus, this therapeutic switch induced a proinflammatory profile probably driven by a slight loss of virus control.

Topics: Anti-HIV Agents; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclohexanes; Female; HIV Infections; Humans; Lymphocyte Activation; Male; Maraviroc; Middle Aged; Monocytes; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Triazoles; Viral Load; Viremia

Therapeutic options are limited for HIV-2 infected persons, largely in part due to the lack of susceptibility to HIV-1 non-nucleoside reverse transcriptase inhibitors and poor susceptibility to some HIV-1 protease inhibitors. This is particularly worrisome for HIV-2 patients with prior antiretroviral failure.. Report the virological response to dolutegravir in HIV-2-infected individuals.. Retrospective observational assessment of all HIV-2 individuals treated with dolutegravir in Spain.. From 297 HIV-2-infected individuals recorded at the Spanish national registry, 26% received antiretroviral therapy. Six out of 8 failing on raltegravir selected for integrase resistance mutations N155H (4), Y143G (1) and Q148R (1). Two patients bearing N155H subsequently received dolutegravir. Both experienced initially more than 1.5 log drop in plasma HIV-2 RNA and significant CD4 gains. Whereas one kept on undetectable viremia 6 months later, the other experienced viral rebound.. Dolutegravir may be a good therapeutic option for patients with HIV-2 infection, including those that previously failed other integrase inhibitors.

Topics: Adult; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-2; Humans; Male; Mutation; Oxazines; Piperazines; Pyridones; Raltegravir Potassium; Retrospective Studies; Spain; Viremia

P1066 is an open-label study of raltegravir in HIV positive youth, ages 4 weeks-18 years. Here we summarize P1066 pharmacokinetic (PK) data and a population PK model for the pediatric chewable tablet and oral granules. Raltegravir PK parameters were calculated using noncompartmental analysis. A 2-compartment model was developed using data from P1066 and an adult study of the pediatric formulations. Interindividual variability was described by an exponential error model, and residual variability was captured by an additive/proportional error model. Twelve-hour concentrations (C12h ) were calculated from the model-derived elimination rate constant and 8-hour observed concentration. Simulated steady-state concentrations were analyzed by noncompartmental analysis. Target area under the curve (AUC0-12h ) and C12h were achieved in each cohort. For the pediatric formulations, geometric mean AUC0-12h values were 18.0-22.6 μM-hr across cohorts, and C12h values were 71-130 nM, with lower coefficients of variation versus the film-coated tablet. A 2-compartment model with first-order absorption adequately described raltegravir plasma PK in pediatric and adult patients. Weight was a covariate on clearance and central volume and was incorporated using allometric scaling. Raltegravir chewable tablets and oral granules exhibited PK parameters consistent with those from prior adult studies and older children in P1066, as well as lower variability than the film-coated tablet.

Topics: Adolescent; Adult; Age Factors; Anti-HIV Agents; Area Under Curve; Child; Child, Preschool; Female; HIV Infections; Humans; Infant; Infant, Newborn; Male; Models, Biological; Raltegravir Potassium; Tablets

To assess the prevalence of minority resistant variants (MRVs) at baseline and their impact on the virological response. The ANRS 139 TRIO trial evaluated the combination of raltegravir, etravirine and darunavir, plus an optimized background therapy, in 87% of cases. Patients were highly experienced and harboured multiresistant viruses, but were naive to the three drugs, and showed a high level of virological suppression.. Ultra-deep sequencing of reverse transcriptase, protease and integrase regions was performed at the trial baseline, and sequences were interpreted according to the ANRS algorithm. MRVs were assessed using MiSeq and 454 technologies (limit of detection 1%).. At baseline, minority variants with at least one NRTI, one NNRTI, one PI, one major PI or an integrase inhibitor resistance-associated mutation were present in 46%, 45%, 68%, 24% and 13% of patients, respectively. When minority variants are taken into account, the prevalence of resistance to etravirine, darunavir and raltegravir at baseline was 29%, 40% and 9%, respectively. No difference was observed in the prevalence of MRVs between patients with virological failure and those with virological success, except a trend for patients exhibiting baseline etravirine MRVs (50% versus 26%, P = 0.09).. We have shown a high level of MRVs at baseline in highly pre-treated patients harbouring multiresistant viruses. However, these MRVs were not associated with an increased risk of virological failure, except for a trend for etravirine MRVs.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Viral; High-Throughput Nucleotide Sequencing; HIV Infections; HIV Integrase; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Longitudinal Studies; Mutation; Nitriles; Pyridazines; Pyrimidines; Raltegravir Potassium; Treatment Outcome; Viral Load

Daily administration (q24h) of raltegravir has been shown to be as efficacious as twice-daily administration (q12h) in the hollow-fiber infection model (HFIM) system. However, q24h regimens were not noninferior to q12h dosing in a clinical trial. We hypothesized that between-patient variability in raltegravir pharmacokinetics (PK) was responsible for the discordance in conclusions between the in vitro and in vivo studies. Hollow-fiber cartridges were inoculated with HIV-infected H9 cells and uninfected CEM-SS cells. Four cartridges received the total daily exposure (800 mg) q24h and four received half the daily exposure (400 mg) q12h. PK profiles with half-lives of 8, 4, 3, and 2 h were simulated for each dosing interval. Cell-to-cell viral spread was assessed by flow cytometry. Viral inhibition was similar between q24h and q12h dosing at the 8- and 4-h half-lives. The q24h dosing was not as efficacious as the q12h dosing when faster half-lives were simulated; a lack of viral suppression was observed at days 3 and 4 for the 2- and 3-h half-lives, respectively. The discrepancy in conclusions between the in vitro HFIM system studies and clinical trials is likely due to the large interindividual variation in raltegravir PK.

Topics: Anti-HIV Agents; Area Under Curve; Cell Line; Dose Fractionation, Radiation; Drug Administration Schedule; Drug Therapy, Combination; Flow Cytometry; HEK293 Cells; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Models, Biological; Patient Compliance; Raltegravir Potassium; T-Lymphocytes

Topics: Anti-HIV Agents; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Tablets; Viral Load

The objective of the study was to assess plasma concentrations of efavirenz, darunavir/ritonavir and raltegravir in patients with human immunodeficiency virus-hepatitis C virus (HIV-HCV)-coinfection without liver cirrhosis.. In this observational, open-label study, adult HIV-infected outpatients treated with tenofovir/emtricitabine plus efavirenz (600 mg daily), darunavir/ritonavir (800/100 mg daily) or raltegravir (400 mg twice daily) for at least 4 weeks were asked to participate. Subjects with liver cirrhosis were excluded. The trough concentration (C trough) of darunavir/ritonavir and raltegravir and the mid-dose concentration (C12h) of efavirenz were assessed at steady state by a validated high-performance liquid chromatography (HPLC)-tandem mass spectrometry method.. A total of 96 HIV-positive patients were enrolled into the study. Thirty-four patients were treated with efavirenz, 33 with darunavir/ritonavir and 29 with raltegravir. The geometric mean plasma C trough [coefficient of variation (%)] of darunavir was comparable between HIV+/HCV+ and HIV+/HCV- subjects: 2644 ng/ml (155%) and 2491 ng/ml (139%), respectively (geometric mean ratio (GMR) = 0.81; 95% confidence interval (CI) = 0.79-1.56; p = 0.69). These values were comparable for raltegravir: 108 ng/ml (149%) in the HIV+/HCV+ group and 96 ng/ml (161%) in the HIV+/HCV- group (GMR = 0.84; 95% CI = 0.61-1.44; p = 0.72). On the contrary, the geometric mean plasma C12h of efavirenz was significantly higher among the 15 HIV+/HCV+ patients (1915 ng/ml, 159%) than among the 19 HIV+/HCV- patients (1505 ng/ml, 167%; GMR = 1.41; 95% CI = 1.19-1.71; p = 0.009).. The mean plasma concentration of efavirenz was significantly higher in HCV-positive than in HCV-negative patients without liver cirrhosis, while the mean plasma levels of darunavir/ritonavir and raltegravir were comparable in both groups.

Topics: Adult; Alkynes; Analysis of Variance; Anti-HIV Agents; Benzoxazines; Coinfection; Cyclopropanes; Darunavir; Female; Hepatitis C; HIV Infections; Humans; Liver Function Tests; Male; Middle Aged; Raltegravir Potassium; Ritonavir

There are few data on the best combination antiretroviral therapy in patients with HIV infection who need cancer chemotherapy because of drug-drug interactions and increased risk of toxic effects.. We evaluated the safety, efficacy and interactions of a raltegravir (RAL)-based regimen in 30 HIV-infected patients who received antineoplastic agents.. A total of 17 patients had a non-AIDS-defining malignancy (7 with Hodgkin disease) and 13 had an HIV-related cancer (9 non-Hodgkin lymphoma, 2 Kaposi sarcoma and 2 anal cancer). Overall, they received 49 cycles of chemotherapy with 19 different antineoplastic drugs, including antimetabolites in 4 patients (5-FU, gemcitabine), alkylating agents in 10 cases (cyclophosphamide, ifosfamide), vinca alkaloids in 17 patients (vincristine, vinblastine), anti-tumour antibiotics in 18 cases (doxorubicin), cisplatin or carboplatin in 6, and monoclonal antibodies in 13 patients (rituximab, trastuzumab, cetuximab). Six patients modified the doses of antineoplastic agents due to toxicity not related to raltegravir. During a median follow-up of 67.8 patient-years (median 170 days in concomitant therapy) there was only 1 case of virological failure and no patient discontinued RAL. Geometric mean trough levels of RAL were 143 ng/ml (79-455). There were no opportunistic infections, median CD4(+) T-cell count increased by 49 cells/ml and four (13%) patients died during the study (not related to AIDS progression).. Our results show that a RAL-based regimen is safe and effective in patients requiring chemotherapy, irrespective of type and of duration of chemotherapy.

Topics: Adult; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Raltegravir Potassium; Treatment Outcome; Viral Load; Young Adult

Integrase strand transfer inhibitors (INSTIs), which block proviral DNA integration into the host chromosome, are clinically effective against HIV-1 isolates exhibiting resistance to other classes of antiretroviral agents. Although naturally occurring amino acid variation has been less frequently observed in the integrase region, the functional constraints of this variation on primary INSTI resistance-associated mutations are not fully understood. In the present study, we focused on the S119G/R/P/T (S119X) polymorphisms, which are frequently observed in HIV-1 sequences derived from clinical specimens (naïve, n=458, 26%). The frequency of the S119X polymorphism together with Q148H/R (n=8, 63%) or N155H (n=12, 83%) was relatively high compared with that of naïve group. Our in vitro assays revealed that S119G/P/T alone exerted no effect on the susceptibility to INSTIs, whereas S119R enhanced the level of INSTI resistance induced by well-known INSTI resistance-associated mutations (Y143C, Q148H or N155H). Notably, the S119R polymorphism contributed to a significant (5.9-fold) increase in dolutegravir resistance caused by G140S/Q148H. Analysis of two cases of virological failure during raltegravir-based therapy showed that the accumulation and the rapid evolution of primary INSTI resistance-associated mutations coincided with the S119R mutation. These data highlight the role of the S119X polymorphism in INSTI resistance, and this polymorphism might be linked to the potential treatment outcome with INSTI-based therapy.

Topics: Amino Acid Sequence; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Oxazines; Piperazines; Polymorphism, Genetic; Pyridones; Raltegravir Potassium; Treatment Outcome; Virion

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Integrase; HIV-1; Humans; Mutation, Missense; Raltegravir Potassium; Treatment Outcome; Viral Load

Enzymes whose catalytic activity depends on multimeric assembly are targets for inhibitors that perturb the interactions between the protein subunits such as the HIV-1 Integrase (IN). Sucrose has been recently crystallized in complex with IN revealing an allosteric binding pocket at the monomer-monomer interface. Herein, molecular dynamics were applied to theoretically test the effect of this small ligand on IN. As a result, such a compound increases the mutual free energy of binding between the two interacting monomers. Biological experiments confirmed the computational forecast.

Topics: Binding Sites; Drug Synergism; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Multimerization; Raltegravir Potassium; Sucrose; Thermodynamics

Determinants of HIV-infected women's genital tract mucosal immune health are not well understood. Because raltegravir (RAL) achieves relatively higher genital tract concentrations than ritonavir-boosted atazanavir (ATV), we examined whether an RAL-based regimen is associated with improved cervical immune reconstitution and less activation in HIV(+) women compared to an ATV-based regimen. Peripheral blood, cervical brushings, cervical-vaginal lavage (CVL), and cervical biopsies were collected from HIV(+) women on tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and either RAL (n=14) or ATV (n=19) with CD4(+) T cells>300 cells/mm(3) and HIV RNA<48 copies/ml. HLA-DR(+)CD38(+) T cells were measured in blood and cervical cells using flow cytometry, CD4(+) and CD8(+) T cells were quantified in cervical biopsies by immunofluorescent analysis, and HIV RNA (VL), ATV, and RAL concentrations were measured in CVL. In a linear regression model of log(CVL concentration) versus both log(plasma concentration) and treatment group, the RAL CVL level was 519% (95% CI: 133, 1,525%) higher than for ATV (p<0.001). Genital tract VL was undetectable in 90% of subjects and did not differ by regimen. There were no significant differences between groups in terms of cervical %HLA-DR(+)CD38(+)CD4(+) or CD8(+) T cells, CD4(+) or CD8(+) T cells/mm(2), or CD4:CD8 ratio. After adjusting for treatment time and group, the CVL:plasma drug ratio was not associated with the cervical CD4:CD8 ratio or immune activation (p>0.6). Despite significantly higher genital tract penetration of RAL compared to ATV, there were no significant differences in cervical immune activation or reconstitution between women on these regimens, suggesting both drug regimens achieve adequate genital tract levels to suppress virus replication.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Blood; CD4 Lymphocyte Count; Female; Genitalia, Female; HIV Infections; HIV-1; Humans; Middle Aged; Raltegravir Potassium; T-Lymphocyte Subsets; Treatment Outcome; Viral Load

The 3'-end processing (3'P) of each viral long terminal repeat (LTR) during human immunodeficiency virus type-1 (HIV-1) integration is a vital step in the HIV life cycle. Blocking the 3'P using 3'P inhibitor has recently become an attractive strategy for HIV-1 therapeutic intervention. Recently, we have developed a novel real-time PCR based assay for the detection of 3'P activity in vitro. The methodology usually involves biotinylated HIV-1 LTR, HIV-1 integrase (IN), and specific primers and probe. In this novel assay, we designed the HIV-1 LTR substrate based on a sequence with a homology to HIV-1 LTR labeled at its 3' end with biotin on the sense strand. Two nucleotides at the 3' end were subsequently removed by IN activity. Only two nucleotides labeled biotin were captured on an avidin-coated tube; therefore, inhibiting the binding of primers and probe results in late signals in the real-time PCR. This novel assay has successfully detected both the 3'P activity of HIV-1 IN and the anti-IN activity by Raltegravir and sodium azide agent. This real-time PCR assay has been shown to be effective and inexpensive for a high-throughput screening of novel IN inhibitors.

Topics: HIV Infections; HIV Integrase; HIV Long Terminal Repeat; HIV-1; Humans; Raltegravir Potassium; Sodium Azide

Raltegravir (RAL)-containing antiretroviral therapy (ART) produced better immunologic and virologic responses than optimized background ART in clinical trials of heavily ART-experienced patients, but few data exist on long-term outcomes in routine HIV care.. We studied ART-experienced HIV outpatient study (HOPS) participants seen at 10 US HIV-specialty clinics during 2007-2011.We identified patients who started (baseline date) either continuous ≥ 30 days of RAL-containing or RAL-sparing ART, and used propensity score (PS) matching methods to account for baseline clinical and demographic differences. We used Kaplan-Meier methods and log-rank tests for the matched subsets to evaluate probability of death, achieving HIV RNA < 50 copies/ml, and CD4 cell count (CD4) increase of ≥ 50 cells mm(- 3) during follow-up.. Among 784 RAL-exposed and 1062 RAL-unexposed patients, 472 from each group were matched by PS. At baseline, the 472 RAL-exposed patients (mean nadir CD4, 205 cells mm(- 3); mean baseline CD4, 460 cells mm(- 3); HIV RNA < 50 copies ml(- 1) in 61%; mean years on prescribed ART, 7.5) were similar to RAL unexposed. During a mean follow-up of over 3 years, mortality rates and immunologic and virologic trajectories did not differ between the two groups. Among patients with detectable baseline HIV RNA levels, 76% of RAL-exposed and 63% of RAL-unexposed achieved HIV RNA < 50 copies ml(- 1) (P = 0.51); 69 and 58%, respectively, achieved a CD4 increase ≥ 50 cells mm(- 3) (P = 0.70).. In our large cohort of US ART-experienced patients with a wide spectrum of clinical history, similar outcomes were observed when prescribed RAL containing versus other contemporary ART.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Female; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Outpatients; Prospective Studies; Raltegravir Potassium; Viral Load

Antiretroviral therapy (ART) has improved lifespan and quality of life of patients infected with the HIV-1. However, ART has several potential limitations, including the development of drug resistance and suboptimal penetration to selected anatomic compartments. Improving the delivery of antiretroviral molecules could overcome several of the limitations of current ART.. Two to ten nanometer diameter inorganic gold crystals serve as a base scaffold to combine molecules with an array of properties in its surface. We show entry into different cell types, antiviral activity of an HIV integrase inhibitor conjugated in a gold nanoparticle and penetration into the brain in vivo without toxicity. Herein, gold nanoparticles prove to be a promising tool to use in HIV therapy.

Topics: Animals; Anti-HIV Agents; Brain; Drug Carriers; Endothelial Cells; Female; Gold; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Macrophages; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Raltegravir Potassium; Tissue Distribution; Virus Replication

HIV-1 integration can be efficiently inhibited by strand-transfer inhibitors such as raltegravir, elvitegravir or dolutegravir. Three pathways conferring raltegravir/elvitegravir cross-resistance (involving integrase residues Q148, N155 and Y143) were identified. Dolutegravir, belonging to the second generation of strand-transfer compounds, inhibits the Y143 and N155 pathways, but is less efficient at inhibiting the Q148 pathway. The aim of this study was to characterize the combination of two pathways involved in raltegravir resistance described in one patient failing a dolutegravir regimen for their propensity to confer dolutegravir resistance.. In this study, a patient first failing a regimen including raltegravir was treated with dolutegravir and showed an increase in viruses carrying a combination of two pathways (N155 and Q148). Impacts of these mutations on integrase activity and resistance to strand-transfer inhibitors were characterized using both in vitro and virological assays.. Our data showed that the combination of N155H, G140S and Q148H mutations led to strong resistance to dolutegravir.. Combination of N155H, G140S and Q148H mutations originating from two distinct resistance pathways to raltegravir or elvitegravir led to a high level of dolutegravir resistance. Due to its high genetic barrier of resistance, it would be reasonable to use dolutegravir in first-line therapy before emergence of raltegravir or elvitegravir resistance.

Topics: Antiretroviral Therapy, Highly Active; Cell Line; DNA, Viral; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Proviruses; Pyridones; Raltegravir Potassium; Sequence Analysis, DNA; Treatment Failure; Viral Load; Virus Replication

Raltegravir (RAL), an HIV integrase inhibitor, is metabolized mainly by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in UGT1A1 may cause alterations in the pharmacodynamics of RAL, which is taken twice daily with no dietary restrictions. We compared the effect of two polymorphic alleles in this gene, UGT1A1*6 and UGT1A1*28 on plasma RAL concentrations in Japanese HIV-1-infected patients. Of 114 Japanese HIV-1-infected patients who received RAL, the frequencies of UGT1A1*6 and UGT1A1*28 were 18% and 13%, respectively. The percentage of homozygotes for UGT1A1*6 and UGT1A1*28 was 6% and 4%, respectively, the percentage of compound heterozygotes for UGT1A1*6 and UGT1A1*28 was 2%, and that of heterozygotes for UGT1A1*6 and UGT1A1*28 was 22% and 17%, respectively. RAL plasma trough concentrations were compared for each polymorphism. Significantly higher levels of RAL were observed with patients who were homozygous for UGT1A1*6 (median: 1.0 μg/mL) than for the normal allele (median: 0.11 μg/mL; p = 0.021). Multivariate logistic regression analysis showed that the presence of one or two alleles of UGT1A1*6 or two alleles of UGT1A1*28 were independent factors associated with high RAL plasma trough concentrations (≥ 0.17 μg/mL). These results indicated that UGT1A1*6 and UGT1A1*28 are both factors influencing the RAL plasma trough concentrations in Japanese HIV-1-infected patients.

Topics: Glucuronosyltransferase; Heterozygote; HIV Infections; HIV Integrase Inhibitors; Homozygote; Humans; Japan; Polymorphism, Genetic; Raltegravir Potassium; Regression Analysis

Raltegravir (RAL) plus tenofovir/emtricitabine (TDF/FTC) is a recommended initial antiretroviral regimen. A substantial proportion of persons diagnosed with HIV infection and starting antiretrovirals in the U.S. are African-American (AA); however, the effects of this regimen on metabolic parameters have largely been studied in white patients.. Single-arm, open-label study of untreated AA HIV-infected patients administered RAL with TDF/FTC for 104 weeks. Changes in fasting lipids, insulin resistance, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), limb and trunk fat, and bone mineral density (BMD) were assessed at weeks 56 and 104.. Thirty (85% men) participants were included. Median entry characteristics included age of 38 years, CD4 323 cells/mm3, HIV RNA level 29,245 copies/ml, and body mass index 28.1 kg/m2. At 56 and 104 weeks, significant increases in VAT, trunk fat, limb fat, and overall fat were observed. Bone mineral density decreased by 1.5% by week 104.There were no significant changes in non-HDL-cholesterol, fasting triglycerides, or insulin resistance. A median CD4 cell count increase of 318 cells/mm3 (IQR 179, 403; full range 40, 749) (P<0.001) was observed. Assuming missing=failure, 78 and 70% had HIV RNA levels<40 copies/ml at weeks 56 and 104, respectively. There were no treatment-related discontinuations and no new antiretroviral resistance mutations were detected.. In this cohort of AAs, initiation of RAL with TDF/FTC was associated with significant general increases in fat. Significant changes in lipids or insulin resistance were not observed and there was a small decline in BMD. Therapy was well tolerated and effective. These results are consistent with findings of studies of initial antiretroviral therapy in racially diverse cohorts and inform treatment selection for AA patients starting therapy for HIV infection.

Topics: Adult; Anti-HIV Agents; Black or African American; Bone Density; Cohort Studies; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lipid Metabolism; Longitudinal Studies; Male; North Carolina; Raltegravir Potassium; Tenofovir

Merck recently signed an agreement with The Medicines Patent Pool (MPP) to license intellectual property relating to pediatric formulations of its integrase HIV drug, raltegravir (Ral) (the 'Agreement'). The Agreement is alleged to clear the way for cheaper formulations for use in developing and some middle income countries and allows for the development of novel pediatric formulations of Ral as well as novel combinations. Merck's license is royalty free and under the terms of the Agreement, manufacturers anywhere in the world who meet the quality assurance criteria, can manufacture and sell pediatric versions of the drug in the licensed countries under the agreed conditions without paying a royalty to Merck. The Agreement covers at least 92 countries and MPP reports that 98.1% of children with HIV in the developing world live in the included countries. The Agreement has been criticized as a public relations exercise. The article asks if the criticism is justified and explores several aspects of the Agreement in addressing the question.

Topics: Anti-HIV Agents; Child; Developing Countries; Drug Industry; HIV Infections; Humans; Intellectual Property; Patents as Topic; Raltegravir Potassium

The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade.. The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex).. No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K + G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades.. No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K + G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed.

Topics: Anti-HIV Agents; Cohort Studies; Drug Resistance, Viral; Europe; Genotype; HIV Infections; HIV-1; Humans; Integrase Inhibitors; Mutation, Missense; Raltegravir Potassium

The R263K substitution in integrase has been selected in tissue culture with dolutegravir (DTG) and has been reported for several treatment-experienced individuals receiving DTG as part of salvage therapy. The R263K substitution seems to be incompatible with the presence of common resistance mutations associated with raltegravir (RAL), a different integrase strand transfer inhibitor (INSTI). T66I is a substitution that is common in individuals who have developed resistance against a different INSTI termed elvitegravir (EVG), but it is not known whether these two mutations might be compatible in the context of resistance against DTG or what impact the combination of these substitutions might have on resistance against INSTIs. E138K is a common secondary substitution observed with various primary resistance substitutions in RAL- and EVG-treated individuals. Viral infectivity, replicative capacity, and resistance against INSTIs were measured in cell-based assays. Strand transfer and 3' processing activities were measured biochemically. The combination of the R263K and T66I substitutions decreased HIV-1 infectivity, replicative capacity, and strand transfer activity. The addition of the E138K substitution partially compensated for these deficits and resulted in high levels of resistance against EVG but not against DTG or RAL. These findings suggest that the presence of the T66I substitution will not compromise the activity of DTG and may also help to prevent the additional generation of the R263K mutation. Our observations support the use of DTG in second-line therapy for individuals who experience treatment failure with EVG due to the T66I substitution.. The integrase strand transfer inhibitors (INSTIs) elvitegravir and dolutegravir are newly developed inhibitors against human immunodeficiency virus type 1 (HIV-1). HIV drug-resistant mutations in integrase that can arise in individuals treated with elvitegravir commonly include the T66I substitution, whereas R263K is a signature resistance substitution against dolutegravir. In order to determine how different combinations of integrase resistance mutations can influence the outcome of therapy, we report here the effects of the T66I, E138K, and R263K substitutions, alone and in combination, on viral replicative capacity and resistance to integrase inhibitors. Our results show that the addition of R263K to the T66I substitution diminishes viral replicative capacity and strand transfer activity while not compromising susceptibility to dolutegravir. This supports the use of dolutegravir in second-line therapy for patients failing elvitegravir therapy who harbor the T66I resistance substitution.

Topics: Amino Acid Substitution; Cell Line, Tumor; Drug Resistance, Viral; HEK293 Cells; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV; HIV Infections; Humans; Maintenance Chemotherapy; Male; Middle Aged; Nevirapine; Raltegravir Potassium; RNA, Viral; Viral Load

Monocytes are increasingly implicated in the inflammatory consequences of HIV-1 disease, yet their phenotype following antiretroviral therapy (ART) initiation is incompletely defined. Here, we define more completely monocyte phenotype both prior to ART initiation and during 48 weeks of ART.. Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained at baseline (prior to ART initiation) and at weeks 12, 24, and 48 of treatment from 29 patients participating in ACTG clinical trial A5248, an open label study of raltegravir/emtricitibine/tenofovir administration. For comparison, cryopreserved PBMCs were obtained from 15 HIV-1 uninfected donors, each of whom had at least two cardiovascular risk factors. Thawed samples were stained for monocyte subset markers (CD14 and CD16), HLA-DR, CCR2, CX3CR1, CD86, CD83, CD40, CD38, CD36, CD13, and CD163 and examined using flow cytometry.. In untreated HIV-1 infection there were perturbations in monocyte subset phenotypes, chiefly a higher frequency and density (mean fluorescence intensity-MFI) of HLA-DR (%-p = 0.004, MFI-p = .0005) and CD86 (%-p = 0.012, MFI-p = 0.005) expression and lower frequency of CCR2 (p = 0.0002) expression on all monocytes, lower CCR2 density on inflammatory monocytes (p = 0.045) when compared to the expression and density of these markers in controls' monocytes. We also report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls. After ART, these perturbations tended to improve, with decreasing expression and density of HLA-DR and CD86, increasing CCR2 density on inflammatory monocytes, and increasing expression and density of CX3CR1 on patrolling monocytes.. In HIV-1 infected patients, ART appears to attenuate the high levels of activation (HLA-DR, CD86) and to increase expression of the chemokine receptors CCR2 and CX3CR1 on monocyte populations. Circulating monocyte phenotypes are altered in untreated infection and tend to normalize with ART; the role of these cells in the inflammatory environment of HIV-1 infection warrants further study.

Topics: Adult; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Cell Separation; CX3C Chemokine Receptor 1; Drug Combinations; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Female; Flow Cytometry; HIV Infections; HIV Integrase Inhibitors; HIV-1; HLA-DR Antigens; Humans; Immunophenotyping; Male; Middle Aged; Monocytes; Raltegravir Potassium; Receptors, CCR2; Receptors, Chemokine; Viral Load; Viremia

Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon-ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir.

Topics: Adult; Antiviral Agents; Carbamates; Coinfection; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Imidazoles; Interferon-alpha; Isoquinolines; Liver; Liver Cirrhosis; Male; Middle Aged; Polyethylene Glycols; Pyrrolidines; Raltegravir Potassium; Recombinant Proteins; Ribavirin; Sulfonamides; Valine

The objective of this study was to evaluate the incidence, prevalence and clinical consequences of virological failure (VF) to raltegravir-based regimens in Spain.. A multicentre, retrospective, observational study was performed in 10 tertiary hospitals (January 2006 to June 2013). The study included HIV-1-infected patients with loss of virological suppression (LVS; two consecutive HIV-1 RNA ≥50 copies/mL) while receiving raltegravir. VF and low-level viraemia (LLV) were defined as two consecutive HIV-1 RNA ≥200 copies/mL and 50 to <200 copies/mL, respectively. Integrase strand-transfer inhibitor resistance was investigated at LVS. During the 48 weeks following LVS, recorded data included clinical characteristics, treatment discontinuations, AIDS-associated events and deaths. Effectiveness of therapy following LVS was evaluated by ITT and PP. Multivariate regression was used to assess predictors of efficacy.. Of the 15 009 HIV-infected patients in participating centres, 2782 (18.5%) had received raltegravir-based regimens. Of those, 192 (6.9%), 125 (4.5%) and 67 (2.4%) experienced LVS, VF and LLV, respectively. The incidence of VF was 1.8 (95% CI, 1.5-2.1) per 100 patients/year. The prevalence of VF was 4.5% (95% CI, 3.8%-5.3%). Integrase-associated mutations were found in 78.8% of patients with integrase genotyping results available. High-level resistance to dolutegravir was not observed. Salvage therapy failed in 34.1% of patients; progression to AIDS/death occurred in 8.3% during the first year following LVS. The latter was associated with intravenous drug use, time on raltegravir and lower CD4+ count nadir in patients who started raltegravir-based treatments as salvage regimens.. VF with raltegravir is infrequent, but often associated with major clinical complications in treatment-experienced patients.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Incidence; Prevalence; Raltegravir Potassium; Retrospective Studies; Spain; Tertiary Care Centers; Treatment Failure; Viral Load

Administering raltegravir once daily would make adherence to antiretroviral treatment easier, especially if the concomitant drugs are also administered once daily. We report our experience on the use of raltegravir, both once- and twice-daily.Retrospective review of HIV-infected patients on treatment with raltegravir 800 mg once or 400 mg twice a day plus 2 analogs. Patients were classified as group A (subjects switched to raltegravir due to adverse events on a previous regimen or drug-drug interactions) and group B (subjects who restarted antiretroviral treatment after a previous drop-out). The primary clinical endpoint was the percentage of subjects with virological suppression after 96 weeks. Treatment's effectiveness (noncomplete/missing equals failure) was also evaluated. Pharmacokinetic study was performed in unselected patients. Plasma raltegravir concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry.A total of 133 patients were included in the study (74 and 59 on raltegravir once- and twice-daily). There were only 4 virological failures in the entire cohort during the follow-up. Thus, the Kaplan-Meier estimation of efficacy by on-treatment analysis was 96.3% (CI95, 92.8-99.8) at week 96, independently of the dosing regimen and of the raltegravir concentrations. Similar exposures to raltegravir based on AUC0-τ, but higher Cmax and significantly lower Ctrough were observed when raltegravir was given once daily compared with 400 mg twice daily. In fact, 14 out of 56 Ctrough concentrations (25%) from patients taking raltegravir once daily were below the IC95 of wild-type HIV-1 clinical isolates while only 2 samples from patients receiving 400 mg twice a day were below this value, although no relationship between Ctrough and efficacy was found. The main limitations of the study are that the raltegravir dosing regimen was not randomized and more than 50% of the patients were virologically suppressed at baseline.Regimens comprising raltegravir 800 mg once daily plus 2 nucleos(t)ide reverse transcriptase inhibitors can be an efficacious and safe option, particularly in virologically suppressed patients and those with a viral load <100,000 copies/mL.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Inhibitors

We analyzed the early kinetics with integrase inhibitor treatment to gain new insights into viral dynamics.. We analyzed data from 39 HIV-1 infected, treatment-naive, participants: 28 treated with raltegravir (RAL; multiple doses) monotherapy for 9 days, and 11 with RAL 400 mg twice daily and emtricitabine (200 mg daily)/tenofovir disoproxil fumarate (300 mg daily). Plasma HIV-1 RNA was measured frequently; the data was fitted using a mathematical model of viral dynamics distinguishing between infected cells with unintegrated HIV DNA and productively infected cells. Parameters were estimated using mixed-effect models.. RAL treatment led to a biphasic viral decline with a rapid first phase (1a) lasting approximately 5 days followed by a slower phase (1b). Phase 1a is attributed to the rapid elimination of productively infected cells. Phase 1b reflects the loss of infected cells with nonintegrated provirus due to cell loss and integration of HIV DNA. The half-lives of productively infected cells and of infected cells that had completed reverse transcription but had not yet integrated HIV DNA were approximately 19 h and between 3.6 and 5.8 days, respectively. The effectiveness of RAL in preventing proviral integration was 94% and 99.7%, for the combination therapy and monotherapy groups, respectively.. We found that the first phase of viral decay with RAL therapy was composed of two subphases corresponding to the half-lives of infected cells with integrated proviruses and with unintegrated HIV-DNA.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; DNA, Viral; HIV Infections; HIV-1; Humans; Plasma; Raltegravir Potassium; RNA, Viral; Viral Load

The effectiveness of switching from enfuvirtide to raltegravir in HIV-1-infected patients on a suppressive antiretroviral regimen has been poorly studied in the clinical practice of developing countries. We conducted a multicenter retrospective cohort study in HIV-1-infected, multidrug-experienced adults (≥18 years old) with plasma HIV-1-RNA <400 copies/ml for at least 4 months on an enfuvirtide-containing therapy between 2005 and 2010, in whom the attending physician switched from enfuvirtide to raltegravir. Effectiveness endpoints were measured at week 48 after switch. Analyses were conducted on an intent-to-treat basis and two strategies for handling missing outcome data were used (hereafter, strategies 1 and 2). Overall, 87 patients were eligible for analysis. At baseline, the median CD4(+) T cell count was 400 cells/μl and 91.9% of patients had <50 HIV-1-RNA copies/ml. At week 48, the proportions of patients with plasma HIV-1-RNA <50 and <400 copies/ml were, respectively, 86.2% (95% CI=77.1; 92.7%) and 88.5% (95% CI=79.9; 94.3%) (strategies 1 and 2) and 89.7% (95% CI=81.3; 95.2%) and 90.8% (95% CI=82.7; 95.9%) (strategies 1 and 2). This was a -10.3% (95% CI=-2.8; -17.9%) and -9.2% (95% CI=-2; -16.4%) difference from baseline in the proportion of patients with plasma HIV-1-RNA <400 copies/ml. The median increase in CD4(+) T cell counts was 41 and 64 cells/μl (p<0.001) (strategies 1 and 2). No patient withdrew raltegravir or developed opportunistic infections, but one was diagnosed with HIV-related dementia. In conclusion, switching from enfuvirtide to raltegravir in patients on a virologically suppressive regimen is an effective strategy even in a Brazilian clinical setting.

Topics: Adolescent; Adult; Anti-HIV Agents; Brazil; CD4 Lymphocyte Count; Cohort Studies; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

To analyse the determinants of raltegravir CSF penetration, including the pharmacogenetics of drug transporters located at the blood-brain barrier or blood-CSF barrier.. Plasma and CSF raltegravir concentrations were determined by a validated HPLC coupled with mass spectrometry method in adults on raltegravir-based combination antiretroviral therapy undergoing a lumbar puncture. Single nucleotide polymorphisms in the genes encoding drugs transporters (ABCB1 3435, SLCO1A2, ABCC2 and SLC22A6) and the gene encoding hepatocyte nuclear factor 4 α (HNF4α) were determined by real-time PCR.. In 41 patients (73.2% male, 95.1% Caucasians), the median raltegravir plasma and CSF concentrations were 165 ng/mL (83-552) and 31 ng/mL (21-56), respectively. CSF-to-plasma ratios (CPRs) ranged from 0.005 to 1.33 (median 0.20, IQR 0.04-0.36). Raltegravir trough CSF concentrations (n = 35) correlated with raltegravir plasma levels (ρ = 0.395, P = 0.019); CPRs were higher in patients with blood-brain barrier damage (0.47 versus 0.18, P = 0.02). HNF4α 613 CG genotype carriers had lower trough CSF concentrations (20 versus 37 ng/mL, P = 0.03) and CPRs (0.12 versus 0.27, P = 0.02). Following multivariate linear regression analysis, the CSF-to-serum albumin ratio was the only independent predictor of raltegravir penetration into the CSF.. Raltegravir penetration into the CSF shows a large interpatient variability, although CSF concentrations were above the wild-type IC50 in all patients (and above IC95 in 28.6%). In this cohort, blood-brain barrier permeability is the only independent predictor of raltegravir CPR. The impact of single nucleotide polymorphisms in selected genes on raltegravir penetration warrants further studies.

Topics: Adult; Anti-HIV Agents; Blood-Brain Barrier; Cerebrospinal Fluid; Chromatography, High Pressure Liquid; Female; HIV Infections; Humans; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Protein 2; Pharmacogenetics; Plasma; Polymorphism, Single Nucleotide; Pyrrolidinones; Raltegravir Potassium

Clinical use of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be hampered by toxicity, interactions or resistance issues. Simple and effective antiretroviral regimens avoiding both drug classes may be needed for selected patients.. This was a prospective cohort study. Virologically suppressed patients on PI or NRTI regimens, with problems of tolerability, safety concerns due to comorbidities or risk of drug interactions for both PIs and NRTIs, were given the opportunity to switch their regimen to etravirine plus raltegravir. Patients were required not to have prior virological failure to raltegravir and if there was prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure, only patients in whom efficacy of etravirine could be anticipated through the Stanford Drug Resistance Database were included. Follow-up was scheduled for at least 48 weeks, unless the patient was lost to follow-up or discontinued therapy.. Twenty-five patients were included. Their median age was 54 years; they had a median of 16 years on antiretroviral therapy and a median of nine previous regimens; 21 (84%) patients had previous virological failure; and 15 (60%) patients had a genotypic test that showed three or more NRTI mutations in 9 (36%), four or more PI mutations in 11 (44%) and at least one NNRTI mutation in 8 (32%) patients. At 48 weeks efficacy was 84% (95% CI 65.3%-93.6%) by intent-to-treat analysis and 91.3% (95% CI 73.2%-97.6%) by per-protocol analysis. One (4%) patient died, two (8%) discontinued due to intolerance and one (4%) experienced virological failure. The CD4/CD8 ratio and plasma lipids improved.. Dual therapy with etravirine plus raltegravir was well tolerated and maintained durable viral suppression in selected virologically suppressed patients for whom both PI and NRTI therapy was challenging.

Topics: Anti-HIV Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Nitriles; Pilot Projects; Prospective Studies; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)/ritonavir sparing regimens may be useful to some HIV-infected patients. Nevirapine (NVP) and raltegravir (RAL) are both potent antiretrovirals with good long-term safety profiles.. We retrospectively identified from our electronic database all patients with HIV RNA<50 copies/ml for >6 months on an NVP-containing regimen and no prior exposure to integrase strand transfer inhibitors who were switched to RAL plus NVP. Data was collected for 36 months or until discontinuation of RAL plus NVP for any reason.. A total of 39 patients (30 male) were included in this analysis. Median duration of prior antiretroviral therapy was 14 years (IQR 10-17) and median duration with plasma HIV-1 RNA<50 copies/ml prior to switch was 50 months (IQR 22-96). Switched regimens included mainly a boosted PI (n=24) or tenofovir disoproxil fumarate/emtricitabine (n=12). After switching, the percentages of patients with HIV-1 RNA<50 copies/ml were 87.2% (95% CI 76.7, 97.7) and 82.1% (95% CI 70.0, 94.1) at 6 and 12 months, respectively, in the intent-to-treat-exposed analysis, 97.1% (95% CI 91.6, 100) and 94.1% (95% CI 86.2, 100), respectively, in the per-protocol analysis. All patients with follow-up to month 24 (n=22) or month 36 (n=14) had HIV-1 RNA<50 copies/ml. One virological failure was observed (related to archived non-nucleoside reverse transcriptase inhibitor resistance mutation). During follow-up, no patient experienced Grade 3 or 4 adverse events. Median values of serum creatinine and lipids significantly improved after switch.. In patients with prolonged HIV-1 RNA<50 copies/ml, switching to NVP-RAL combination maintained virological suppression throughout 36 months. This combination deserves further evaluation in patients unable to tolerate NRTI or PI/ritonavir agents.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Combinations; Drug Substitution; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; Protease Inhibitors; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Treatment Outcome; Viral Load

The lack of antiretroviral (ARV) backbone activity associated with raltegravir has been proposed as the main explanation for virological relapse observed in patients with undetectable viraemia who are switched from a ritonavir-boosted protease inhibitor (PI) to raltegravir. However ARV activity remains difficult to assess in this context. The aim of our study was to precisely assess the ARV backbone activity in patients with undetectable viraemia who underwent raltegravir switching strategies and to evaluate the efficacy of such switching strategies based on the genotypic sensitivity score (GSS).. Patients with a plasma human immunodeficiency virus type 1 (HIV-1) RNA level of <50 copies/mL on a stable two ARV-class regimen were enrolled if they switched one of their ARV drugs to raltegravir 400 mg twice daily. The GSS was calculated using a genotyping test performed on the HIV-1 RNA of the last plasma measurement with a HIV-1 RNA level of >50 copies/mL before the switch and on the results of all previous genotyping tests. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24.. Fifty-six patients were enrolled in this study. The proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24 was 92.9 % (range 83.0-97.2 %) in the intent-to-treat analysis and 98.1 % (90.0-99.7 %) in per-protocol analysis. When the backbone was fully active, the proportion was 100.0 % (86.7-100.0 %) at week 24 and week 48 in the per-protocol analysis. We observed a decrease in plasma total cholesterol and triglycerides of -12.7 % (p = 0.005) and -26.5 % (p = 0.001), respectively.. Raltegravir switching strategies are effective when the associated backbone is fully active according to the GSS. In the context of undetectable viraemia, where ARV activity remains difficult to assess, the determination of the GSS requires the entire ARV history of the patient and all previous HIV-RNA genotyping test results.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; France; Genotype; HIV; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Viremia

Occupational transmission of HIV among healthcare personnel is rare but has repeatedly been published in the literature. Early initiation of postexposure HIV prophylaxis (HIV-PEP) is crucial to prevent virus transmission. For this reason the need for HIV-PEP has to be evaluated immediately and if necessary, started as soon as possible. This article presents an early intervention program in a university hospital which enables healthcare personnel immediate 24/7/365 access to a HIV-PEP prophylaxis kit following occupational HIV exposure.

Topics: Administration, Oral; Anti-HIV Agents; Deoxycytidine; Drug Administration Schedule; Drug Combinations; Early Medical Intervention; Emergency Treatment; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Germany; HIV Infections; Humans; Infectious Disease Transmission, Patient-to-Professional; Lopinavir; Needlestick Injuries; Organophosphorus Compounds; Post-Exposure Prophylaxis; Pyrrolidinones; Raltegravir Potassium; Ritonavir

Apart from the BENCHMRK study, there are no large observational experiences describing the long-term efficacy and safety of rescue regimens for human immunodeficiency virus type 1 (HIV-1) infection. Antiretroviral-experienced patients with detectable viraemia starting a raltegravir (RAL)-based regimen between March 2007 and June 2009 were consecutively enrolled and followed for ≥4 years. Data were censored at Week 206 for homogeneity. Of 333 patients, 258 (77.5%) were still on RAL-based therapy at Week 206, and 241 had undetectable HIV-1 RNA (73% in intention-to-treat analysis). Of the 75 subjects who discontinued RAL therapy, 36 were lost to follow-up, 15 changed their regimen due to virological failure, 2 simplified their regimen stopping RAL, 9 stopped all antiretrovirals and 13 died. Overall, 100 subjects (30.0%) had at least one detectable viraemia, but only 32 (9.6%) had true viral failure. Seventeen patients continued their failing regimen. 'Blips' were experienced by 53 patients (15.9%), whilst 15 (4.5%) had confirmed viral rebound due to adherence issues and were re-suppressed upon treatment re-introduction. In a multivariate analysis of predictors of interruption or failure, each baseline HIV-1 RNA log10 increase was associated with an adjusted hazard ratio for failure of 1.6; having more than 13 previous treatment courses also emerged as a predictor. Overall, adverse events were rare (n=64), with 13 deaths. Tumours were mainly early events, often fatal (7/15), mainly non-Hodgkin's lymphomas (8), followed by hepatocarcinoma (2). RAL proved effective and well tolerated in this cohort, and few patients experienced viral failure after 4 years.

Topics: Anti-HIV Agents; Female; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Salvage Therapy; Treatment Outcome; Viral Load

Combination Antiretroviral Therapy (cART) can suppress plasma HIV below the limit of detection in normal assays. Recently reported results suggest that viral replication may continue in some patients, despite undetectable levels in the blood. It has been suggested that the appearance of the circularized episomal HIV DNA artifact 2-LTR following treatment intensification with the integrase inhibitor raltegravir is a marker of ongoing viral replication. Other work has suggested that lymphoid organs may be a site of reduced antiviral penetration and increased viral production. In this study we model the hypothesis that this ongoing replication occurs in lymphoid follicle sanctuary sites and investigate the patterns of 2-LTR formation expected after raltegravir application. Experimental data is used to estimate the reaction and diffusion parameters in the model, and Monte-Carlo simulations are used to explore model behavior subject to variation in these rates. The results suggest that conditions for the formation of an observed transient peak in 2-LTR formation following raltegravir intensification include a sanctuary site diameter larger than 0.2mm, a viral basic reproductive ratio within the site larger than 1, and a total volume of active sanctuary sites above 20mL. Significant levels of uncontrolled replication can occur in the sanctuary sites without measurable changes in the plasma viral load. By contrast, subcritical replication (where the basic reproductive ratio of the virus is less than 1 in all sites) always results in monotonic increases of measured 2-LTR following raltegravir intensification, occurring at levels below the limit of detection.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Lymph Nodes; Models, Biological; Monte Carlo Method; Pyrrolidinones; Raltegravir Potassium; Viral Load; Viremia; Virus Replication

The latent HIV reservoir is a major impediment to curing HIV infection. The contribution of CD4(+) T cell activation status to the establishment and maintenance of the latent reservoir was investigated by enumerating viral DNA components in a cohort of 12 individuals commencing antiretroviral therapy (ART) containing raltegravir, an integrase inhibitor. Prior to ART, the levels of total HIV DNA were similar across HLA-DR(+) and HLA-DR(-) (HLA-DR(±)) CD38(±) memory CD4(+) T cell phenotypes; episomal two-long terminal repeat (2-LTR) HIV DNA levels were higher in resting (HLA-DR(-) CD38(-)) cells, and this phenotype exhibited a significantly higher ratio of 2-LTR to integrated HIV DNA (P = 0.002). After 1 year of ART, there were no significant differences across each of the memory phenotypes of any HIV DNA component. The decay dynamics of integrated HIV DNA were slow within each subset, and integrated HIV DNA in the resting HLA-DR(-) CD38(-) subset per mm(3) of peripheral blood exhibited no significant decay (half-life of 25 years). Episomal 2-LTR HIV DNA decayed relative to integrated HIV DNA in resting cells with a half-life of 134 days. Surprisingly, from week 12 on, the decay rates of both total and episomal HIV DNA were lower in activated CD38(+) cells. By weeks 24 and 52, HIV RNA levels in plasma were most significantly correlated with the numbers of resting cells containing integrated HIV DNA. On the other hand, total HIV DNA levels in all subsets were significantly correlated with the numbers of HLA-DR(+) CD38(-) cells containing integrated HIV DNA. These results provide insights into the interrelatedness of cell activation and reservoir maintenance, with implications for the design of therapeutic strategies targeting HIV persistence.. It is generally believed that HIV is not cleared by extensive antiretroviral therapy (ART) due to the difficulty in eradicating the latent reservoir in resting CD4(+) T cells. New therapies that attempt to activate this reservoir so that immune or viral cytopathic mechanisms can remove those infected cells are currently being investigated. However, results obtained in this research indicate that activation, at least on some level, already occurs within this reservoir. Furthermore, we are the first to describe the dynamics of different HIV DNA species in resting and activated memory CD4+ T cell subsets that point to the role different levels of activation play in maintaining the HIV reservoir.

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Cohort Studies; DNA, Viral; HIV Infections; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Virus Latency

Numerous studies have analyzed the effects of raltegravir intensification on HIV-1 viral replication in infected individuals receiving suppressive combined antiretroviral treatment (cART). Nevertheless, there are only two studies on the effect of raltegravir in HTLV-1 infection, and none in HTLV-2.. To study the effect of raltegravir on HTLV-2 infection in HIV-1-co-infected individuals.. This retrospective longitudinal study included four HTLV-2-HIV-1-co-infected individuals who received raltegravir-based cART during 48 weeks and 11 HTLV-2-HIV-1-co-infected individuals under cART without raltegravir during 48 weeks. HTLV-2 proviral load, CD4 and CD8 count and frequency were analyzed.. HTLV-2 proviral load significantly increased at week 24 compared to baseline among all the patients who received raltegravir (p=0.003), while no significant increases were found in the control group. No significant variation in either CD8 or CD4 counts was found during the follow up in both groups.. Raltegravir induced a transient increment on total HTLV-2 DNA proviral load in HTLV-2/HIV-1-coinfected individuals on suppressive cART after 24 weeks.

Topics: Anti-HIV Agents; Coinfection; Female; HIV Infections; HTLV-II Infections; Human T-lymphotropic virus 2; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Viral Load

Potential liver toxicity is an important consideration for antiretroviral selection among patients coinfected with HIV and viral hepatitis (B and/or C). We sought to describe the hepatic safety profile of raltegravir in this population.. Using data from HIV clinical cohorts at Johns Hopkins University and the University of North Carolina at Chapel Hill, we evaluated factors associated with liver enzyme elevations (LEEs) and calculated adverse event incidence rates for patients initiated on raltegravir-containing regimens prior to 1 January 2010. LEEs were graded according to Division of AIDS definitions.. During the study period, 456 patients received raltegravir - of whom 36% were hepatitis-coinfected (138 HCV, 17 HBV, 11 HBV+HCV). Coinfected patients were more likely to have baseline abnormal LEEs and developed severe (grade 3-4) LEEs at a rate 3.4× that of HIV-monoinfected patients (95% CI 1.28, 9.61). Among all participants, the incidence rate for first occurrence of severe LEEs was 5 per 100 person-years (95% CI 3, 7). In adjusted analyses, coinfected patients had a 2.7-fold increased hazard of severe LEEs (95% CI 1.03, 7.04). 60% of severe abnormalities occurred within 6 months after starting raltegravir; the drug was discontinued in 3 (1.3%) coinfected patients and 18 (6.2%) monoinfected patients.. Compared with HIV-monoinfected patients, those with HIV-hepatitis coinfection are at increased hazard of developing LEEs on raltegravir, at a level similar to other antiretrovirals. Severe events were uncommon, rarely leading to raltegravir discontinuation. With appropriate monitoring, raltegravir-based therapy is safe in hepatitis-coinfected patients.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Coinfection; Female; Hepatitis B; Hepatitis C; HIV Infections; Humans; Liver; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load; Young Adult

Topics: Cyclohexanes; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Treatment Failure; Triazoles; Viral Load

Topics: Adult; Anti-Retroviral Agents; HIV Infections; Humans; Male; Prurigo; Pyrrolidinones; Raltegravir Potassium

Multiple human proteins have been shown to both support and restrict viral replication, and confirmation of virus-associated changes in the expression of these genes is relevant for future therapeutic efforts. In this study a well-characterized panel of 49 individuals either infected with HIV-1 or uninfected was compiled and analyzed for the effect of HIV infection status, viral load, and antiretroviral treatment on specific gene expression. mRNA was extracted and reverse transcribed from purified CD4+ cells, and quantitative real-time PCR was utilized to scrutinize differences in the expression of four host genes that have been demonstrated to either stimulate (HSP90 and LEDGF/p75) or restrict (p21/WAF1 and APOBEC3G) proviral integration. HIV infection status was associated with slight to moderate alterations in the expression of all four genes. After adjusting for age, mRNA expression levels of HSP90, LEDGF/p75 and APOBEC3G were found to all be decreased in infected patients compared to healthy controls by 1.43-, 1.26-, and 4.71-fold, respectively, while p21/WAF1 expression was increased 2.35-fold. Furthermore, individuals receiving raltegravir exhibited a 1.28-fold reduction in LEDGF/p75 compared to those on non-raltegravir antiretroviral treatment. Identification of these and similar HIV-induced changes in gene expression may be valuable for delineating the extent of host cell molecular mechanisms stimulating viral replication.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; APOBEC-3G Deaminase; CD4-Positive T-Lymphocytes; Child; Cross-Sectional Studies; Cyclin-Dependent Kinase Inhibitor p21; Cytidine Deaminase; Female; Gene Expression; Gene Expression Regulation; HIV Infections; HIV-1; HSP90 Heat-Shock Proteins; Humans; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Messenger; Transcription Factors; Young Adult

We sought to determine the pharmacokinetic disposition of raltegravir in the blood and seminal plasma of HIV-infected men.. We conducted a pharmacokinetic study using a staggered sampling approach. A total of 16 HIV-infected men receiving raltegravir-based therapy were recruited into the study. Each participant provided six blood plasma and six seminal plasma samples for quantification of drug concentrations in both compartments. Blood and semen samples were obtained within 1 h of each other and were collected prior to the morning dose and at 1, 2, 4, 8 and 12 h post-ingestion. Drug concentrations were determined by liquid chromatography tandem mass spectrometry.. A total of 96 semen samples and 96 blood samples were obtained from all participants during the study period. The median age and baseline CD4(+) T-cell count of the study participants were 48 years (IQR 42-53) and 450 cells/mm(3) (IQR 289-585). Virological suppression to <50 copies/ml had been maintained for a median of 21 months (IQR 7-35) at the time of study enrolment. The median seminal plasma-to-blood plasma ratios and AUC0-12 h seminal plasma-to-blood plasma ratios of raltegravir were 3.25 (IQR 1.46-5.37) and 2.26 (IQR 1.05-4.45), respectively.. Concentrations of raltegravir in seminal plasma are several fold higher than those attained in blood plasma and those required to inhibit viral replication in this compartment. Further research examining the therapeutic and prophylactic implications of these findings is warranted.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Semen; Time Factors; Viral Load

Topics: Adolescent; Adult; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pregnancy Outcome; Raltegravir Potassium; Viral Load; Viremia; Young Adult

Previous studies demonstrate that soluble HIV proteins impact both hepatocyte function and HCV replication in vitro. It has also been reported that HIV can productively infect hepatocytes. We therefore investigated the impact of HIV infection of hepatocytes on HCV expression. The Huh7.5JFH1 cell line that constitutively expresses infectious HCV was infected with the lab-adapted strains HIVNL4-3 or HIVYK-JRCSF. HCV expression was quantified via HCV core antigen ELISA, Western blot, and strand-specific real-time PCR for positive-sense and negative-sense HCV RNA. After HIVNL4-3 infection of Huh7.5JFH1 cells, positive-sense and negative-sense HCV RNA levels were elevated compared to HIV uninfected cells. Increased HCV RNA synthesis was also observed after infection of Huh7.5JFH1 cells with HIVYK-JRCSF. HIV-induced HCV core production was decreased in the presence of the anti-HIV drugs AZT, T20, and raltegravir, although these medications had a minimal effect on HCV expression in the absence of HIV. HCV core, NS3, and NS5A protein expression were increased after HIV infection of Huh7.5JFH1 cells. Chemically inactivated HIV had a minimal effect on HCV expression in Huh7.5JFH1 cells suggesting that ongoing viral replication was critical. These data demonstrate that HIV induces HCV RNA synthesis and protein production in vitro and complement previous in vivo reports that HCV RNA levels are elevated in individuals with HIV/HCV co-infection compared to those with HCV mono-infection. These findings suggest that HIV suppression may be a critical factor in controlling liver disease, particularly if the underlying liver disease is not treated.

Topics: Cell Line; Enfuvirtide; Hepacivirus; Hepatocytes; HIV Envelope Protein gp41; HIV Infections; Humans; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Real-Time Polymerase Chain Reaction; Virus Replication; Zidovudine

HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P<0.0001) increased from baseline. Trunk/limb fat ratio (P = 0.0022), fat mass ratio (P = 0.0020), fat mass index (P = 0.0011) and percent leg fat normalized to BMI (P<0.0001) improved after 48 weeks. Relative abundance of mtDNA, expression of PPAR gamma, adiponectin, Cyt b, and MCP-1 genes increased, whereas Cox IV, TNF alpha, and CD68 did not change significantly from baseline. Switching from d4T to RAL in patients with HALS is associated with an increase in limb fat mass and an improvement in markers of adipocyte differentiation and mitochondrial function in SAT.

Topics: Adult; Anti-HIV Agents; Body Composition; DNA, Mitochondrial; Female; Gene Expression; HIV Infections; Humans; Lipodystrophy; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Stavudine; Subcutaneous Fat

Model studies of the subtype B and non-subtype B integrases are still required to compare their susceptibility to antiretroviral drugs, evaluate the significance of resistance mutations and identify the impact of natural polymorphisms on the level of enzymatic reactivity. We have therefore designed the consensus integrase of the HIV-1 subtype A strain circulating in the former Soviet Union territory (FSU-A) and two of its variants with mutations of resistance to the strand transfer inhibitor raltegravir. Their genes were synthesized, and expressed in E coli; corresponding His-tagged proteins were purified using the affinity chromatography. The enzymatic properties of the consensus integrases and their sensitivity to raltegravir were examined in a series of standard in vitro reactions and compared to the properties of the integrase of HIV-1 subtype B strain HXB2. The consensus enzyme demonstrated similar DNA-binding properties, but was significantly more active than HXB-2 integrase in the reactions of DNA cleavage and integration. All integrases were equally susceptible to inhibition by raltegravir and elvitegravir, indicating that the sporadic polymorphisms inherent to the HXB-2 enzyme have little effect on its susceptibility to drugs. Insensitivity of the mutated enzymes to the inhibitors of strand transfer occurred at a cost of a 30-90% loss of the efficacies of both 3'-processing and strand transfer. This is the first study to describe the enzymatic properties of the consensus integrase of HIV-1 clade A and the effects of the resistance mutations when the complex actions of sporadic sequence polymorphisms are excluded.

Topics: Anti-Retroviral Agents; DNA, Viral; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Models, Chemical; Models, Theoretical; Mutation; Pyrrolidinones; Raltegravir Potassium

HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages.. In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages.. Raltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART.

Topics: Animals; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Cell Line; Chromatography, High Pressure Liquid; Cytokines; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Enzyme-Linked Immunosorbent Assay; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Homeostasis; Humans; Inflammation; Interleukin-6; Kupffer Cells; Lipid Metabolism; Lipids; Macrophages; Male; Mice; Mice, Inbred C57BL; Raltegravir Potassium; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

To characterize the HIV-2 integrase gene polymorphisms and the pathways to resistance of HIV-2 patients failing a raltegravir-containing regimen, we studied 63 integrase strand transfer inhibitors (INSTI)-naïve patients, and 10 heavily pretreated patients exhibiting virological failure while receiving a salvage raltegravir-containing regimen. All patients were infected by HIV-2 group A. 61.4% of the integrase residues were conserved, including the catalytic motif residues. No INSTI-major resistance mutations were detected in the virus population from naïve patients, but two amino acids that are secondary resistance mutations to INSTIs in HIV-1 were observed. The 10 raltegravir-experienced patients exhibited resistance mutations via three main genetic pathways: N155H, Q148R, and eventually E92Q - T97A. The 155 pathway was preferentially used (7/10 patients). Other mutations associated to raltegravir resistance in HIV-1 were also observed in our HIV-2 population (V151I and D232N), along with several novel mutations previously unreported. Data retrieved from this study should help build a more robust HIV-2-specific algorithm for the genotypic interpretation of raltegravir resistance, and contribute to improve the clinical monitoring of HIV-2-infected patients.

Topics: Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; HIV-2; Humans; Polymorphism, Genetic; Pyrrolidinones; Raltegravir Potassium

The possibility of replacing raltegravir or elvitegravir with dolutegravir in heavily treatment-experienced patients failing on raltegravir/elvitegravir has been evaluated in VIKING trials. All studied patients failed by the most common pathways, Y143, Q148 and N155, and dolutegravir demonstrated efficacy except for Q148 viruses. The aim of this study was to explore, in the same way, the behaviour of dolutegravir in comparison with raltegravir and elvitegravir against the atypical resistance integrase profiles, G118R and F121Y, described in HIV-1 patients failing on raltegravir therapy.. The behaviour of integrases with mutations G118R and F121Y towards raltegravir, elvitegravir and dolutegravir was analysed by evaluating phenotypic susceptibility and by means of in silico techniques (investigating binding affinities and the stabilization of the inhibitors in terms of their hydrogen bond network).. The phenotypic analysis of G118R and F121Y showed high resistance to raltegravir, elvitegravir and dolutegravir with a fold change >100 when the clinically derived integrase was used, and resistance was also seen when mutations were tested alone in an NL43 backbone, but more often with a lower fold change. In silico, results showed that G118R and F121Y enzymes were associated with reduced binding affinities to each of the inhibitors and with a decreased number of hydrogen bonds compared with the wild-type complexes.. This study showed that G118R and F121Y mutations, rarely described in patients failing on raltegravir, induced broad cross-resistance to all currently used integrase inhibitors. These results are in accordance with our thermodynamic and geometric analysis indicating decreased stability compared with the wild-type complexes.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Protein Binding; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; Treatment Failure

Topics: Anti-HIV Agents; Female; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Tuberculosis

In sub-Saharan Africa, HIV-infected adults who fail second-line antiretroviral therapy (ART) often do not have access to third-line ART. We examined the clinical impact and cost-effectiveness of making third-line ART available in Côte d'Ivoire.. We used a simulation model to compare 4 strategies after second-line ART failure: continue second-line ART (C-ART2), continue second-line ART with an adherence reinforcement intervention (AR-ART2), immediate switch to third-line ART (IS-ART3), and continue second-line ART with adherence reinforcement, switching patients with persistent failure to third-line ART (AR-ART3). Third-line ART consisted of a boosted-darunavir plus raltegravir-based regimen. Primary outcomes were 10-year survival and lifetime incremental cost-effectiveness ratios (ICERs), in $/year of life saved (YLS). ICERs below $3585 (3 times the country per capita gross domestic product) were considered cost-effective.. Ten-year survival was 6.0% with C-ART2, 17.0% with AR-ART2, 35.4% with IS-ART3, and 37.2% with AR-ART3. AR-ART2 was cost-effective ($1100/YLS). AR-ART3 had an ICER of $3600/YLS and became cost-effective if the cost of third-line ART decreased by <1%. IS-ART3 was less effective and more costly than AR-ART3. Results were robust to wide variations in the efficacy of third-line ART and of the adherence reinforcement, as well as in the cost of second-line ART.. Access to third-line ART combined with an intense adherence reinforcement phase, used as a tool to distinguish between patients who can still benefit from their current second-line regimen and those who truly need third-line ART would provide substantial survival benefits. With minor decreases in drug costs, this strategy would be cost-effective.

Topics: Adult; Africa South of the Sahara; Antiretroviral Therapy, Highly Active; Cost-Benefit Analysis; Darunavir; Drug Costs; Female; Health Resources; HIV Infections; Humans; Male; Medication Adherence; Middle Aged; Models, Theoretical; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Survival Analysis; Treatment Failure

Raltegravir is a switch option for HIV/HCV co-infected individuals due to its hepatic neutral profile. We evaluated the effect of a switch to Raltegravir from other antiretroviral agents in HIV and HCV-co-infected individuals naïve to HCV therapy.. Observational, single-centre study. Data on alanine aminotransferase levels, HCV-VL, CD4 cell count, HIV viral load levels and hepatic fibrosis score were collated six months pre-switch, at the time of switch and six months post switch to Raltegravir therapy. Results were compared utilizing the Kruskal-Wallis test.. Twenty-seven individuals were identified. Median age was 43 years, median duration of HIV infection was 7 years and median documented period of HCV infection at the time of switch was 26 months. A sustained improvement in ALT levels was observed. Median ALT levels were 254 IU/L at the time of switch, decreasing significantly to 176 IU/L, (p = 0.0226) and 90 IU/L (p = 0.0138) 1 month post switch and 6 months post switch respectively. The median Hepatitis C viral load level at the time of the switch was 341,783 copies/mL, which decreased to 224,066 copies/mL 6 months after switch (p = 0.04).. A switch to Raltegravir in individuals with HIV/HCV co-infection was effective in maintaining HIV virological suppression with improvement in drug-associated hepatotoxicity as measured by ALT.

Topics: Adult; Aged; Alanine Transaminase; Antiviral Agents; CD4 Lymphocyte Count; Coinfection; Female; Hepacivirus; Hepatitis C; HIV; HIV Infections; Humans; Liver; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Viral Load

An 18-year-old postpartum woman with HIV, on lamivudine-zidovudine, lopinavir-ritonavir and raltegravir, presented with a 1-week history of rash and fevers. Initially admitted to obstetrics and gynaecology service for treatment of possible endometritis, she was transferred to the HIV medicine service for high fever, respiratory distress, hypotension and tachycardia. On admission, she was febrile (102°F) with findings of cervical and submandibular lymphadenopathy, diffuse morbilliform rash, generalised pruritus, facial oedema, and oedematous hands and feet. Consultations to various specialty services were initiated to rule out infectious, dermatological, rheumatological and drug-induced aetiologies. On the fourth day of hospitalisation, laboratory findings of significant eosinophilia and hepatitis (alanine aminotransferase 147 IU/L and aspartate aminotransferase 124 IU/L), in conjunction with the identification of the timing of medication use, led to a diagnosis of DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome secondary to raltegravir. After discontinuing raltegravir and starting prednisone, her DRESS symptoms completely resolved.

Topics: Adolescent; Anti-HIV Agents; Drug Combinations; Drug Hypersensitivity Syndrome; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Lamivudine; Lopinavir; Pleural Effusion; Postpartum Period; Pyrrolidinones; Radiography; Raltegravir Potassium; Respiratory Distress Syndrome; Ritonavir; Zidovudine

Adenosine triphosphate-binding cassette transporter G2 (ABCG2) is expressed on the cerebrospinal fluid (CSF) side of choroid plexus epithelial cells, which form the blood-CSF barrier. Raltegravir was recently identified as a substrate of ABCG2. In the present study, we analyzed the relationship between single-nucleotide polymorphisms of ABCB1 and ABCG2 genes and raltegravir concentrations in 31 plasma and 14 CSF samples of HIV-infected patients treated with raltegravir-containing regimens. The mean CSF raltegravir concentration was significantly lower in CA (25.5 ng/mL) and AA (<10 ng/mL) genotypes at position 421 in ABCG2 gene compared with CC (103.6 ng/mL) genotype holders (P = 0.016).

Topics: Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Gene Expression Regulation; Genetic Variation; Genotype; HIV Infections; Humans; Neoplasm Proteins; Pyrrolidinones; Raltegravir Potassium

Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) and integrase (IN) strand transfer inhibitors (INSTI) are key components of antiretroviral regimens. To explore potential interactions between NNRTI and INSTI resistance mutations, we investigated the combined effects of these mutations on drug susceptibility and fitness of human immunodeficiency virus type 1 (HIV-1). In the absence of drug, single-mutant viruses were less fit than the wild type; viruses carrying multiple mutations were less fit than single-mutant viruses. These findings were explained in part by the observation that mutant viruses carrying NNRTI plus INSTI resistance mutations had reduced amounts of virion-associated RT and/or IN protein. In the presence of efavirenz (EFV), a virus carrying RT-K103N together with IN-G140S and IN-Q148H (here termed IN-G140S/Q148H) mutations was fitter than a virus with a RT-K103N mutation alone. Similarly, in the presence of EFV, the RT-E138K plus IN-G140S/Q148H mutant virus was fitter than one with the RT-E138K mutation alone. No effect of INSTI resistance mutations on the fitness of RT-Y181C mutant viruses was observed. Conversely, RT-E138K and -Y181C mutations improved the fitness of the IN-G140S/Q148H mutant virus in the presence of raltegravir (RAL); the RT-K103N mutation had no effect. The NNRTI resistance mutations had no effect on RAL susceptibility. Likewise, the IN-G140S/Q148H mutations had no effect on EFV or RPV susceptibility. However, both the RT-K103N plus IN-G140S/Q148H and the RT-E138K plus IN-G140S/Q148H mutant viruses had significantly greater fold increases in 50% inhibitory concentration (IC50) of EFV than viruses carrying a single NNRTI mutation. Likewise, the RT-E138K plus IN-G140S/Q148H mutant virus had significantly greater fold increases in RAL IC50 than that of the IN-G140S/Q148H mutant virus. These results suggest that interactions between RT and IN mutations are important for NNRTI and INSTI resistance and viral fitness.. Nonnucleoside reverse transcriptase inhibitors and integrase inhibitors are used to treat infection with HIV-1. Mutations that confer resistance to these drugs reduce the ability of HIV-1 to reproduce (that is, they decrease viral fitness). It is known that reverse transcriptase and integrase interact and that some mutations can disrupt their interaction, which is necessary for proper functioning of these two enzymes. To determine whether resistance mutations in these enzymes interact, we investigated their effects on drug sensitivity and viral fitness. Although individual drug resistance mutations usually reduced viral fitness, certain combinations of mutations increased fitness. When present in certain combinations, some integrase inhibitor resistance mutations increased resistance to nonnucleoside reverse transcriptase inhibitors and vice versa. Because these drugs are sometimes used together in the treatment of HIV-1 infection, these interactions could make viruses more resistant to both drugs, further limiting their clinical benefit.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; HEK293 Cells; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Inhibitory Concentration 50; Mutation; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Virion; Virus Replication

The rapid early-phase decay of plasma HIV-1 RNA during integrase inhibitor-based therapy is not fully understood. The accumulation of biologically active episomal HIV-1 cDNAs, following aborted integration, could contribute to antiviral potency in vivo.. This prospective, controlled clinical observation study explored raltegravir's impact on the dynamics of HIV-1 RNA in plasma, and concentrations of total HIV-1 cDNA, episomal 2-long terminal repeat (LTR) circles and HIV-1 integrants in peripheral blood mononuclear cells (PBMC). Individuals starting therapy with two nucleoside reverse transcriptase inhibitors plus either raltegravir (raltegravir group; n = 10 patients) or boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitor (control group; n = 10 patients) were followed for 48 weeks.. Suppression of HIV-1 RNA (<50 copies/mL) was reached earlier (5/10 versus 0/10 at week 4; 8/10 versus 4/10 at week 12) on raltegravir. Significant total HIV-1 cDNA reductions in PBMC were reached by day 99 and persisted until day 330, with median factors of decrease of 7.2 and 8.9, respectively. Broad inter-individual variations, yet no treatment-associated differences, were noted for HIV-1 cDNA concentrations. Despite reductions in HIV-1 RNA (∼3 log) and total HIV-1 cDNA (∼1 log), concentrations of integrants and 2-LTR circles remained largely unchanged.. These results extend the previously reported early benefit of raltegravir on the decline of plasma viraemia to treatment-naive patients. The modest treatment-associated, yet group-independent, decline in total HIV-1 cDNA load and the lack of significant changes in integrated and episomal HIV-1 cDNA suggest that most integrated DNA is archival and targeting of HIV reservoirs other than PBMC may underlie beneficial effects of raltegravir.

Topics: Adult; Aged; Female; HIV Infections; HIV Integrase Inhibitors; HIV Long Terminal Repeat; HIV-1; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Pilot Projects; Proviruses; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load; Virus Integration; Young Adult

The end-stage LIVER disease and RALtegravir-Agence Nationale de Recherche sur le Sida et les hépatites (LIVERAL-ANRS) 148 study aimed to evaluate the safety, efficacy, and pharmacokinetic parameters of raltegravir (RAL) in human immunodeficiency virus (HIV)-infected patients with end-stage liver disease (ESLD) (substudy 1) and to assess the lack of pharmacokinetic interaction between RAL and the immunosuppressive regimen introduced after liver transplant (substudy 2).. All patients received 400 mg RAL twice daily plus 2 nucleoside reverse transcriptase inhibitors. Liver function and immunovirological parameters were monitored throughout the study. Serial blood samples were drawn to explore RAL pharmacokinetics. Plasma concentrations of protein unbound, total RAL, and RAL glucuronide were determined by liquid chromatography-tandem mass spectrometry.. Ten patients with ESLD were analyzed in substudy 1. Despite an increased RAL exposure, RAL was well tolerated in all patients and no patient had to stop RAL therapy because of adverse events. Four patients were analyzed in substudy 2. No pharmacokinetic interaction was observed between cyclosporine, mycophenolic acid, and RAL. RAL tolerability was excellent; there were no episodes of acute rejection or opportunistic infection. HIV-RNA levels remained controlled and CD4 cell counts remained stable in all patients throughout the study.. The results of the substudy 1 support RAL administration to patients with ESLD. Substudy 2 assesses the safety, tolerability, and efficacy of RAL therapy in HIV-infected patients after liver transplant. RAL might be recommended as a suitable antiretroviral therapy in HIV-infected patients undergoing liver transplant.

Topics: Adult; Anti-HIV Agents; Chromatography, Liquid; Drug-Related Side Effects and Adverse Reactions; End Stage Liver Disease; Female; HIV Infections; Humans; Male; Middle Aged; Plasma; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Tandem Mass Spectrometry; Treatment Outcome

Integrase inhibitors are a promising class of antiretroviral drugs to treat chronic human immunodeficiency virus (HIV) infection. During HIV infection, macrophages can extravasate from the blood to the brain, while producing chemotaxic proteins and cytokines, which have detrimental effects on central nervous system cells. The main goal of this study was to understand the effects of raltegravir (RAL) on human brain macrophage production of immune-mediators when infected with HIV, but did not compare with other antiretroviral agents.. Pro-inflammatory cytokines, IFN-γ, IL-10, IL-12-p70, IL-1, IL-8, TNF-α, and IL-6 were measured simultaneously in tissue culture supernatants from primary brain derived macrophages, microglia. We tested the effects of RAL on markers of astrocytosis and neurite integrity in primary human neuroglial cultures.. RAL administered at 20 nM effectively suppressed HIV infection in microglia over 9 days. Only IL-8, IL-10, and TNF-α were above the detection limit in the majority of samples and RAL significantly suppressed the rate of cytokine production in HIV-infected microglia. During RAL-alone, the rate of IL-8 secretion was higher.. RAL did not affect neurite area but inhibited astrocyte growth in the neuroglial cultures. Exploring the effects of RAL on pro-inflammatory molecule production in brain macrophages may contribute to designing ARV neuroprotective strategies in chronic HIV infection.

Topics: Brain; Cytokines; HIV Infections; Humans; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Macrophages; Microglia; Pyrrolidinones; Raltegravir Potassium; Tumor Necrosis Factor-alpha

Recent clinical data have suggested high raltegravir concentrations in gut tissue after oral administration, with implications for treatment and prevention. We have used in silico, in vitro, ex vivo and in vivo models to further investigate the accumulation of raltegravir in gut tissue.. Affinity of raltegravir for gut tissue was assessed in silico (Poulin-Theil method), in vitro (Caco-2 accumulation) and ex vivo (rat intestine) and compared with the lipophilic drug lopinavir. Finally, raltegravir concentrations in plasma, gut contents, small intestine and large intestine were determined after oral dosing to Wistar rats 1 and 4 h post-dose. Samples were analysed using LC-MS/MS and scintillation counting.. Gut tissue accumulation of raltegravir was less than for lopinavir in silico, in vitro and ex vivo (P < 0.05). After oral administration to rats, raltegravir concentrations 4 h post-dose were lower in plasma (0.05 μM) compared with small intestine (0.47 μM, P = 0.06) and large intestine (1.36 μM, P < 0.05). However, raltegravir concentrations in the contents of both small intestine (4.0 μM) and large intestine (40.6 μM) were also high.. In silico, in vitro and ex vivo data suggest low raltegravir accumulation in intestinal tissue. In contrast, in vivo animal data suggest raltegravir concentrates in intestinal tissue even when plasma concentrations are minimal. However, high raltegravir concentrations in gut contents are the likely driving factor behind this observation, rather than blood-to-tissue drug distribution. The methods described can be combined with clinical investigations to provide a complete strategy for selection of drugs with high gut accumulation.

Topics: Administration, Oral; Animals; Anti-HIV Agents; Chromatography, Liquid; HIV Infections; Intestines; Male; Pre-Exposure Prophylaxis; Pyrrolidinones; Raltegravir Potassium; Rats, Wistar; Tandem Mass Spectrometry

To decrease drug burden among HIV-1-positive adults, we need a new gold standard for antiretroviral therapy maintenance strategies.. This retrospective study aimed to assess efficacy in maintenance strategy of atazanavir (ATV) and raltegravir (RAL) dual therapy. The proportion of patients with HIV-1 RNA < 40 copies/ml at specific time points was recorded. Immunological response, safety, and pharmacokinetics were assessed.. Overall, 39 patients were switched to a RAL/ATV (n = 32) or RAL/ATV plus ritonavir (n = 7) regimen. Almost all patients (95%) received RAL twice daily. Most patients (70%) received a 400 mg ATV dosing per day, once (26%) or twice daily (44%). The percentages of virological success at weeks 24, 48, 96, and 144 were 92% (95% confidence interval (CI), 83-10), 86% (95% CI, 74-98), 70% (95% CI, 52-88), and 63% (95% CI, 42-84), respectively. Overall, 12 (31%) patients stopped dual therapy: 7 patients because of adverse events, mostly clinical myositis (n = 3). Confirmed virological failure occurred in three patients; two of them developed RAL resistance patterns. A significant increase in the CD4+/CD8 + T-cell ratio was observed at week 48 (p < 0.005). Only grade 1-2 adverse events were observed. Trough plasma levels presented a wide variability. Suggested trough concentrations were achieved in 79% and 94% of patients for ATV and RAL, respectively. An unboosted 400 mg per day ATV dosing seemed to be appropriate, regarding the targeted levels achieved and the lack of grade 3 or 4 hyperbilirubinemia.. We demonstrated, on a 3-year follow-up, the efficacy and safety of RAL plus ATV maintenance dual therapy.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Ritonavir; Treatment Outcome; Viral Load

Topics: Adult; Amlodipine; Anti-HIV Agents; Antihypertensive Agents; Chromatography, Liquid; Cross-Over Studies; Drug Interactions; Female; HIV Infections; Humans; Hypertension; Male; Middle Aged; Plasma; Pyrrolidinones; Raltegravir Potassium; Tandem Mass Spectrometry; Time Factors; Young Adult

Platelets are key cells in atherosclerosis and acute cardiovascular events. Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are found in HIV-infected patients and may contribute to the excess cardiovascular risk. The integrase inhibitor raltegravir (RAL) has been associated with better residual viral suppression and reduction in inflammatory and coagulation biomarkers. The aim of our study was to investigate whether RAL-treated patients have reduced platelet reactivity and PMA.. We performed a cross-sectional study involving 80 virologically suppressed adult HIV1-infected patients on a RAL-based (n = 25), nonnucleoside reverse transcriptase inhibitor (NNRTI)-based (n = 30) or a protease inhibitor based (n = 25) regimen and 30 healthy controls. Platelet reactivity was determined by measuring platelet P-selectin expression and the binding of fibrinogen to platelets to stimulation with two concentrations of ADP. PMA was determined by measuring the expression of the platelet marker CD42b on CD14 positive cells.. HIV-infected individuals had higher platelet reactivity and PMA than controls. RAL-treated individuals showed significantly lower P-selectin expression to stimulation with low (P = 0.026 vs. NNRTI and P = 0.005 vs. protease inhibitor group) and high-dose ADP (P = 0.009 vs. NNRTI and P = 0.003 vs. protease inhibitor group). A similar trend for was found for fibrinogen binding, although only the difference in P-selectin expression between RAL and protease inhibitor treated patients reached statistical significance (P = 0.038). PMA was also lower in the RAL group than in the NNRTI (P = 0.037) and protease inhibitor (P = 0.034) groups.. Use of a RAL-based regimen was associated with a reduction in persistent HIV-induced platelet hyperreactivity and PMA compared with NNRTI and protease inhibitor based regimen.

Topics: Blood Platelets; Coronary Artery Disease; Cross-Sectional Studies; HIV Infections; Humans; Monocytes; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Risk Factors; Treatment Outcome

A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy.

Topics: AIDS Dementia Complex; Anti-Retroviral Agents; Central Nervous System; Cognition Disorders; Darunavir; Disease Progression; Drug Resistance, Viral; Drug Substitution; HIV; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Time Factors; Viremia; Zidovudine

The first integrase inhibitor to be approved for children; antiretroviral effect similar to that observed in adults in treatment failure; no first-line evaluation.

Topics: Administration, Oral; Adolescent; Age Factors; Child; Child, Preschool; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Tablets; Treatment Outcome; Viral Load

To evaluate the frequency of myopathy and serum creatine kinase (CK) elevation associated with the use of the integrase inhibitor raltegravir we conducted a retrospective, cohort analysis assessing the incidence of skeletal muscle toxicity among HIV-infected patients treated with raltegravir. Adult HIV-infected patients who started a raltegravir-containing therapy were enrolled into the study. The skeletal muscle toxicity was defined by the presence of one or more of the following parameters: (1) isolated and significant CK elevation without signs or symptoms; (2) diffuse myalgia without weakness; (3) proximal muscle weakness; (4) rhabdomyolysis. On the whole, 155 patients were included in the study, with a mean age of 49.2 years; the median duration of the raltegravir treatment was 30.7 months. The overall frequency of skeletal muscle toxicity was 23.9%, with an incidence of 4.7/100 person-years. An isolated CK elevation was reported in 21.3% of cases, while less than 3% of patients complained of myalgia or muscle weakness. The CK elevation was usually of grade 1 or 2 and self-limiting, and laboratory or clinical abnormalities did not require discontinuation of raltegravir in any patient. Factors significantly associated with skeletal muscle toxicity were previous use of zidovudine, higher baseline CK levels, previous increase of the CK levels, and a higher body mass index. Skeletal muscle toxicity is not an unusual adverse event in subjects receiving raltegravir, but it is usually represented by a mild-to-moderate increase in CK concentration, while clinical symptoms of myopathy are very uncommon.

Topics: Anti-HIV Agents; Creatine Kinase; Female; HIV Infections; Humans; Male; Middle Aged; Muscle Weakness; Muscle, Skeletal; Myalgia; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Rhabdomyolysis

Raltegravir, as the first HIV integrase inhibitor, has been used and prospectively monitored since 2010 in our HIV outpatient centre, where over 1,200 patients are monitored. The aim of our report is to perform an interim assessment of the background, the safety profile and the clinical-laboratory monitoring of all patients treated with a combination antiretroviral therapy (cART) including raltegravir, for at least 12 months. In all, 109 pretreated patients started a raltegravir-containing cART when aged 44.8 plus or minus 19.2 years, with a history of HIV infection lasting 13.4 plus or minus 9.7 years. All subjects were monitored for at least 12 months (mean 17.2 plus or minus 10.3 months). In the vast majority of cases (93 of 109: 85.3%), multiple (3-16) prior cART changes prompted raltegravir introduction in advanced-salvage lines: 72 of 109 (66.1%) patients had even developed a concurrent triple-class resistance to anti-HIV compounds. The most frequent companion antiretroviral agents were: darunavir/ritonavir (75 cases), maraviroc (47 subjects), and etravirine (38 cases). The most common underlying conditions were: AIDS (46 patients), liver cirrhosis (31 cases), AIDS-related or other malignancies (23 cases), and major cardio-cerebro-vascular events (18 cases). A chronic HCV and HBV hepatitis were of concern in 48 and 23 patients, respectively. The adjunct of raltegravir favourably affected all clinical-laboratory markers of HIV disease progression, and those of the broad spectrum of comorbidities, except for two patients who failed the raltegravir-containing cART due to insufficient adherence. Despite the already compromised clinical situation, a minority of subjects experienced mild-transient clinical-laboratory untoward events possibly attributable to raltegravir, such that no patients discontinued raltegravir during the observation period. Only three AIDS-defining conditions became apparent during raltegravir-based cART; chemotherapy and/or radiotherapy cycles were performed as scheduled in patients suffering from cancer; chronic hepatitis B and C progressed to liver cirrhosis and/or hepatocarcinoma in only 2 and 6 patients. Otherwise, treatment with pegylated interferon-ribavirin became feasible in 25 patients of 48 with chronic HCV. During raltegravir-containing cART, neither autoimmune disorders nor novel malignancies were diagnosed. Only mild-transient gastrointestinal disorders, fatigue, dizziness, insomnia and cutaneous rash were reported, al

Topics: Adult; Aged; Ambulatory Care Facilities; Anti-Retroviral Agents; Female; HIV Infections; Humans; Italy; Male; Middle Aged; Prospective Studies; Raltegravir Potassium; Risk Factors; Treatment Outcome

To evaluate the efficiency and safety of using raltegravir (RAL) twice daily in conjunction with a once-daily fixed dose combination of abacavir (ABC)/lamivudine (3TC) in patients with HIV infection and active tuberculosis who have not previously received antiretroviral therapy (ART) and have taken rifabutin as antituberculosis therapy (ATT).. The efficiency of ART was evaluated in 28 patients from a change in HIV RNA levels and from an increase in CD4+ lymphocyte counts during 48-week treatment that had been completed by 15 (53.6%) patients. The main reason for therapy discontinuation was that the patients returned to the use psychoactive agents.. After 24 and 48 weeks of ART, the level of HIV RNA reached the undetectable values (less than 50 copies/ml) in 81.25 and 75% of the patients, respectively (according to an analysis including the patients who had completed the study in conformity with the requirements of the protocol). In only 2 patients, the virological therapy proved to be ineffective, which was likely to be associated with noncompliance with drug therapy. Following 24- and 48-week therapy, the increase in median CD4+ lymphocyte counts was 70 and 208.5 per μl, respectively. The concurrent use of ART and ATT caused positive changes in the lung skiagraphic pattern in 92.9% of the patients and complete resolution of lung tissue infiltration in 71.4%. Mixed infection ended in a fatal outcome caused by a progressive tuberculous process in 3 (10.7%) patients, in 2 of them within the first 8 weeks of treatment. The concomitant use of ATT including rifabutin and an ART (RAL + ABC/3TC) regimen was safe since one patient was noted to have a RAL-related adverse event (AE) (an allergic reaction) and caused the patient to discontinue therapy. ATT was not discontinued because of AE in any case.. The ART regimen containing RAL and a fixed dose combination of ABC/3TC for adult patients with tuberculosis concurrent with HIV infection who are on combined therapy using rifabutin for tuberculosis may be recommended for the treatment of this category of patients.

Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rifabutin; RNA, Viral; Time Factors; Treatment Outcome; Tuberculosis; Young Adult

An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the quantification of raltegravir (RTG) plasma concentrations in samples from HIV patients treated with the drug.. Plasma samples were extracted by liquid-liquid extraction followed by evaporation to dryness and reconstitution in mobile phase. The chromatographic separation was carried out on an AQUITY UPLC C18 column with an isocratic mobile phase consisting of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid (50:50 vol/vol). The detection was performed on a triple quadrupole tandem mass spectrometer using multi-reaction monitoring via electrospray ionization source with positive ionization mode.. Under these conditions, a single chromatographic run could be completed within 1 minute. The method was validated by estimating the precision and the accuracy for inter- and intra-day analysis in the concentration range of 5-2560 ng/mL. The method was linear over the investigated range with all the correlation coefficients, r, greater than 0.995 on 5 replicates. The intra- and inter-day precision (percentage of coefficient of variation) ranged from 2.4% to 11.2%, and the inaccuracy (percent of relative standard deviation) ranged from 2.5% to 12.9%. No significant matrix effect was observed. The mean recovery value of RTG was 80%.. This rapid and sensitive method was validated and could be applied to pharmacokinetic studies for the determination of RTG concentrations in human plasma samples.

Topics: HIV Infections; Humans; Liquid-Liquid Extraction; Pyrrolidinones; Raltegravir Potassium; Tandem Mass Spectrometry

We describe a case of acute HIV infection in the third trimester of pregnancy associated with an extremely high viral load and the use of raltegravir to prevent HIV mother-to-child transmission.

Topics: Adult; Female; HIV Infections; HIV Seropositivity; Humans; Infectious Disease Transmission, Vertical; Integrase Inhibitors; Mothers; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pregnancy Trimester, Third; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

There is an urgent need to improve the evidence base for provision of second-line antiretroviral therapy (ART) following first-line virological failure. This is particularly the case in Sub-Saharan Africa where 70% of all people living with HIV/AIDS (PHA) reside. The aim of this study was to simulate the potential risks and benefits of treatment simplification in second-line therapy compared to the current standard of care (SOC) in a lower-middle income and an upper-middle income country in Sub-Saharan Africa.. We developed a microsimulation model to compare outcomes associated with reducing treatment discontinuations between current SOC for second-line therapy in South Africa and Nigeria and an alternative regimen: ritonavir-boosted lopinavir (LPV/r) combined with raltegravir (RAL). We used published studies and collaborating sites to estimate efficacy, adverse effect and cost. Model outcomes were reported as incremental cost effectiveness ratios (ICERs) in 2011 USD per quality adjusted life year ($/QALY) gained.. Reducing treatment discontinuations with LPV/r+RAL resulted in an additional 0.4 discounted QALYs and increased the undiscounted life expectancy by 0.8 years per person compared to the current SOC. The average incremental cost was $6,525 per treated patient in Nigeria and $4,409 per treated patient in South Africa. The cost-effectiveness ratios were $16,302/QALY gained and $11,085/QALY gained for Nigeria and South Africa, respectively. Our results were sensitive to the probability of ART discontinuation and the unit cost for RAL.. The combination of raltegravir and ritonavir-boosted lopinavir was projected to be cost-effective in South Africa. However, at its current price, it is unlikely to be cost-effective in Nigeria.

Topics: Antiretroviral Therapy, Highly Active; Cost-Benefit Analysis; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Models, Biological; Models, Economic; Nigeria; Pyrrolidinones; Quality-Adjusted Life Years; Raltegravir Potassium; Ritonavir; South Africa

This study aimed to identify factors associated with virological response (VR) to raltegravir (RAL)-containing regimens in 468 treatment-experienced but integrase inhibitor-naive HIV-1 patients receiving a RAL-containing regimen. VR was defined at Month 6 (M6) as HIV-1 RNA viral load (VL) <50 copies/mL. The impacts on VR of baseline integrase mutations, VL, CD4 count, genotypic sensitivity score for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors, and the number of new antiretrovirals used for the first time associated with RAL were investigated. For patients with VL >50 copies/mL at M6, integrase mutations selected were characterised. Median baseline VL was 4.2 log(10)copies/mL (IQR 3.3-4.9 log(10) copies/mL) and CD4 count was 219 cells/mm(3) (IQR 96-368 cells/mm(3)). At M6, 71% of patients were responders. In multivariate analysis, baseline VL and CD4 count and ≥ 2 new antiretrovirals among darunavir, etravirine, maraviroc and enfuvirtide were associated with VR to RAL. Neither HIV-1 subtype nor baseline integrase polymorphisms were associated with VR to RAL. Among 63 failing patients at M6, selection of ≥ 1 change in the integrase gene was observed in 49 (77.8%), and 27/63 (42.9%) were considered as RAL-associated resistance mutations. Factors independently associated with the occurrence of ≥ 1 RAL-associated resistance mutation were VL at failure >3 log(10) and having no new drugs associated with RAL. RAL showed great potency in treatment-experienced patients. The number of new drugs associated with RAL was an important factor associated with VR. HIV-1 subtype and baseline integrase polymorphisms do not influence the RAL VR.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Failure; Viral Load

One of the goals of antiretroviral therapy (ART) is to attenuate HIV-induced systemic immune activation and inflammation. We determined the dynamics of biomarkers of immune activation, microbial translocation and inflammation during initial ART with a nucleos(t)ide-sparing regimen of darunavir/ritonavir plus raltegravir. We also evaluated associations between these biomarkers and the virological response to the regimen.. We determined baseline and week 24 and 48 levels of CD4+ and CD8+ T cell activation (% HLA-DR+/CD38+), interleukin-6 (IL-6), interferon-γ-inducible protein-10 (IP-10), soluble CD14 (sCD14), D-dimer and lipopolysaccharide. Associations between the biomarkers at baseline were assessed using Spearman's rank correlation. The Wilcoxon signed rank test analysed changes from baseline. Comparisons between groups were made using the Wilcoxon rank sum test, and Cox proportional hazards models assessed predictors of virological failure (VF).. Assays were completed on 107 of 112 subjects after excluding five subjects who had only baseline samples. The subjects included were 94 (88%) men with a median age of 37 years, a median baseline CD4 count of 261.5 cells/mm(3) and a median baseline viral load (VL) of 75 876 copies/mL. Subjects with a baseline VL >100 000 copies/mL had higher baseline T cell activation, IL-6, IP-10, sCD14 and D-dimer. These biomarkers declined during treatment (P < 0.05). Although subjects who experienced VF had higher baseline CD4+ T cell activation (P = 0.035), only baseline VL independently predicted VF (hazard ratio for >100 000 versus ≤100 000 copies/mL was 4.5-5.6, P ≤ 0.002).. Darunavir/ritonavir plus raltegravir attenuated immune activation, inflammation and microbial translocation. T cell activation remained higher in subjects with VF than those without. Baseline VL >100 000 copies/mL remained the primary driver of VF.

Topics: Adult; Anti-HIV Agents; Biomarkers; Darunavir; Female; HIV Infections; Humans; Immunophenotyping; Lymphocyte Activation; Male; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; T-Lymphocytes; Viral Load

Topics: Administration, Oral; Anti-HIV Agents; Antitubercular Agents; Coinfection; Drug Interactions; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium; Rifampin; Tuberculosis

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium

The risk of HIV-1 mother-to-child transmission (MTCT) is clearly correlated with the maternal HIV cell-free viral load (VL) at delivery. Preventing MTCT in late-presenting (after 28 weeks) HIV-infected pregnant women remains a clinical challenge, and ensuring a rapid decrease of maternal VL is an important preventive strategy. Raltegravir (RGV) has a higher first and second phase viral decay rate, has a high placental transfer, with a potential preloading effect for neonate, and demonstrates effective accumulation in cervicovaginal secretions. We report 14 cases in which RGV was used late in pregnancy for HIV-1 MTCT prophylaxis. All women were RGV naive and the prophylaxis regimens included RGV plus at least two other antiretroviral agents. At RGV initiation, the median gestational age was 36 weeks (range 34-38) and the median maternal plasma HIV-1 RNA viral load was 35,364 copies/ml (range 636-391,535). At delivery, the median gestational age was 38 weeks (range 37-40). The median exposure time to RGV was 17 days (range 7-32), with a mean maternal VL decay of 2.6 log. At delivery, seven women had undetectable (<50 copies/ml) VL, four had between 64 and 457 copies/ml, and in three VL was not available. All but one infant's HIV-RNA tests were negative at 1 and 3 months (one case of in utero MTCT). Raltegravir-containing antiretroviral regimens induced a rapid HIV-RNA decline in maternal VL at delivery, and were safe and effective in preventing MTCT for late-presenting, HIV-infected women.

Topics: Adolescent; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; RNA, Viral; Treatment Outcome; Viral Load; Young Adult

Y143C,R substitutions in HIV-1 integrase define one of three primary raltegravir (RAL) resistance pathways. Here we describe clinical isolates with alternative substitutions at position 143 (Y143A, Y143G, Y143H, and Y143S [Y143A,G,H,S]) that emerge less frequently, and we compare the genotypic and phenotypic profiles of these viruses to Y143C,R viruses to reconcile the preferential selection of Y143C,R variants during RAL treatment. Integrase amino acid sequences and RAL susceptibility were characterized in 117 patient isolates submitted for drug resistance testing and contained Y143 amino acid changes. The influence of specific Y143 substitutions on RAL susceptibility and their preferential association with particular secondary substitutions were further defined by evaluating the composition of patient virus populations along with a large panel of site-directed mutants. Our observations demonstrate that the RAL resistance profiles of Y143A,G,H,S viruses and their association with specific secondary substitutions are similar to the well-established Y143C profile but distinct from the Y143R profile. Y143R viruses differ from Y143A,C,G,H,S viruses in that Y143R confers a greater reduction in RAL susceptibility as a single substitution, consistent with a lower resistance barrier. Among Y143A,C,G,H,S viruses, the higher prevalence of Y143C viruses is the result of a lower genetic barrier than that of the Y143A,G,S viruses and a lower resistance barrier than that of the Y143H viruses. In addition, Y143A,C,G,H,S viruses require multiple secondary substitutions to develop large reductions in RAL susceptibility. Patient-derived viruses containing Y143 substitutions exhibit cross-resistance to elvitegravir.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Genes, Reporter; HEK293 Cells; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Luciferases; Mutagenesis, Site-Directed; Pyrrolidinones; Quinolones; Raltegravir Potassium; Tyrosine

Liver enzyme elevations (LEE) were investigated in 2717 episodes of initiation of antiretroviral therapy since January 2010 in 1982 HIV patients. Serum hepatitis C virus (HCV)-RNA was positive in 24%. Any grade of LEE was recognized in 9% of episodes, being 6% in HCV-negative and 17% in HCV-positive patients (P < 0.001). Grades 3-4 LEE only occurred in 0.4% of patients. Overall, LEE were more frequent with ritonavir-boosted darunavir and atazanavir than with raltegravir and etravirine.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Coinfection; Cyclopropanes; Darunavir; Female; Follow-Up Studies; Hepatitis C; HIV Infections; Humans; Liver; Male; Nevirapine; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, ultimately the consequence of cytolytic infection of CD4(+) T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia, yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4(+) T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4(+) T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals.

Topics: Carrier State; CD4-Positive T-Lymphocytes; Cell Death; Cell Line; Cell Survival; Cells, Cultured; DNA Damage; DNA Repair; DNA-Activated Protein Kinase; Enzyme Activation; Histones; HIV Infections; HIV Integrase Inhibitors; HIV-1; Human Immunodeficiency Virus Proteins; Humans; Phosphorylation; Proviruses; Pyrrolidinones; Raltegravir Potassium; Tumor Suppressor Protein p53; Virus Integration; Virus Replication

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Lopinavir; Male; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir

Vertical transmission of human immunodeficiency virus (HIV) represents an important worldwide health problem and rapid decline in viral load is essential for HIV pregnant women to prevent mother to child transmission. Specific issues such as late presentation of pregnant HIV-infected women remain a clinical challenge. We present a case of an HIV-infected woman who presented to our hospital at 35 weeks of pregnancy, who was successfully treated with raltegravir-based first-line combined antiretroviral regimen. Even though there is limited information about safety and tolerability of the use of raltegravir in pregnancy, in our case this drug resulted in a rapid decline in HIV-RNA viral load, without side effects. The aim of the present study and literature review was to demonstrate that raltegravir can be a good treatment choice for very late presenting pregnant women.

Topics: Adult; Antiretroviral Therapy, Highly Active; Delayed Diagnosis; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Pyrrolidinones; Raltegravir Potassium; Viral Load

The cross-resistance profiles of elvitegravir and dolutegravir on raltegravir-resistant variants is still controversial or not available in macrophages and lack extensive evaluations on wide panels of clonal variants. Thus, a complete evaluation in parallel with all currently available integrase inhibitors (INIs) was performed.. The integrase coding region was RT-PCR-amplified from patient-derived plasma samples and cloned into an HIV-1 molecular clone lacking the integrase region. Twenty recombinant viruses bearing mutations to all primary pathways of resistance to raltegravir were phenotypically evaluated with each integrase inhibitor in freshly purified CD4+ T cells or monocyte-derived macrophages.. Y143R single mutants conferred a higher level of raltegravir resistance in macrophages [fold change (FC) 47.7-60.24] compared with CD4+ T cells (FC 9.55-11.56). All other combinations had similar effects on viral susceptibility to raltegravir in both cell types. Elvitegravir displayed a similar behaviour both in lymphocytes and macrophages with all the tested patterns. When compared with raltegravir, none to modest increases in resistance were observed for the Y143R/C pathways. Dolutegravir maintained its activity and cross-resistance profile in macrophages. Only Q148H/R variants had a reduced level of susceptibility (FC 5.48-18.64). No variations were observed for the Y143R/C (+/-T97A) or N155H variants.. All INIs showed comparable antiretroviral activity in both cell types even if single mutations were associated with a different level of susceptibility in vitro to raltegravir and elvitegravir in macrophages. In particular, dolutegravir was capable of inhibiting with similar potency infection of raltegravir-resistant variants with Y143 or N155 pathways in both HIV-1 major cell reservoirs.

Topics: Anti-HIV Agents; Cells, Cultured; Cloning, Molecular; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV-1; Humans; Lymphocytes; Macrophages; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; Recombination, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Sequence Analysis, DNA

Although 2-long terminal repeat (2-LTR) circles are only a fraction of the total viral DNA in infected cells, sequence analysis of 2-LTR circles reveals critical information regarding viral DNA synthesis and the nature of actively replicating virus. It was observed that a large proportion of the 2-LTR circular molecules in the peripheral blood mononuclear cell (PBMC) DNA of infected individuals are mutated at the circle junction. The integrase inhibitor raltegravir (RAL) blocks the strand transfer step of the integration of HIV-1; as a consequence of abortive integration a significant increase of episomal 2-LTR circles is observed. Moreover, it was demonstrated that in patients treated with highly active retroviral therapy (HAART) changes in 2-LTR concentration did not affect junction sequences and flanking regions of 2-LTR. Here we evaluated whether RAL therapy could have a differential impact on the 2-LTR circle junctional sequences in patients with different virological profiles at the time of starting RAL therapy. Sequence analysis indicates that RAL acts differently in the two populations.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Male; Middle Aged; Molecular Sequence Data; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA

Topics: Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium

Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in the absence of antiretroviral therapy (ART). However, precise frequencies of CD4(+) T cells carrying replication-competent HIV and/or the dynamics of the infectious viral reservoirs in response to initiation and discontinuation of ART in elite controllers are unknown. We show that the size of the pool of CD4(+) T cells harboring infectious HIV diminished significantly after initiation of ART and rebounded to baseline upon cessation of therapy. Our data provide compelling evidence that persistent viral replication occurs in untreated elite controllers even in the absence of detectable plasma viremia.

Topics: Adenine; Anti-HIV Agents; Asymptomatic Diseases; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Deoxycytidine; DNA, Viral; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Immunity, Innate; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Viremia; Virus Replication

Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients.. This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits.. Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL [95% confidence interval (CI): 58,970-86,480], Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients.. Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.

Topics: Adult; Aged; Anti-HIV Agents; Area Under Curve; Darunavir; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

The efficacy and safety of raltegravir (RAL) with tenofovir (TDF)/emtricitabine (FTC) have been well studied in human immunodeficiency virus (HIV)-infected patients. However, limited clinical data are available on the use of RAL with abacavir (ABC)/lamivudine (3TC) or zidovudine (ZDV)/3TC. We investigated HIV-1-infected Korean adults, including 13 antiretroviral-naïve patients and 15 antiretroviral-experienced patients, treated with RAL plus ABC/3TC or ZDV/3TC. Virological suppression was achieved in 12 of the 13 (92%) antiretroviral-naïve patients within 24 weeks and in all (100%) patients within 96 weeks. In 13 of the 15 treatment-experienced patients, ritonavir-boosted lopinavir (LPV/r) was replaced with RAL because of hyperlipidemia (n = 11) and diarrhea (n = 2). A significant decrease in median total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels was observed in these patients (P < 0.01, each). No adverse event related to RAL was observed in any of the 28 patients. The RAL plus ABC/3TC or ZDV/3TC regimens were effective and safe in antiretroviral-naïve Korean HIV-infected patients, and replacing LPV/r with RAL significantly improved lipid abnormalities in patients previously treated with regimens including LPV/r.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lipids; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Republic of Korea; Retrospective Studies; Treatment Outcome; Viral Load; Young Adult; Zidovudine

The Abbott RealTime (ART) HIV-1 assay targets the integrase region and is designed to tolerate mismatches. Variability in integrase sequences comprising the assay target regions from >1000 clinical specimens submitted for phenotypic and genotypic raltegravir resistance testing were analyzed. In this large collection of sequences from clinical specimens, the number and location of raltegravir resistance associated mutations did not differ from those tested previously and shown not to result in under-estimation of viral loads.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Genetic Variation; HIV Infections; HIV Integrase; HIV-1; Mutation; Pyrrolidinones; Raltegravir Potassium; Viral Load

In treatment-naive, human immunodeficiency virus (HIV)-infected persons, combination antiretroviral therapy (cART) incorporating raltegravir (RAL) is highly effective for virologic suppression, but characteristics of immunologic recovery have not been described.. We performed a 48-week substudy of 15 patients, median age 40 years, within a phase 2 randomized trial of RAL-cART in treatment-naive patients with chronic HIV infection.. Plasma viral load decreased from 5.2 ± 5.3 log10 HIV RNA copies/mL to 2.2 ± 2.4 log10 copies/mL at week 4, reaching <50 copies/mL at week 8 in 13 of 15 patients. Total CD4 T cells increased at week 4, as did central memory CD4 T cells in association with reduction of the immune activation markers HLA-DR and CD38 and immune exhaustion marker PD1 in CD4 and CD8 T cells. Naive CD4 T cells increased at week 24 with appearance of HIV gag-specific interleukin 2, interferon-γ, and CD107a responses in CD4 and CD8 T cells at week 48. Plasma lipopolysaccharide and soluble CD14 decreased, but at week 48 were elevated as compared to healthy volunteers. Altogether, the week 48 immune profile was more favorable in patients taking RAL-cART than in patients treated with non-RAL-cART.. RAL in first-line treatment regimens results in rapid immune reconstitution with residual low-level microbial translocation.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Immunophenotyping; Middle Aged; Pyrrolidinones; Raltegravir Potassium; T-Lymphocytes, Regulatory; Time Factors; Treatment Outcome; Viral Load; Young Adult

In this study, we assessed phenotypic susceptibility to dolutegravir and raltegravir in a large variety of HIV-1 'non-B' subtypes (n = 72) issued from integrase inhibitor-naive clinical isolates. All samples were susceptible to both dolutegravir and raltegravir with median IC50 values of 1.22 nmol/l and 1.53 nmol/l, respectively; similar to that observed for the B subtype. Thus, despite the high prevalence of polymorphic substitutions in integrase in 'non-B' clinical isolates, phenotypic susceptibility to dolutegravir remained unchanged.

Topics: Anti-HIV Agents; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV-1; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Mutation, Missense; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium

To investigate the concentration of the integrase strand inhibitor raltegravir (RAL) throughout gastrointestinal (GI) tissue, especially gut-associated lymphoid tissue (GALT), as an adjunct to current prevention and cure strategies.. Open-label pharmacokinetic (PK) study.. HIV-negative men received RAL 400 mg twice daily for 7 days. Seven blood plasma specimens were collected over 12-h intervals; timed tissue specimens from terminal ileum, splenic flexure, and rectum were also obtained by colonoscopy following the first dose and on day 7 [multiple dose (MD)]. RAL concentrations were measured by validated LC-MS assay with 1 ng/ml lower limit of detection. Data were analyzed by noncompartmental methods (WinNonlin 6). Tissue exposures are reported as composite medians and tissue density of 1.04 g/ml is assumed for comparisons.. Fourteen men completed evaluations. Median (range) age was 24 (19-49) years and BMI 25 (19-31) kg/m². After the first dose, area under the time-concentration curve (AUC)(0-12h) was highest in the terminal ileum (594 μg*h/ml). Exposures were 160, 68 and 39-fold greater than blood plasma at the terminal ileum, splenic flexure and rectum, respectively. After multiple doses, exposure was highest at the splenic flexure (2240 μg*h/ml); exposure at the terminal ileum and rectum were equivalent (both 788 μg*h/ml). Following multiple doses, exposures were 160 to 650-fold greater than blood plasma throughout the colon.. RAL rapidly disseminates into GI tissue and concentrations remain significantly higher than blood plasma. RAL exposure in GI tissue remains higher than any antiretroviral investigated to date. These data suggest that RAL should result in full suppression of viral replication in GI tissue and GALT.

Topics: Adult; Area Under Curve; Dose-Response Relationship, Drug; Gastrointestinal Tract; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Lymphocytes; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Viral Load; Young Adult

Integration of the DNA copy of the HIV-1 genome into a host chromosome is required for viral replication and is thus an important target for antiviral therapy. The HIV-encoded enzyme integrase (IN) catalyzes two essential steps: 3' processing of the viral DNA ends, followed by the strand transfer reaction, which inserts the viral DNA into host DNA. Raltegravir binds to IN and blocks the integration of the viral DNA. Using the Rous sarcoma virus-derived vector RCAS, we previously showed that mutations that cause one viral DNA end to be defective for IN-mediated integration led to abnormal integrations in which the provirus had one normal and one aberrant end, accompanied by rearrangements in the host genome. On the basis of these results, we expected that suboptimal concentrations of IN inhibitors, which could block one of the ends of viral integration, would lead to similar aberrant integrations. In contrast to the proviruses from untreated cells, which were all normal, ∼10-15% of the proviruses isolated after treatment with a suboptimal dose of raltegravir were aberrant. The aberrant integrations were similar to those seen in the RCAS experiments. Most of the aberrant proviruses had one normal end and one aberrant end and were accompanied by significant rearrangements in the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes. The rearrangements of the host DNA raise concerns that these aberrant integrations might have unintended consequences in HIV-1-infected patients who are not consistent in following a raltegravir-containing treatment regimen.

Topics: Cell Line, Tumor; DNA, Viral; Dose-Response Relationship, Drug; Enzyme Inhibitors; HEK293 Cells; HIV Infections; HIV Integrase; HIV-1; Humans; Models, Genetic; Models, Molecular; Molecular Structure; Nucleic Acid Conformation; Protein Binding; Proviruses; Pyrrolidinones; Raltegravir Potassium; Virus Integration; Virus Replication

Topics: Adolescent; Adult; Alkynes; Benzoxazines; Child; Cyclopropanes; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Long-Term Care; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Viral Load; Virus Replication

This case report describes two severe antiretroviral drug adverse reactions that occurred in the same patient. A 55-year-old HIV-positive African woman received a single epidural triamcinolone injection for pain relief of postherpetic neuralgia. Forty-one days later, she developed severe iatrogenic Cushing's syndrome due to the drug-drug interaction between triamcinolone and her boosted protease inhibitor therapy. The patient's antiretroviral regimen was thus changed to replace her protease inhibitor with the integrase inhibitor raltegravir. Shortly after commencing the drug, the patient developed a severe adverse drug reaction manifesting as Drug Reaction (or Rash) with Eosinophilia and Systemic Symptoms (DRESS) syndrome. First described in 1996, this hypersensitivity syndrome presents with severe skin reaction as well as fever, rash, lymphadenopathy and internal organ involvement with marked eosinophilia. Clinicians should be aware of raltegravir-induced DRESS syndrome as well as the potential for drug-drug interactions due to protease inhibitor-based therapy.

Topics: Anti-HIV Agents; Anti-Inflammatory Agents; Antiretroviral Therapy, Highly Active; Drug Hypersensitivity Syndrome; Drug Interactions; Eosinophilia; Exanthema; Female; Fever; HIV Infections; HIV Integrase Inhibitors; Humans; Neuralgia, Postherpetic; Patient Safety; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Triamcinolone

Mother-to-child transmission (MTCT) of HIV infection is now uncommon in the UK and the management of HIV-positive pregnant women is usually relatively straightforward. However, HIV viral load suppression may be difficult to achieve peripartum for women who book very late in pregnancy and those with a poor adherence to antiretroviral therapy (ART). These pregnancies are at a higher risk of MTCT due to high viral load (VL). Therefore, the development of interventions to achieve a rapid reduction of HIV VL is essential. We describe three relevant cases that presented to our unit over a 12-month period and discuss the strategies employed to manage these challenging cases. All babies were born healthy and were HIV proviral DNA-negative at 12 weeks postpartum. No serious adverse events were reported for the mothers or their babies.

Topics: Adult; Anti-Retroviral Agents; Directly Observed Therapy; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Hospitalization; Humans; Infectious Disease Transmission, Vertical; Peptide Fragments; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Topics: Female; Fibrin Fibrinogen Degradation Products; HIV Infections; HIV Integrase Inhibitors; HIV Long Terminal Repeat; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium

We describe the pharmacokinetics of raltegravir of a preterm newborn after short-course treatment of the mother tested HIV + the day of delivery. At age 1 month, the circulating concentration of raltegravir in the newborn was 29 ng/ml (the IC95 of RAL against HIV-1 is 15 ng/ml). Raltegravir should therefore be considered a potential transplacental postexposure prophylaxis for HIV-1 and an alternative to the use of boosted lopinavir in this context.

Topics: Female; HIV Infections; Humans; Infant, Newborn; Maternal-Fetal Exchange; Mothers; Placenta; Pregnancy; Pyrrolidinones; Raltegravir Potassium

There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, thus undermining efficacy of treatment. The goal of this study was to characterize viral resistance emergence and address viral population evolution during the first phase of viral decay after treatment containing initiation.. 454 sequencing was used to characterize viral genetic diversity and polymorphism composition of the HIV-1 integrase gene during the first two weeks following initiation of raltegravir-containing HAART in four ART-experienced subjects. No low-prevalence Raltegravir (RAL) drug resistance mutations (DRM) were found at baseline. All patients undergoing treatment received a fully active ART according to GSS values (GSS ≥ 3.5). No emergence of DRM after treatment initiation was detected. Longitudinal analysis showed no evidence of any other polymorphic mutation emergence or variation in viral diversity indexes.. This suggests that fully active salvage antiretroviral therapy including raltegravir achieves a complete blockade of HIV-1 replication in plasma. It is unlikely that raltegravir-resistant HIV-1 may be selected in plasma during the early HIV-1 RNA decay after treatment initiation if the administered therapy is active enough.

Topics: Adult; Anti-HIV Agents; Female; Genetic Variation; HIV Infections; HIV Integrase; HIV-1; Humans; Male; Middle Aged; Plasma; Pyrrolidinones; Raltegravir Potassium; RNA Stability; RNA, Viral; Salvage Therapy; Virus Replication

Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and penicillin during 32 weeks of continuous drug monitoring.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Creatine Kinase; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Muscle Weakness; Myalgia; Pyrrolidinones; Raltegravir Potassium; Zidovudine

Stepwise multiple regression analyses were applied to 44 atazanavir pharmacokinetic profiles from 44 HIV-1 infected patients concomitantly treated with raltegravir with the goal of identifying limited sampling strategies for the prediction of drug AUC(0-12) . Atazanavir trough-based equations failed to reliably predict daily drug exposure in patients with low drug bioavailability. Conversely, different algorithms based on few samples and associated with good correlation, acceptable bias and imprecision with the measured atazanavir AUC(0-12) were identified. These models could be used to predict atazanavir exposure for clinic or research purposes.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Atazanavir Sulfate; Biological Availability; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Young Adult

Rural persons with HIV face barriers to care that may influence adoption of advances in therapy. We performed a retrospective cohort study to determine rural-urban variation in adoption of raltegravir-the first HIV integrase inhibitor-in national Veterans Affairs (VA) healthcare. There were 1,222 veterans with clinical indication for raltegravir therapy at time of its FDA approval in October 2007, of whom 223 (19.1%) resided in rural areas. Urban persons were more likely than rural to initiate raltegravir within 180 days (17.3% vs. 11.2%, P = 0.02) and 360 days (27.5% vs. 19.7%, P = 0.02), but this gap narrowed slightly at 720 days (36.3% vs. 31.8%, P = 0.19). In multivariable analysis adjusting for patient characteristics, urban residence predicted raltegravir adoption within 180 days (odds ratio 1.72, 95% CI 1.09-2.70) and 360 days (OR 1.63, 95% CI 1.13-2.34), but not 720 days (OR 1.26, 95% CI 0.84-1.87). Efforts are needed to reduce geographic variation in adoption of advances in HIV therapy.

Topics: Adolescent; Adult; Aged; CD4 Lymphocyte Count; Child; Child, Preschool; Delivery of Health Care; Diffusion of Innovation; Female; Health Services Accessibility; Healthcare Disparities; HIV Infections; HIV Integrase Inhibitors; Humans; Infant; Infant, Newborn; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Patient Acceptance of Health Care; Pyrrolidinones; Raltegravir Potassium; Residence Characteristics; Retrospective Studies; Rural Health Services; Rural Population; Surveys and Questionnaires; United States; United States Department of Veterans Affairs; Urban Population; Veterans; Viral Load; Young Adult

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cameroon; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Middle Aged; Pyrrolidinones; Raltegravir Potassium

The mechanism of raltegravir (RAL)-resistant evolutions has not already been elucidated. Because the emergence of RAL resistance is usually initiated by the N155H mutant, we assessed the role of minor N155H-mutated variants in circulating RNA and archived DNA in five heavily treated patients experiencing long-term RAL therapy failure and harbouring three different resistance profiles determined by standard genotyping.. Allele-specific polymerase chain reaction (AS-PCR) was used to detect N155H mutants in longitudinal stored plasma and whole-blood samples before, during and after RAL-based regimens in five patients infected with the HIV-1 B subtype.. No minor N155H-mutated variant was found by AS-PCR in either plasma or whole-blood samples collected at baseline and after RAL withdrawal in any of the five patients. During RAL failure, the mutation N155H was detected at different levels in three patients displaying the N155H pathway and gradually declined when the double mutant Q148H+G140S was selected in one patient. In two patients with the Q148H resistance pathway, no N155H variant was identified by AS-PCR in either viral RNA or DNA.. The N155H mutation present at various levels from minority to majority showed no relationship with the three RAL-associated resistance profiles, suggesting that this mutant may not play a role in determining different resistance profiles. Moreover, pre-existing N155H is very infrequent and, if selected during RAL failure, the N155H mutant disappears quickly after RAL withdrawal.

Topics: CD4 Lymphocyte Count; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Longitudinal Studies; Male; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; RNA, Viral; Salvage Therapy; Sequence Analysis, RNA; Treatment Failure; Viral Load

HIV-infected subjects on antiretroviral therapy often fail to normalize the CD4/CD8 ratio despite CD4 count normalization. We aimed to analyze the biological significance of this finding.. Cross-sectional analysis in 20 HIV-infected subjects on stable triple-ART, plasma HIV RNA <40 copies/mL for at least 2 years and CD4 count >350 cells/mm(3). Laboratory measurements included T-cell activation (HLADR(+), CD38(+)) and senescence (CD57(+)), lipopolysaccharide (LPS), sCD14 and the HIV latent reservoir (number of latently infected memory CD4 cells carrying replication-competent virus).. CD4/CD8 ratio was positively correlated with CD4 nadir (r = 0.468, p = 0.038) and accumulated ART exposure (r = 0.554, p = 0.0011), and negatively with viral load before ART initiation (r = -0.547, p = 0.013), CD4(+)HLADR(+)CD38(+) T-cells (r = -0.428, p = 0.086) and CD8(+)CD57(+) T-cells (r = -0.431, p = 0.084). No associations with LPS, sCD14 or HIV latent reservoir were found. After the multivariate analyses, the CD4/CD8 ratio remained independently associated with CD4(+)HLADR(+)CD38(+) T-cells and CD8(+)HLADR(+) T-cells.. In our study in subjects on suppressive ART the CD4/CD8 ratio was independently associated with T-cell activation. Our results must be confirmed in larger studies, as this parameter might be a useful clinical tool to identify subjects with ongoing immune activation despite long-term viral suppression.

Topics: Adult; Anti-Retroviral Agents; Bacterial Translocation; CD4-CD8 Ratio; Clinical Trials, Phase II as Topic; Cross-Sectional Studies; Cyclohexanes; Female; HIV Infections; Host-Pathogen Interactions; Humans; Lymphocyte Activation; Male; Maraviroc; Middle Aged; Multivariate Analysis; Pyrrolidinones; Raltegravir Potassium; Risk Factors; Statistics, Nonparametric; T-Lymphocytes; Triazoles; Viral Load

The HIV integrase inhibitor raltegravir (RAL) can exacerbate autoimmune diseases in genetically predisposed mice. To evaluate whether this may occur in clinical practice, we clinically monitored HIV-positive patients treated with RAL and measured a panel of autoantibodies (auto-Abs) during the first year of RAL treatment.. This was a longitudinal study in 109 antiretroviral-experienced patients who started a RAL-based regimen and were followed up for more than 2 years. A total of 45 patients were tested at baseline (before starting RAL) and after 12 months for the presence of the following auto-Abs: anti-nuclear antibodies, anti-double-stranded DNA, anti-smooth-muscle antibodies, anti-thyreoglobulin and anti-thyroid peroxidase antibodies, anti-cardiolipin immunoglobulin G and immunoglobulin M and anti-nuclear extractable antigens, including anti-SM ribonucleoprotein antigen, anti-Ro antigen and anti-La antigen.. A low rate of clinically relevant autoimmune diseases was observed at study entry (3/109; 2.8%; 95% CI 0.004, 0.059). No exacerbations were observed during follow-up. During the second year of RAL-based therapy a previously healthy patient developed psoriasis. At baseline, 17/45 (37.8%) patients tested for the presence of auto-Abs were positive. Most patients (n=13) were positive for anti-cardiolipin. After 12 months of RAL exposure, 9/45 patients were positive (20%; P=0.063). A positive correlation was found between HIV-1 RNA and anti-cardiolipin antibody concentration (P=0.010).. According to these results, RAL does not promote antibody-mediated immune disorders, at least not in the mid-term. A prolonged follow-up and an extension of the panel of auto-Abs are recommended to support these results.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases; CD4 Lymphocyte Count; Female; Follow-Up Studies; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Receptors, IgE; Retrospective Studies; Viral Load

To evaluate the incidence and risk factors for significant creatine kinase elevation in HIV-1-infected patients who were prescribed a raltegravir-containing antiretroviral therapy.. A retrospective analysis of a prospectively collected cohort involving all consecutive patients who were prescribed a raltegravir-containing antiretroviral regimen between June 2005 and December 2010.. Significant creatine kinase elevation was defined as an elevation of at least 3-fold from the upper limit of normal (ULN) (grade 2, WHO classification) while receiving raltegravir. Blood analysis at each visit included at least creatine kinase, as well as plasma HIV-1 RNA and CD4 cell count.. There were 475 patients who had been exposed to raltegravir for a median of 11.5 (IQR 8.2-15.2) months. An increase of creatine kinase ≥ 3-fold ULN was detected in 53 (11.2%) patients, representing an incidence of 3.8/100 person-years. Symptoms were reported by seven patients (1.5%), they showed either grade 1 (n = 3) or 2 (n = 4) creatine kinase increases. The median duration of raltegravir therapy before creatine kinase elevation was 5.9 (IQR 3.3-9.3) months. Evidence of creatine kinase elevation prior to raltegravir therapy [hazard ratio (HR) 3.30; 95% CI 1.59 ± 6.86; P = 0.001], abnormal baseline creatine kinase (HR 3.24; 95% CI 1.63 ± 6.45; P = 0.001) and male gender (HR 4.17; 95% CI 1.33 ± 1.27; P = 0.001) were identified as independent risk factors for creatine kinase elevation during raltegravir treatment.. Although ≈ 1 in 10 patients on raltegravir therapy developed significant creatine kinase elevation as defined in this study, symptoms were uncommon, not severe and occurred in patients with easily identifiable risk factors.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blood Chemical Analysis; CD4 Lymphocyte Count; Cohort Studies; Creatine Kinase; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Prevalence; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; RNA, Viral

About 10% of the human immunodeficiency virus (HIV) patients show thrombocytopenia. We describe the case of an HIV/HCV-positive patient whose autoimmune thrombocytopenia resolved with the addition of raltegravir to previous highly active antiretroviral therapy (HAART). It is noteworthy that the effect on platelet count appeared to be independent of viral load suppression, which was achieved with previous antiretroviral regimens. In fact, it has been suggested that the positive effect exerted by raltegravir on autoimmune diseases is due to its inhibition on herpes viruses, and hence on activation of endogenous human retroviruses. This consideration, if confirmed, could open new avenues in the treatment of autoimmune thrombocytopenia in the HIV setting.

Topics: Anti-HIV Agents; HIV Infections; Humans; Male; Purpura, Thrombocytopenic, Idiopathic; Pyrrolidinones; Raltegravir Potassium

The initiation of drug therapy results in a reduction in the human immunodeficiency virus type 1 (HIV-1) population, which represents a potential genetic bottleneck. The effect of this drug-induced genetic bottleneck on the population dynamics of the envelope (Env) regions has been addressed in several in vivo studies. However, it is difficult to investigate the effect on the env gene of the genetic bottleneck induced not only by entry inhibitors but also by non-entry inhibitors, particularly in vivo. Therefore, this study used an in vitro selection system using unique bulk primary isolates established in the laboratory to observe the effects of the antiretroviral drug-induced bottleneck on the integrase and env genes. Env diversity was decreased significantly in one primary isolate [KP-1, harbouring both CXCR4 (X4)- and CCR5 (R5)-tropic variants] when passaged in the presence or absence of raltegravir (RAL) during in vitro selection. Furthermore, the RAL-selected KP-1 variant had a completely different Env sequence from that in the passage control (particularly evident in the gp120, V1/V2 and V4-loop regions), and a different number of potential N-glycosylation sites. A similar pattern was also observed in other primary isolates when using different classes of drugs. This is the first study to explore the influence of anti-HIV drugs on bottlenecks in bulk primary HIV isolates with highly diverse Env sequences using in vitro selection.

Topics: Amino Acid Sequence; Anti-HIV Agents; Base Sequence; Cyclohexanes; DNA, Viral; Genetic Variation; Genotype; Glycosylation; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Lamivudine; Maraviroc; Molecular Sequence Data; Phylogeny; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Receptors, CXCR4; Saquinavir; Sequence Analysis, DNA; Triazoles; Viral Tropism

Raltegravir (RAL) is the only licensed human immunodeficiency virus (HIV) integrase inhibitor. The factors associated with the virological response to RAL-containing regimens and the prevalence of integrase mutations associated with RAL failure deserve further investigation. From the Antiretroviral Resistance Cohort Analysis database, we selected triple-class-experienced subjects failing their current treatment with complete treatment history available. Selection criteria included HIV-RNA, CD4 count and HIV genotype within 3 months of RAL initiation. Factors associated with 24-week response were analysed; genotypic sensitivity scores (GSS) and weighted-GSS were evaluated. Virological response was achieved in 74.3% of 105 subjects. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00-6.87). was found to be a associated with response. Weighted-GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96-4.33) When stratifying for different cut-offs (<1 as reference, 1-1.49, ≥1.5), a borderline significant increase in the probability of response appeared for GSS ≥1.5 (p 0.053, OR 4.00; 95% CI 0.98-16.25). GSS ≥1 showed the highest sensitivity, 82.6%. Receiver operating characteristic curves depicted the widest area under the curve (0.663, p 0.054) of GSS ≥1. Unresponsiveness to RAL-containing regimens among triple-class-experienced subjects was low. The activity of the background regimen was strongly associated with response. Although few integrase genotypes were available at failure, half of these were without integrase resistance mutations. The substantial rate of RAL failure in the absence of known RAL-resistance mutations may be associated with adherence issues and this issue warrants further analysis in longer observations.

Topics: Adult; Anti-HIV Agents; Databases, Factual; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; ROC Curve; Treatment Failure

Topics: Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium

Topics: Anti-HIV Agents; Area Under Curve; Cyclohexanes; Darunavir; HIV Infections; Humans; Male; Maraviroc; Middle Aged; Nitriles; Prospective Studies; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Semen; Sulfonamides; Triazoles

Effective antiretroviral therapy (ART) dramatically reduces human immunodeficiency virus (HIV) transmission. However, isolated shedding of HIV type 1 (HIV-1) in semen (IHS) can occur in the absence of detectable viremia or genital infections. We hypothesized that ART intensification with medications active in semen might prevent IHS.. Paired blood and semen samples were collected monthly for 6 months from HIV-infected men starting ART that was intensified (iART) with maraviroc and raltegravir in an open-label fashion. Semen parameters were compared to those of historical controls starting standard ART (sART).. Compared with 25 controls who started sART, the semen HIV-1 load in 13 subjects who started iART was more rapidly suppressed (P = .043). IHS was detected at >1 visit in 2 participants (15%) receiving iART and in 12 controls (48%) receiving sART (P = .040). Among iART recipients, IHS was associated with lower raltegravir concentrations in blood and semen, compared with complete HIV-1 suppression (P = .03). Prolonged, high-level IHS (ie, shedding of >5000 RNA copies/mL) was observed in 1 iART recipient (8%), despite rapid viremia suppression and therapeutic drug levels; for 10 months, this virus remained R5 tropic, drug susceptible, and similar in sequence to virus recovered from blood. IHS was not seen after >3 years of effective ART in a parallel, prospective cohort study.. iART transiently reduced the occurrence of IHS early after ART initiation but did not prevent high-level IHS. IHS was not seen after more prolonged sART.

Topics: Amino Acid Sequence; Anti-Retroviral Agents; Base Sequence; Case-Control Studies; Cyclohexanes; HIV Infections; HIV-1; Humans; Incidence; Male; Maraviroc; Molecular Sequence Data; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Semen; Sequence Analysis, RNA; Sexual Behavior; Time Factors; Treatment Outcome; Triazoles; Viral Load; Viremia; Virus Shedding

Despite the efficacy of raltegravir in reducing viral load in HIV-infected patients, evidence for its safety in late pregnancy is lacking. A high rate of placental transfer was recently demonstrated.. A treatment-naïve 34-year-old HIV-1-positive woman of African origin began treatment with zidovudine/lamivudine, lopinavir/ritonavir, and raltegravir at 35 weeks of pregnancy. After 11 days of treatment with raltegravir, a substantial reduction in viral load was achieved. Concurrently, she had a 23-fold increase in serum alanine aminotransferase and a 10-fold increase in serum aspartate aminotransferase, both of which returned to normal when raltegravir treatment was discontinued. A healthy boy was delivered at term. The infant's tests for HIV were negative at five months, and he had no health problems at eight months.. This is the first case report, to our knowledge, of increased maternal serum transaminase levels following the use of raltegravir in a woman at a late stage of pregnancy.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Female; Gestational Age; HIV Infections; HIV-1; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pyrrolidinones; Raltegravir Potassium; Viral Load

Detection of episomal HIV cDNA has been associated with greater levels of CD8 and CD4 T-cell activation in HIV-1-infected highly active antiretroviral therapy (HAART)-suppressed individuals. However, HAART intensification exclusively reduced CD8 T-cell activation.. We evaluated activation markers 12 weeks after raltegravir withdrawal in a previously described 48-week raltegravir intensification study. The subjects (n = 34) were subgrouped into 2-LTR(+) (n = 12) or 2-LTR(-) (n = 22) subgroups according to delectability of 2-LTR episomes during the intensification period.. The initial differences in CD8 T-cell activation between subgroups were lost after intensification. Linear mixed models revealed significant reductions in CD8 T-cell activation in both 2-LTR(-) and 2-LTR(+) subgroups, suggesting that raltegravir impacts subjects irrespective of 2-LTR detection. Remarkably, a partial rebound in CD8 activation markers after raltegravir discontinuation was observed in the 2-LTR(+) subgroup. This restored the differences between subgroups observed at study entry, particularly in terms of CD38 expression within CD8 memory T-cells. Conversely, CD4 T-cell activation remained unchanged in both subgroups during the study period, although an early and transient CD45RA(-) CD4 T-cell redistribution from tissues was apparent.. CD8 T-cell activation undergoes reversible changes during raltegravir intensification and discontinuation in patients showing detectable 2-LTR circles. The general decrease in CD8 T-cell activation and a transient CD45RA(-) CD4 T-cell redistribution in intensified individuals may reflect residual viral replication during apparently suppressive HAART.

Topics: ADP-ribosyl Cyclase 1; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; HIV Infections; Humans; Immunologic Memory; Lymphocyte Activation; Male; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load

A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC(50) values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors.

Topics: Anti-HIV Agents; Benzoates; Cell Proliferation; Cells, Cultured; Drug Design; HIV Infections; HIV-1; Humans; Molecular Structure; Oxadiazoles; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Virus Replication

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

Topics: Adult; Carbamates; Cardiomyopathies; Chemical and Drug Induced Liver Injury; Creatine Kinase; Cyclohexanes; Drug Substitution; Drug Therapy, Combination; Fatty Liver; Furans; Hepatitis C, Chronic; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Liver Cirrhosis; Male; Maraviroc; Organophosphates; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Triazoles

Stepwise multiple regression analyses were applied to 50 raltegravir pharmacokinetic profiles from 50 HIV patients with the goal to identify limited sampling strategies for the prediction of drug area under the time-concentration curve (AUC(0-12)). Raltegravir single sampling point-based equations failed to reliably predict daily drug exposure. Conversely, different algorithms based on few samples and associated with good correlation, acceptable bias, and imprecision with the measured raltegravir AUC(0-12) were identified. These models could used to predict raltegravir exposure for clinic or research purposes.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Area Under Curve; Female; Half-Life; HIV Infections; Humans; Male; Middle Aged; Models, Biological; Pyrrolidinones; Raltegravir Potassium

To record the experience with use of raltegravir (RTG) for devising highly active antiretroviral therapy (HAART) regimens based on RTG in high vascular risk patients.. A retrospective study was conducted on high vascular risk patients taking RTG. Case was a patient who, at the time raltegravir was started, had ≥ 20% 10-year risk of cardiovascular disease, estimated by the algorithm of the European AIDS Clinical Society. Patients should have been on stable HAART including RTG for at least six months. A matched control with ≥ 20% risk of cardiovascular disease, was selected for each case.. Ten controls and ten cases were selected. After six months using RTG, a significant decreased was seen in levels of HDL cholesterol (median -2,5mg/dL in controls versus 2,5mg/dL in cases, p=0.015), triglycerides (10mg/dL versus -101 mg/dL, p=0.009), and TC/HDL-C ratio (0.17 versus -0.73, p=0.002). Ten-year risk of cardiovascular disease was -4.85% in cases versus -0.05% in controls (p=0.07).. RTG shows a good profile to be used in people with high vascular risk, with a decrease in TC/HDL-C ratio and vascular risk.

Topics: Aged; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Case-Control Studies; Cholesterol, HDL; HIV Infections; HIV Integrase Inhibitors; Humans; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Risk; Treatment Outcome; Triglycerides

Highly active antiretroviral therapy (HAART) of HIV+ patients with haemophilia poses specific questions on safety and effectiveness because of long-lasting HIV infection, multidrug resistance, concomitant chronic liver disease and bleeding risk. Raltegravir belongs to a new class of drugs that inhibits HIV integrase and is known to have a good effectiveness and safety profile. The aim of this study was to evaluate safety and effectiveness of HAART with raltegravir in patients with haemophilia. HIV+ patients with haemophilia treated with raltegravir for ≥ 6 months were included in this retrospective study. Safety criteria were: occurrence of any adverse event, unexpected blood test abnormalities and increased consumption of coagulation factors. Effectiveness criteria were: no disease progression, viral load <40 HIV-RNA copies mL(-1) and increased or stable CD3+ CD4+ cell count above 200 cells cmm(-1). Seven patients with HCV co-infection underwent treatment with raltegravir for a median of 20 months (min-max: 7-30). Before starting treatment with raltegravir, three patients had CD3+ CD4+ cell counts <200 cells cmm(-1). The median viral load was 7547 copies mL(-1) (min-max: <40-37,807). During treatment, no new sign of disease progression was observed. All patients showed suppression of viral replication (<40 HIV-RNA copies mL(-1)). CD3+ CD4+ cell counts showed a median increase of 152 cells cmm(-1) (min-max: 40-525). Two patients suffered from peripheral neuropathy, which was deemed as possibly associated with raltegravir. There was no evidence of increased bleeding frequency, modification of bleeding sites and lack of response to replacement therapy. Raltegravir-based HAART appeared to be effective and generally well-tolerated in patients with haemophilia, and it might represent a useful option in these patients.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; Disease Progression; Drug Resistance, Multiple, Viral; Hemophilia A; HIV Infections; HIV Integrase Inhibitors; Humans; Italy; Lymphocyte Count; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Viral Load; Young Adult

Raltegravir is metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). We analyzed the genotypes of UGT1A1 (*6, *27, and *28) and their contribution to plasma raltegravir concentrations in 56 Japanese HIV-1-infected patients in the National Hospital Organization Nagoya Medical Center of Japan. Among the 56 patients, the UGT1A1 genotype in two patients was *6 homozygote. Heterozygous variants were found in 13 patients for *6 and in 11 patients for *28, while all of the patients were found to carry wild-type sequences at the position corresponding to the *27 allele. Plasma raltegravir concentration of a male patient with *6 homozygote (0.53 μg/ml) was modestly higher than that of patients with wild type (0.12 μg/ml) or *6 heterozygote (0.16 μg/ml). Another female patient with the *6 homozygote had a low plasma raltegravir concentration (0.03 μg/ml). Patients heterozygous for the *6 or *28 allele did not display significantly different plasma raltegravir concentrations compared to patients homozygous for the respective wild-type allele. Thus, in the present study, we showed that heterozygous reduced-function *6 and *28 alleles appear to have no significant effect on plasma raltegravir concentrations in Japanese HIV-1-infected patients. However, variability in raltegravir concentration and small patient population precluded a correlation between UGT1A1*6 homozygosity and plasma raltegravir concentration. To clarify the contribution of UGT1A1*6 or *28 polymorphisms to plasma raltegravir concentrations, further investigations on larger subject populations are required.

Topics: Adult; Aged; Aged, 80 and over; Anti-Retroviral Agents; Asian People; Female; Genotype; Glucuronosyltransferase; HIV Infections; HIV-1; Humans; Male; Middle Aged; Polymorphism, Genetic; Pyrrolidinones; Raltegravir Potassium; Young Adult

Topics: Anti-Retroviral Agents; Female; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Quinolones; Raltegravir Potassium

Topics: Anti-HIV Agents; DNA, Viral; Dose-Response Relationship, Drug; Drug Administration Schedule; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

The design of novel integrase (IN) inhibitors has been aided by recent crystal structures revealing the binding mode of these compounds with a full-length prototype foamy virus (PFV) IN and synthetic viral DNA ends. Earlier docking studies relied on incomplete structures and did not include the contribution of the viral DNA to inhibitor binding. Using the structure of PFV IN as the starting point, we generated a model of the corresponding HIV-1 complex and developed a molecular dynamics (MD)-based approach that correlates with the in vitro activities of novel compounds. Four well-characterized compounds (raltegravir, elvitegravir, MK-0536, and dolutegravir) were used as a training set, and the data for their in vitro activity against the Y143R, N155H, and G140S/Q148H mutants were used in addition to the wild-type (WT) IN data. Three additional compounds were docked into the IN-DNA complex model and subjected to MD simulations. All three gave interaction potentials within 1 standard deviation of values estimated from the training set, and the most active compound was identified. Additional MD analysis of the raltegravir- and dolutegravir-bound complexes gave internal and interaction energy values that closely match the experimental binding energy of a compound related to raltegravir that has similar activity. These approaches can be used to gain a deeper understanding of the interactions of the inhibitors with the HIV-1 intasome and to identify promising scaffolds for novel integrase inhibitors, in particular, compounds that retain activity against a range of drug-resistant mutants, making it possible to streamline synthesis and testing.

Topics: Amino Acid Substitution; Binding Sites; DNA, Viral; Drug Design; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Dynamics Simulation; Mutation; Oxazines; Piperazines; Protein Binding; Pyridones; Pyrrolidinones; Quantitative Structure-Activity Relationship; Quinolones; Raltegravir Potassium; Spumavirus; Thermodynamics

Topics: Adult; Anti-HIV Agents; Brain Edema; Darunavir; Diagnosis, Differential; Dideoxynucleosides; Emergencies; Female; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Nitriles; Posterior Leukoencephalopathy Syndrome; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

Limited studies in healthy volunteers and in HIV-1-infected patients have shown that raltegravir pharmacokinetics are characterized by high inter-patient variability. Only scanty data are, however, available on intra-patient raltegravir variability. The present study was designed to evaluate in parallel the inter- and intra-patient variability of raltegravir pharmacokinetics in HIV-1-infected patients during routine therapeutic drug monitoring (TDM).. Fifteen HIV-infected patients treated with highly active antiretroviral therapy containing 400 mg of raltegravir twice daily were included in the study. Pharmacokinetic evaluations were performed during two consecutive visits. Only patients given raltegravir for at least 1 month and with no changes in antiretroviral and concomitant therapy between the two pharmacokinetic evaluations were considered. Raltegravir plasma concentrations were determined by a validated HPLC method. Blood samples were collected at 0, 1, 2, 3 and 4 h after the morning drug dose. Raltegravir AUC(0-12) was estimated using a recently developed algorithm.. The pharmacokinetic evaluation was repeated after an average of 52 ± 68 days. Raltegravir AUC(0-12) values ranged from 1495 to 49 051 ng · h/mL. The main finding was that intra-patient variability was a large component of the overall variability in raltegravir pharmacokinetics. In some instances the difference between raltegravir AUC(0-4) and AUC(0-12) measured in the same patient during two consecutive evaluations exceeded 110% and 75%, respectively.. The pharmacokinetics of raltegravir in HIV-1-infected subjects are characterized not only by inter-patient variability but also by high intra-patient variability. This condition limits the application of TDM for raltegravir, and might potentially affect patient outcome.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chromatography, High Pressure Liquid; HIV Infections; HIV-1; Humans; Middle Aged; Plasma; Pyrrolidinones; Raltegravir Potassium; Reproducibility of Results; Time Factors

Elvitegravir is a strand transfer inhibitor of HIV-1 integrase that is currently undergoing phase 3 clinical testing. The two predominant metabolites of elvitegravir, M1 and M4 (elvitegravir hydroxide and elvitegravir glucuronide), have been shown to inhibit HIV-1 integrase in vitro. While they are markedly less potent than elvitegravir and present only at low levels in plasma clinically, we investigated their potential to select for elvitegravir resistance in vitro. Resistance selection experiments using metabolites M1 and M4 led to the development of the previously reported elvitegravir integrase resistance mutations H51Y, T66A, E92G, and S147G, as well as a novel S153F substitution. Additional resistance selection experiments using elvitegravir led to the development of previously reported integrase inhibitor resistance mutations (T66I, F121Y, and S153Y) as well as a novel R263K integrase mutation. Phenotypic analyses of site-directed mutants with these mutations demonstrated broad cross-resistance between elvitegravir and its M1 and M4 metabolites with more limited cross-resistance to the integrase inhibitor raltegravir. Overall, our in vitro studies demonstrate that the resistance profile of the M1 and M4 metabolites of elvitegravir overlaps with that of the parent molecule elvitegravir; as such, their presence at low levels is not considered clinically relevant.

Topics: Cell Line; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Quinolones; Raltegravir Potassium

CD4 gains in HIV patients on HAART result from release of T cells recently migrated from the thymus, redistribution from lymphoid tissues, proliferation in the periphery and/or reduced apoptosis. The relative contribution of each mechanism in CD4 restoration in patients with suppressed viremia switching antiretrovirals is unclear.. HIV patients with undetectable viremia on HAART were identified at our clinic. A subset switched to raltegravir was compared with another group that kept therapy unmodified. Naive and memory CD4 T-cells were measured by flow cytometry using CD45RA and CD27, respectively. Activation was examined using CD38 and recent thymic emigrants using CD31. Apoptosis was analyzed measuring soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL).. Thirty-seven patients were examined, 19 switched to raltegravir and 18 controls, after a median of 26 months of suppressed viremia. At 6 months, mean CD4 cell counts significantly increased in raltegravir patients from 322 to 448 cells/μl (P = 0.026) but not in controls (from 312 to 330 cells/μl; P  = 0.813). No significant changes were recognized in activation or CD31 expression in any group. In raltegravir patients, however, the proportion of naive CD4 T cells significantly increased (P = 0.014) as well as CD38 expression in these cells (P = 0.036). A positive correlation was found between CD38 and CD31 expression in naive CD4 T cells (R  = 0.51, P < 0.001). TRAIL and FasL did not decline significantly in any group.. HIV patients with prolonged undetectable viremia on HAART experience more pronounced CD4 gains after raltegravir switching than keeping the same regimen. An increased production of naive CD4 T cells largely explains this effect.

Topics: ADP-ribosyl Cyclase 1; Adult; Antiretroviral Therapy, Highly Active; Case-Control Studies; CD4 Lymphocyte Count; Fas Ligand Protein; Flow Cytometry; HIV Infections; HIV Integrase Inhibitors; Humans; Leukocyte Common Antigens; Middle Aged; Platelet Endothelial Cell Adhesion Molecule-1; Pyrrolidinones; Raltegravir Potassium; TNF-Related Apoptosis-Inducing Ligand; Treatment Outcome; Tumor Necrosis Factor Receptor Superfamily, Member 7

The dynamics of raltegravir-resistant variants and their impact on virologic response in 23 HIV-1-infected patients, who started a salvage raltegravir-containing regimen, were investigated.. Integrase population sequencing and Ultra-Deep-454 Pyrosequencing (UDPS) were performed on plasma samples at baseline and at raltegravir failure. All integrase mutations detected at a frequency ≥1% were considered to be reliable for the UDPS analyses. Phylogenetic and phenotypic resistance analyses were also performed.. At baseline, primary resistance mutations were not detected by both population and UDPS genotypic assays; few secondary mutations (T97A-V151I-G163R) were rarely detected and did not show any statistically association either with virologic response at 24-weeks or with the development of resistant variants at failure. At UDPS, not all resistant variants appearing early during treatment evolved as major populations during failure; only specific resistance pathways (Y143R-Q148H/R-N155H) associated with an increased rate of fitness and phenotypic resistance were selected.. Resistance to raltegravir in integrase strand transfer inhibitor-naive patients remains today a rare event, which might be changed by future extensive use of such drugs. In our study, pathways of resistance at failure were not predicted by baseline mutations, suggesting that evolution plus stochastic selection plays a major role in the appearance of integrase-resistance mutations, whereas fitness and resistance are dominant factors acting for the late selection of resistant quasispecies.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Integrase; HIV-1; Humans; Male; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation, Missense; Phenotype; Phylogeny; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sequence Analysis, DNA

In Vietnam, where an estimated 280,000 people will be HIV-positive by 2012, recommended antiretroviral regimens do not include more recently developed therapeutics, such as Integrase inhibitors (INI) and coreceptor antagonists. This study examined HIV-1 coreceptor tropism and INI drug resistance profiles, in parallel with CCR5 genotypes, in a cohort of 60 HIV-positive individuals from different regions of Vietnam. No evidence of INI resistance was detected. Some 40% of individuals had X4-tropic HIV-1, making them unsuitable for treatment with CCR5 antagonists. We identified a novel CCR5 variant-S272P-along with other, previously reported variants: G106R, C178R, W153C, R223Q, and S336I. Interestingly, CCR5 variants known to affect HIV-1 infectivity were observed only in individuals harboring X4-tropic virus. Together, this study presents valuable baseline information on HIV-1 INI resistance, coreceptor tropism, and CCR5 variants in HIV-positive individuals in Vietnam. This should help inform policy on the future use of novel antiretrovirals in Vietnam.

Topics: CCR5 Receptor Antagonists; Drug Resistance, Viral; Female; Genetic Predisposition to Disease; Genome, Viral; Genotype; HIV Envelope Protein gp120; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Molecular Sequence Data; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Tropism; Vietnam

Topics: Adolescent; Female; HIV Infections; Humans; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Pyrrolidinones; Raltegravir Potassium; Viral Load; Viremia

Among 103 patients with multidrug-resistant HIV who initiated raltegravir, etravirine, and darunavir/ritonavir-containing regimen in the ANRS 139 TRIO trial, 100 participated in extended follow-up and continued study treatment until week 96. Among them, 87 (87%) received an optimized background therapy including either nucleoside reverse transcriptase inhibitors or enfuvirtide, they were 78 (78%) at week 96. At week 96, 88% achieved durable virologic response (<50 copies/mL). CD4 response was maintained (median change of +150 cells/mm(3)). No major toxicity was reported. This triple drug combination showed sustained efficacy and thus should be strongly considered for patients with multiclass-resistant virus.

Topics: Adult; Darunavir; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides

There are pediatric patients receiving many highly active antiretroviral therapy (HAART) regimens entailing drug resistance mutations that complicate HAART effective therapies.. This was a multicenter retrospective study of 19 multidrug-resistant children and adolescents enrolled from July 2007 to October 2009. Patients were nonresponders because no reduction in HIV type 1 (HIV-1) RNA to undetectable levels was observed during their previous antiretroviral treatment history. The long-term effectiveness of raltegravir (RAL)-based salvage therapy was assessed through a longitudinal analysis of immunologic, virologic, and clinical status of the patients.. Median age was 16.0 (15.0-18.0) years. At baseline, median HIV-1 RNA was 10,000 (4.0 log10 copies/mL) (interquartile range [IQR]: 4300-83,000), and median CD4T-cell count was 329 (18.2% cells/μL) (IQR: 175-452). The backbone regimen included at least 1 fully active drug in 17/19 (89%) patients. Median follow-up with HAART including RAL was 80.1 weeks (IQR: 49.4-96.4): 16/19 (84%) exposed for >120 weeks and 6/19 (32%) >100 weeks. After RAL-based therapy, 4/19 (21%) patients achieved HIV-1 RNA <400 copies and 13/17 (68%) reached HIV-1 RNA <50 copies: 6 (32%) within the first month and 7 (37%) within the first 4 months. CD4+ T-cell recovery (70% to 90% of the baseline values) was observed in 17/19 (89%) patients. No deaths, AIDS-defining illnesses, or symptoms of severe intolerance were recorded. Only 2 patients experienced mild-moderate short-term skin rash. Two (11%) patients had sustained and optimum adherence to HAART. No patients showed resistance mutations to RAL after follow-up.. We observed a sustained antiviral response and improved immunologic indices in multidrug-resistant pediatric patients, most of whom had received RAL as part of salvage regimens with at least 1 fully active drugs.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Salvage Therapy; Treatment Outcome; Viral Load

Topics: Adult; Anti-HIV Agents; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Maternal-Fetal Relations; Pregnancy; Pyrrolidinones; Raltegravir Potassium; Young Adult

To determine whether the absorption of four antiretroviral agents-raltegravir, etravirine, emtricitabine, and tenofovir-is compromised when administered by gastrostomy tube.. Pharmacokinetic analysis.. University medical center.. A 52-year-old African-American man coinfected with advanced multidrug-resistant human immunodeficiency virus (HIV) and chronic hepatitis B, who was receiving treatment with raltegravir, etravirine, emtricitabine, and tenofovir, and developed ulcerative esophagitis with perforation, requiring a gastrostomy tube.. Due to the patient's esophageal perforations, all nutrition and drug therapy had to be provided by gastrostomy tube. As his antiretroviral regimen of raltegravir, etravirine, and emtricitabine-tenofovir was not available in liquid or powder formulations, the oral tablets were crushed or dispersed and mixed with water, then administered by gastrostomy tube. To ensure that the absorption of the drugs was sufficient for antiretroviral response, plasma samples were collected at 2 hours and 12 hours after dosing, and drug concentrations were quantitated by using validated assays. The 2- and 12-hour postdose plasma concentrations were 1220 and 446 ng/ml for raltegravir, 212 and 274 ng/ml for etravirine, 1148 and 164 ng/ml for emtricitabine, and 320 and 94 ng/ml for tenofovir, respectively. The patient's plasma concentrations were then compared with those in published pharmacokinetic studies of oral regimens administered to HIV-infected persons and healthy volunteers. Overall, the plasma concentrations of the antiretrovirals administered by gastrostomy tube were similar to published values. No drug toxicities were observed in this patient.. These pharmacokinetic data suggest that absorption of raltegravir, etravirine, emtricitabine, and tenofovir was not compromised when the drugs were administered by gastrostomy tube. These findings provide a basis for further investigation of the pharmacokinetics, safety, tolerance, and antiretroviral response to raltegravir, etravirine, and emtricitabine-tenofovir when the oral route of administration is not possible.

Topics: Drug Interactions; Drug Resistance, Multiple; Drug Therapy, Combination; Gastrostomy; HIV Infections; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18 hours and 9-12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population.

Topics: Adult; Cyclohexanes; Disease Management; End Stage Liver Disease; Fatal Outcome; HIV Infections; Humans; Male; Maraviroc; Metabolic Clearance Rate; Pyrrolidinones; Raltegravir Potassium; Renal Insufficiency; Triazoles

Current HIV-1 antiretroviral therapy (ART) greatly reduces virus replication but does not significantly affect the viral reservoir. Raltegravir, a recently introduced integrase inhibitor, could, at least theoretically, reduce residual viremia in patients on ART and affect the viral reservoir size. The aim of this study was to assess whether switching therapy in treatment-experienced patients that were virally suppressed to a raltegravir-containing regimen reduces the size of the viral reservoir, and if such treatment leads to a change in levels of HIV 2-LTR circles in this patient group.. 14 ART experienced individuals with a suppressed viral load (<50 HIV-1 RNA copies/mL plasma) at baseline (for at least 2 months) were switched to a raltegravir-containing regimen. Blood samples were taken at baseline and at ≥2 timepoints up to 48±6 weeks. Levels of total HIV-1 DNA and 2-LTR circles in peripheral blood mononuclear cells (PBMCs) were measured using real-time PCR assays.. There was no significant change in HIV-1 total DNA levels over the study duration (p = 0.808), median slope 0.24 (conservative nonparametric 95% CI: -11.78, 26.23). Low levels of 2-LTR circles were detected in 2 patients. One had 16 copies/10(6) PBMCs at baseline and the other had 34 copies/10(6) PBMCs at week 51.. The switch to a raltegravir containing regimen was not associated with a significant change in HIV-1 total DNA levels in this cohort. There were no observed changes in the levels of HIV-1 2-LTR circles associated with raltegravir treatment initiation.

Topics: Adult; Antiviral Agents; Cohort Studies; DNA; DNA Primers; DNA, Viral; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Real-Time Polymerase Chain Reaction; Terminal Repeat Sequences; Viral Load

We studied the presence of primary resistance to raltegravir (RAL), natural polymorphisms, and selection pressure on HIV-1 integrase. We found a high frequency of integrase polymorphisms related to the resistance to RAL and sequence stability. Further studies are needed to determine the importance of these polymorphisms to RAL resistance.

Topics: Amino Acid Sequence; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brazil; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase; HIV-1; Humans; Male; Molecular Sequence Data; Phylogeny; Polymorphism, Genetic; Pyrrolidinones; Raltegravir Potassium; Selection, Genetic; Sequence Homology, Amino Acid; Treatment Failure

We investigated the dynamics of HIV RNA and HIV DNA levels after the commencement of raltegravir-based antiretroviral therapy (ART) in primary (PHI) and chronically HIV-infected (CHI) individuals (the PINT study).. We recruited 8 PHI and 8 CHI ART-naive individuals who commenced a 1-year combination regimen of Truvada and the integrase inhibitor raltegravir.. Nonlinear mixed effects modelling was used to determine multiphasic decay of plasma HIV RNA levels (pVL), as well as dynamics of total, episomal [2-long terminal repeats (LTR)] and integrated HIV DNA in CD4 T cells from peripheral blood.. Although pVL decreased faster through first and second phase for PHI individuals there was no difference in the final level reaching a mean of 9 copies/ml by week 16 that was maintained thereafter. Total HIV DNA and integrated HIV DNA levels from CHI patients were significantly higher than from PHI patients. However, at no time did 2-LTR levels differ between groups. Of note, 2-LTR circles exhibited an initial increase peaking at week 3 followed by biphasic decay with a half-life of 29 days. Second phase integrated HIV DNA levels were significantly correlated with duration of infection and consistent with this form of infection occurring at approximately 100 000 integration events per day in the absence of ART, achieving its 50% level 2 years after infection.. Integrated HIV DNA levels accumulate with duration of untreated HIV infection. The relatively short half-life and high levels of 2-LTR circles after 1 year support continued HIV transmission during ART.

Topics: Blotting, Western; CD4 Lymphocyte Count; Chronic Disease; Deoxycytidine; DNA, Viral; Drug Combinations; Drug Therapy, Combination; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organophosphorus Compounds; Pyrrolidinones; Raltegravir Potassium; Real-Time Polymerase Chain Reaction; RNA, Viral

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Skin Diseases

The failure of raltegravir (RAL) is generally associated with the selection of mutations at integrase position Y143, Q148, or N155. However, a relatively high proportion of failures occurs in the absence of these changes. Here, we report the phenotypic susceptibilities to RAL and elvitegravir (EVG) for a large group of HIV-infected patients failing on RAL-containing regimens. Plasma from HIV-infected individuals failing on RAL-containing regimens underwent genotypic and phenotypic resistance testing (Antivirogram v2.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2.5 (interquartile range [IQR], 2.1 to 3.1). Fourteen samples from patients with RAL failures showed diminished RAL susceptibility, with a median FC of 38.5 (IQR, 10.8 to 103.2). Primary integrase resistance mutations were found in 11 of these samples, displaying a median FC of 68.5 (IQR, 23.5 to 134.3). The remaining 3 samples showed a median FC of 2.5 (IQR, 2 to 2.7). EVG susceptibility was diminished in 19/40 samples from patients with RAL failures (median FC, 7.71 [IQR, 2.48 to 99.93]). Cross-resistance between RAL and EVG was high (R(2) = 0.8; P < 0.001), with drug susceptibility being more frequently reduced for EVG than for RAL (44.3% versus 24.6%; P = 0.035). Susceptibility to RAL and EVG is rarely affected in the absence of primary integrase resistance mutations. There is broad cross-resistance between RAL and EVG, which should preclude their sequential use. Resistance to EVG seems to be more frequent and might be more influenced by integrase variability.

Topics: Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase Inhibitors; Humans; Molecular Sequence Data; Pyrrolidinones; Quinolones; Raltegravir Potassium

The genetic barrier for the evolution of integrase inhibitors (INIs) including raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) resistance was compared between HIV-1 subtypes CRF01_AE and B.. Analysis of 66 substitutions associated with INI resistance at 41 amino acid positions in 144 nucleotide sequences (109 HIV-1 subtype CRF01_AE and 35 HIV-1 subtype B) of integrase-coding region of polymerase gene derived from INI-naive patients.. 28/41 studied amino acid positions were conserved, leading to a similar genetic barrier between the two subtypes. At six codon positions with different genetic barriers, six mutations (V72I, L101I, A124T, T125K, and G140C/S) displayed a higher genetic barrier and one mutation (V201I) showed a lower genetic barrier in subtype CRF01_AE than subtype B.. Most studied amino acid positions including all corresponding to RAL and EVG primary mutations show a high level of conservation, indicating the same genetic barrier between subtypes CRF01_AE and B. Nevertheless, different genetic barriers were observed in two mutations described to be associated with DTG resistance (L101I, A124T) and other five RAL and EVG secondary mutations (V72I, T125K, G140C/S, V201I), which could have an impact on the development of resistance to RAL, EVG, and DTG.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutant Proteins; Mutation, Missense; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium; RNA, Viral; Sequence Analysis, DNA

Topics: Adolescent; Anti-HIV Agents; Child; Child Welfare; Child, Preschool; Dose-Response Relationship, Drug; Drug Resistance, Viral; Female; HIV Infections; Humans; Infant; Male; Pyrrolidinones; Raltegravir Potassium; United States

Mutations at amino acids 143, 148, and 155 in HIV-1 integrase (IN) define primary resistance pathways in subjects failing raltegravir (RAL)-containing treatments. Although each pathway appears to be genetically distinct, shifts in the predominant resistant virus population have been reported under continued drug pressure. To better understand this dynamic, we characterized the RAL susceptibility of 200 resistant viruses, and we performed sequential clonal analysis for selected cases. Patient viruses containing Y143R, Q148R, or Q148H mutations consistently exhibited larger reductions in RAL susceptibility than patient viruses containing N155H mutations. Sequential analyses of virus populations from three subjects revealed temporal shifts in subpopulations representing N155H, Y143R, or Q148H escape pathways. Evaluation of molecular clones isolated from different time points demonstrated that Y143R and Q148H variants exhibited larger reductions in RAL susceptibility and higher IN-mediated replication capacity (RC) than N155H variants within the same subject. Furthermore, shifts from the N155H pathway to either the Q148R or H pathway or the Y143R pathway were dependent on the amino acid substitution at position 148 and the secondary mutations in Y143R- or Q148R- or H-containing variants and correlated with reductions in RAL susceptibility and restorations in RC. Our observations in patient viruses were confirmed by analyzing site-directed mutations. In summary, viruses that acquire mutations defining the 143 or 148 escape pathways are less susceptible to RAL and exhibit greater RC than viruses containing 155 pathway mutations. These selective pressures result in the displacement of N155H variants by 143 or 148 variants under continued drug exposure.

Topics: Amino Acid Substitution; Anti-HIV Agents; Drug Resistance, Viral; Evolution, Molecular; HIV Infections; HIV Integrase; HIV-1; Humans; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA

Raltegravir is an integrase inhibitor (INI) licensed for clinical use and other INI are in advanced stage of development. Different resistance mutations in HIV integrase from patients using these antiretroviral drugs have been described and G148H/R/K, N155H and less frequently Y143C/H/R are considered major resistant mutations to raltegravir. Both Stanford Database and Geno2Pheno list F121Y as conferring intermediate resistance "in vitro" both to raltegravir and elvitegravir. We report for the first time the "in vivo" selection F121Y and evolution to Y143R in a 31years old male clade B HIV-1 infected patient failing a raltegravir-containing salvage regimen. Plasma samples nine months prior to raltegravir (RAL-Naïve) and at weeks 32, 40 and 88 after RAL-containing regimen were analyzed. Antiretroviral susceptibility was evaluated at Stanford and Geno2Pheno from sequences obtained with RT-PCR. After a Viral load at week 12 below 50 copies/mL, viremia raised at week 20 to 4.5log10. The emergence of F121Y was observed at week 32 and 40, alongside with L74I, T97A, Q137H and V151I. At week 88 F121Y was no longer detected, L74I and T97A were maintained and Y143R emerged. F121Y might be an alternative pathway to Y143R. Changing of RAL-containing regimen upon the identification of F121Y might avoid the evolution of raltegravir resistance.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Male; Molecular Sequence Data; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Polymerase Chain Reaction; Salvage Therapy; Selection, Genetic; Sequence Analysis, DNA; Time Factors; Treatment Failure; Viral Load

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Nephrolithiasis; Pyrrolidinones; Raltegravir Potassium; Recurrence

The prevalence of HIV-1 integrase mutations related to resistance to the next-generation integrase inhibitor (INI), dolutegravir (DTG), was assessed in 440 INI-naïve subjects and in 120 patients failing a raltegravir (RTG)-containing regimen. Of the mutations selected by DTG in vitro, S153FY was not detected in any isolate while L101I and T124A were highly prevalent in both groups and significantly associated with non-B subtype. RTG-selected double and triple mutants, mostly the G140S/Q148H variant, were detected in only 32 (26.7%) RTG-treated patients. As L101I and T124A do not appear to exert any major effect in vivo and double and triple mutants resistant to DTG are infrequently selected by RTG, DTG can be effectively used in INI-naïve patients and may retain activity in many patients failing RTG.

Topics: Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium

We describe a 55-year-old HIV-1-infected male who developed severe dyslipidaemia (total cholesterol 600 mg/dl, triglycerides >5,000 mg/dl, high density lipoprotein <5 mg/dl) after raltegravir was added to his lopinavir/ritonavir-containing regimen. To our knowledge, this is the first reported case of severe dyslipidaemia associated with the addition of raltegravir to a lopinavir/ritonavir-based regimen, suggestive of a possible drug interaction. The lipid profile quickly normalized following discontinuation of lopinavir/ritonavir and continuation of raltegravir, suggesting that lopinavir/ritonavir was the primary driver for the adverse event. With increasing interest in nucleoside-sparing regimens, knowledge of clinically significant adverse events such as this is important for HIV clinicians when selecting regimens for patients with highly resistant virus or drug tolerability issues.

Topics: Cholesterol, HDL; Drug Interactions; Drug Therapy, Combination; Dyslipidemias; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Treatment Outcome; Triglycerides

DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is a life-threatening adverse drug reaction. Raltegravir is an integrase inhibitor used in HIV-1 infection. We report on a patient who developed a DRESS syndrome under raltegravir treatment, which was identified as a probable case of DRESS on the basis of Kardaun and Naranjo scores. The presented case is the first description of a proven raltegravir-induced DRESS syndrome.

Topics: Anti-HIV Agents; Eosinophilia; Female; HIV Infections; Humans; Middle Aged; Pyrrolidinones; Raltegravir Potassium

Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings.. Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96.. Out of 320 patients enrolled, 292 (91.25%) subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11), viral failure (8), adverse events (5), loss to follow-up (3), consent withdrawal (1). Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm(3); 273 out of 300 patients (91%), who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA <50 copies/mL). When analyzing the immuno-virologic outcome according to the number of drugs used in the regimen, 2 (n = 45), 3 (n = 111), 4 (n = 124), or >4 (n = 40), CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm(3), respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides) were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL.. In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Italy; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Viral Load

The goal of post-exposure prophylaxis (PEP) for HIV is to prevent the establishment of a persistent infection following exposure to the virus. Integrase inhibitors have several potential advantages in PEP regimens, including the capacity to inhibit integration of HIV genomes that have already proceeded through reverse transcription, thereby becoming refractory to reverse transcriptase inhibitors. We sought to determine if integrase inhibitors extend the window of time during which PEP intervention might be successful.. Primary costimulated CD4(+) T-cells or macrophages were infected with a luciferase-bearing HIV reporter virus, permitting sensitive detection of viral gene expression under different drug treatment conditions. Relevant antiretroviral agents were added at various pre- or post-infection time points.. We showed that raltegravir effectively blocks HIV infection, even when cells are challenged with a large amount of virus. We also demonstrated that during infection of both primary costimulated CD4(+) T-cells and primary macrophages, raltegravir can inhibit infection when added at later post-infection time points than the reverse transcriptase inhibitor efavirenz.. This longer post-infection efficacy window, coupled with favourable pharmacokinetic properties and low toxicity, suggest that raltegravir may prove useful in HIV PEP.

Topics: Alkynes; Benzoxazines; CD4-Positive T-Lymphocytes; Cyclopropanes; Gene Expression Regulation, Viral; Genes, Reporter; Genes, Viral; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Luciferases; Macrophages; Microbial Sensitivity Tests; Post-Exposure Prophylaxis; Pyrrolidinones; Raltegravir Potassium; Time Factors

Dolutegravir (DTG, S/GSK1349572) is an integrase inhibitor with low nanomolar potency. Susceptibility to dolutegravir and raltegravir was determined for raltegravir-resistant clinical isolates.. Genotypic and phenotypic susceptibility to integrase inhibitors was examined using 39 clinical isolate samples obtained from 18 adults who had exhibited incomplete viral suppression on a raltegravir-based regimen.. Of 39 samples evaluated, 30 had genotypic and phenotypic resistance to raltegravir. All samples lacking raltegravir resistance retained complete susceptibility to dolutegravir. Of the 30 samples with genotypic evidence of raltegravir resistance, the median level of phenotypic resistance to raltegravir was high (median fold change in inhibitory concentration at 50%, >81; range, 3.7 to >87), while the level of resistance to dolutegravir was close to that of wild-type variants (median fold change, 1.5; range, 0.9-19.0). Longitudinal samples from 5 subjects collected during long-term failure of raltegravir revealed time-dependent general decreases in phenotypic susceptibility to raltegravir, with minimal changes in phenotypic susceptibility to dolutegravir. The median fold change to dolutegravir for isolates containing changes at G140S + Q148H, G140S + Q148R, T97A + Y143R, and N155H (thus including raltegravir signature resistance codons) were 3.75, 13.3, 1.05, and 1.37, respectively.. Dolutegravir retained in vitro activity against clinical isolates obtained from subjects who failed raltegravir-based therapy at near wild-type levels for variants containing the Y143 and N155 resistance mutations. Isolates with Q148 plus additional integrase mutations possessed a broader range of and more reduced susceptibility to dolutegravir.

Topics: Adult; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Phenotype; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium

We describe five patients with HIV-2 infection (four antiretroviral-experienced and one antiretroviral-naive) treated with a regimen containing raltegravir. All responded to treatment as demonstrated by viral load and CD4(+) T-cell count monitoring. Our series confirms the clinical effectiveness of raltegravir in HIV-2-infected patients when given with other antiretrovirals to which the virus is susceptible.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Evidence-Based Medicine; Female; HIV Infections; HIV-2; Humans; Male; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Adherence patterns and their influence on virologic outcome are well characterized for protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We aimed to determine how patterns of adherence to raltegravir influence the risk of virological failure. We conducted a prospective multicenter cohort following 81 HIV-infected antiretroviral-naive or experienced subjects receiving or starting twice-a-day raltegravir-based antiretroviral therapy. Their adherence patterns were monitored using the Medication Events Monitoring System. During follow-up (188 days, ±77), 12 (15%) of 81 subjects experienced virological failure. Longer treatment interruption [adjusted odds ratio per 24-hour increase: 2.4; 95% confidence interval: 1.2 to 6.9; P < 0.02] and average adherence (odds ratio per 5% increase: 0.68; 95% confidence interval: 0.46 to 1.00, P < 0.05) were both independently associated with virological failure controlling for prior duration of viral suppression. Timely interdose intervals and high levels of adherence to raltegravir are both necessary to control HIV replication.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Medication Adherence; Memory, Episodic; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Risk Factors; Treatment Failure

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Pyrrolidinones; Raltegravir Potassium

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

The combination of raltegravir (RAL) and etravirine (ETR) represents a novel antiretroviral treatment option in patients with toxicity or long-term exposure to standard therapies including protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI). The objective of this study was to evaluate the capacity of dual RAL/ETR therapy to maintain virological suppression in HIV-1 patients under effective antiretroviral therapy (ART).. Using the Nadis database we retrospectively identified all patients in our centre who were switched from different ART regimens to ETR 200 mg twice daily plus RAL 400 mg twice daily prior to February 2010, having a suppressed HIV-1 plasma viral load (pVL<200 copies/ml) at the moment of switch. Patients already on RAL or ETR at baseline were not excluded from the study. Treatment failure was defined as two consecutive pVL>50 copies/ml or discontinuation of RAL/ETR for any reason.. A total of 18 patients were included. Median baseline characteristics were: age 48 years (IQR 45-56), duration of ART 14 years (IQR 13-16), duration of viral suppression 6 years (IQR 5-9), duration of NRTI exposure 11 years (IQR 8-14) and PI exposure 6 years (IQR 3-9). In intent-to-treat analysis, the efficacy at 6 months of follow-up was 94.4% (n=17/18, 95% CI 74.2, 99%) and 83.3% (n=15/18, 95% CI 60.7, 94.1%) at 12 months. In per-protocol analysis, the efficacy at 12 months was 100% (n=15/15, 95% CI 80.6, 100%). No tolerability-related treatment discontinuation was recorded.. This study, although on a limited number of patients, suggests that raltegravir plus etravirine represents a potential option of NRTI/PI-sparing strategy, deserving further investigation in randomized studies.

Topics: Antiretroviral Therapy, Highly Active; HIV Infections; HIV-1; Humans; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

Despite successful suppression of HIV-1 with HAART, some patients do not have robust immunological recovery. Chronic inflammation from persistent immune activation could contribute to this poor response, resulting in HIV-1 disease progression and the development of some non-HIV-1 comorbidities.. We conducted a pilot study of 30 HIV-1-infected patients with undetectable viral loads and poor CD4(+) T-cell responses on long-term stable HAART to assess whether the addition of raltegravir would have an effect on biomarkers of chronic inflammation. A total of 26 patients were followed for 1 year on the intensified regimen. In addition to T-cell responses, we evaluated changes in activated CD4(+) and CD8(+) T-cells, several pro-inflammatory cytokines and chemokines and memory cell responses to HIV-1-associated peptides.. Although there was no improvement in CD4(+) T-cell counts, the percentage change in CD4(+)%, CD4(+)/CD8(+) ratios and RANTES (regulated on activation normal T-cells expressed and secreted) increased significantly while the percentage change in CD8(+) T-cell counts and CD8(+)%, activated CD4(+) T-cells and several pro-inflammatory chemokines and cytokines decreased significantly. The percentage change in HIV-1-specific nef, pol set 1, gag and env memory T-cells also declined.. The addition of raltegravir to a virologically suppressive HAART regimen in patients with poor immunological responses resulted in the reduction of several pro-inflammatory biomarkers; increases were seen in RANTES levels and CD4(+)/CD8(+) T-cell ratios. The clinical relevance of these observations is beyond the scope of this study.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Biomarkers; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemokine CCL5; Disease Progression; Female; gag Gene Products, Human Immunodeficiency Virus; HIV Infections; HIV-1; Humans; Immunologic Memory; Inflammation; Inflammation Mediators; Lymphocyte Activation; Male; Middle Aged; nef Gene Products, Human Immunodeficiency Virus; Pilot Projects; Pyrrolidinones; Raltegravir Potassium; Viral Load

The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first compared in vivo the pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated in vitro the dissolution of RAL tablets under different conditions. In the in vivo study, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. The in vitro studies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.

Topics: Administration, Oral; Adult; Antiretroviral Therapy, Highly Active; Area Under Curve; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Deglutition; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Mass Spectrometry; Mastication; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Solubility; Tablets; Taste

Central nervous system (CNS) symptoms have been reported in clinical trials and case reports in patients receiving raltegravir. We investigated CNS symptoms in 453 HIV-infected patients. Of these 47 (10.4%) developed at least one drug-related CNS symptom. Predictors of CNS symptoms were concomitant therapy with tenofovir or with proton pump inhibitors that can increase raltegravir concentration. Thus, our data suggest a possible correlation between high raltegravir plasma concentrations and CNS symptoms, and therefore their monitoring in clinical practice.

Topics: Adenine; Anti-HIV Agents; Central Nervous System; Drug Administration Schedule; Drug Interactions; Female; HIV Infections; Humans; Male; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Treatment Outcome; Viral Load

The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL+EFV-NPs) for pre-exposure prophylaxis of HIV. RAL+EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL+EFV-NP were 81.8±6.4 nm and -23.18±7.18 mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL+EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL+EFV-NPs in the gel did not result in nanoparticle aggregation and RAL+EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL+EFV-NPs was lower than raltegravir+efavirenz (RAL+EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL+EFV-NPs or blank gel were not cytotoxic for 14 days in vitro. The intracellular levels of efavirenz in RAL+EFV-NPs treated HeLa cells were above the EC(90) for 14 days whereas raltegravir intracellular concentrations were eliminated within 6 days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30 min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Carriers; Drug Evaluation, Preclinical; Gels; HeLa Cells; HIV Infections; HIV-1; Humans; Lactic Acid; Microbial Sensitivity Tests; Nanoparticles; Phagocytosis; Poloxamer; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrrolidinones; Raltegravir Potassium; Temperature; Time Factors

To describe the efficacy and tolerability of switching to raltegravir (RAL) in virologically suppressed HIV-1-infected patients during routine clinical practice.. A total number of 263 subjects (189 men, median age 48.1 years) with HIV-1 RNA < 50 copies/mL for ≥ 6 months were switched to RAL (400 mg b.i.d). Reasons for change were toxicity (49.0%), drug interactions (6.1%) or convenience (28.6%) (switch from subcutaneous to oral treatment 22.4%, improvement of posology 3.4%). Patients were followed up to 24 months after switching to RAL. Primary end-points were tolerability and virological failure defined as two consecutive measures of HIV-1 RNA > 50 copies/mL.. After a median of 12.4 months (range 2.8-26.4 months), virological failure was observed in 6 (2.3%) patients (2.2 per 100 person-years [95%CI 0.9-4.6]), while AIDS occurred in 1, drug discontinuation in 4, 3 patients died and 10 were lost to follow-up. The median CD4+ T cell count increased from 460 cells/mm3 to 508.6 cells/mm3 (P < 0.001).. Switching to RAL in clinical practice was mainly driven by toxicity, convenience or interactions, they were well tolerated and secured virologic suppression in the vast majority of patients.

Topics: Adult; Aged; Aged, 80 and over; Drug Substitution; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; RNA, Viral; Viral Load; Young Adult

The present study describes a follow-up of a prospective and observational cohort of patients infected with HIV-1 and treated with raltegravir for salvage therapy in Brazil. Two groups of patients were analyzed: switching from T20 to RAL (Group 1, n = 9) and salvage therapy containing RAL (Group 2, n = 10). Blood samples were drawn for CD4(+) T-cell counts and HIV-1 viral load determinations. Protease, reverse transcriptase, and integrase genotyping were performed at baseline and at the time of virologic failure. CD4(+) T-cells increased at 6 and 12 months in both groups; HIV-1 viral load was continuously suppressed for Group 1, and for Group 2 it significantly decreased after starting a RAL-containing regimen. Three out of 10 patients from Group 2 could not suppress HIV-1 viral load. The mutations Q148H + G140S were observed for two patients and for the third patient only mutations to PR/RT inhibitors were detected. The genotypic sensitivity score (GSS) was analyzed for all patients of Group 2 and both patients who developed resistance to raltegravir presented a GSS < 2.0 for the RAL-containing scheme, which could be associated to the lack of effectiveness of the proposed scheme. The present study describes, for the first time in Brazil, the close follow-up of a series of patients using a raltegravir-containing HAART, showing the safety of the enfuvirtide switch to RAL and the effectiveness of a therapeutic regimen with RAL in promoting immune reconstitution and suppressing HIV replication, as well as documenting the occurrence of resistance to integrase inhibitors in the country.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brazil; CD4 Lymphocyte Count; Cyclohexanes; Drug Resistance, Viral; Enfuvirtide; Follow-Up Studies; Genotyping Techniques; HIV Envelope Protein gp41; HIV Infections; HIV Integrase; HIV Protease; HIV Reverse Transcriptase; HIV-1; Humans; Maraviroc; Mutation; Peptide Fragments; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Salvage Therapy; Treatment Outcome; Triazoles; Viral Load; Virus Replication

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Infant, Newborn; Infant, Premature; Infectious Disease Transmission, Vertical; Placenta; Pregnancy; Pregnancy Complications, Infectious; Prenatal Care; Pyrrolidinones; Raltegravir Potassium

Two integrases inhibitors, raltegravir and elvitegravir, have now been approved by regulatory agencies for use in the treatment of HIV-infected patients; and the approval of a third such drug, dolutegravir, is expected during 2013 on the basis of several phase 3 clinical trials. The advent of this new class of antiretroviral (ARV) medications represents a major advance in the management of HIV infection, and each of these three drugs can be expected to continue to be an important component of ARV combination regimens.

Topics: Clinical Trials as Topic; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Quinolones; Raltegravir Potassium

Drug co-administration often affects the patient response to warfarin through various mechanisms. We describe here five HIV-1-infected patients on treatment with warfarin in whom the use of raltegravir was associated with a favourable outcome.

Topics: Anti-HIV Agents; Anticoagulants; Drug Interactions; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Warfarin

Topics: HIV Infections; HIV Integrase Inhibitors; Humans; Raltegravir Potassium

Drug-resistant virus infection has been a major hurdle in the management of human immunodeficiency virus type 1 (HIV-1) infection. Recently, three novel antiretrovirals [raltegravir (RAL), etravirine (ETR), and darunavir (DRV)] were introduced into the market almost simultaneously, and salvage regimens containing these three antiretrovirals have been reported to exhibit strong potency against drug-resistant HIV-1 infection. However, the sustainability of such regimens remains unclear, particularly for patients infected with multidrug-resistant viruses. Here we report a case of super-multidrug-resistant HIV-1 infection which has been successfully controlled by novel combination therapy including RAL, ETR, and DRV for over 2 years, indicating that the novel combination could become an ultimate weapon against drug-resistant HIV infection and could alter the landscape of HIV salvage therapy.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Male; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Salvage Therapy; Sulfonamides; Viral Load

The objective of this study was to address the evolution of human immunodeficiency virus type 1 (HIV-1) mutations resistant to the integrase inhibitor raltegravir after drug interruption. Thirteen HIV-1 infected patients undergoing virological failure due to the selection of raltegravir-resistant variants, who had interrupted raltegravir treatment, were enrolled. For all patients, the virological failure was associated with the selection of variants, with mutations conferring resistance to all of the drugs present in their regimens. Patients were prospectively monitored at baseline (raltegravir interruption) and every 4-24 weeks for clinical, virological and immunological parameters, including HIV-1 viraemia, CD4(+) T-cell counts, and sequence analysis of the HIV-1 integrase sequence. Reversion to the wild-type HIV-1 integrase sequence genotype was observed between 4 and 36 weeks after raltegravir withdrawal in eight out of the 13 patients. Reversion was not observed in three patients. In two patients, reversion was partial at week 24 from raltegravir interruption. These results highlight that in eight out of 13 patients under treatment with raltegravir and experiencing a virological failure, HIV-1 variants harbouring mutations associated with raltegravir resistance become undetectable after drug interruption within a few weeks (in some cases, very rapidly). This occurs under different therapy regimens and in patients receiving 3TC mono-therapy. In the other patients, complete reversion of the integrase sequence is not observed, and either primary or secondary resistance mutations are fixed in the replication competent viral population in vivo also for long time, suggesting that other factors may influence this dynamic process.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase; HIV-1; Humans; Longitudinal Studies; Male; Middle Aged; Mutation, Missense; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Treatment Failure; Viral Load

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Chagas Disease; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Nitroimidazoles; Oligopeptides; Organophosphonates; Paraguay; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Spain; Tenofovir; Trypanocidal Agents; Zidovudine

The effectiveness of etravirine has not been thoroughly investigated in routine clinical practice, where adherence rates and the heterogeneous nature of patients differ from the clinical trial setting. We evaluated the effectiveness of rescue regimens containing etravirine and the factors associated with treatment response. Multicenter retrospective cohort of all consecutive patients was recruited in a routine clinical practice setting. Patients were taking rescue regimens containing etravirine plus an optimized background regimen. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/ml at week 48. The secondary endpoints were those factors associated with treatment response to etravirine. Endpoints were evaluated using univariate and multivariate analysis. A total of 122 patients were included with a median viral load of 11,938 (1055-55,500) copies/ml at baseline. The most frequent drugs in the backbone were darunavir/ritonavir in 98 (80.3%) patients and raltegravir in 76 (62.3%). In the full dataset analysis, 73% (89/122; 95% CI, 64-81%) of patients responded to treatment at week 48; in the on-treatment analysis, 82% (89/109; 95% CI, 71-87%) responded. The factors associated with treatment failure to etravirine [HR (95% CI)] were baseline CD4(+) T cell count <200 cells/mm(3) [2.45 (1.17-5.16)] and use of raltegravir [0.47 (0.22-0.99)] and darunavir [0.45 (0.21-0.98)] as backbone drugs. Skin rash was the only adverse event directly related to etravirine and led to withdrawal in three patients (2.5%). In routine clinical practice, rescue ETR-containing regimens are well tolerated and achieve rates of virological suppression higher than those observed in its pivotal clinical trials, especially when combined with darunavir and raltegravir.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Darunavir; Exanthema; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Ritonavir; RNA, Viral; Sulfonamides; Treatment Failure; Treatment Outcome; Viral Load

The present study aimed to investigate potential drug interactions between darunavir and raltegravir in patients treated for HIV infection. We enrolled HIV-infected subjects on darunavir-containing regimens that underwent measurement of plasma darunavir trough concentration (12±3 h after dosing). Two groups of patients were compared: those taking darunavir plus a nucleoside/nucleotide backbone (group 1) or a backbone+raltegravir (group 2). Interindividual pharmacokinetic variability was evaluated through the coefficient of variation (CV(inter)). We obtained 156 plasma samples from 63 patients, of which 44 in group 1 and 19 in group 2. Overall, darunavir geometric mean concentration was 2.90 mg/L (95% CI 2.34-3.60) while ritonavir geometric mean concentration was 0.21 mg/L (95% CI 0.17-0.27). We observed a high inter-individual variability in darunavir (CV(inter) 59%) and ritonavir (CV(inter) 103%) plasma levels. Darunavir concentration correlated with concomitant ritonavir levels (r=0.476, p<0.001). Patients in group 1 had a higher darunavir geometric mean concentration than those in group 2 [3.44 mg/L (95% CI 2.79-4.23) versus 1.95 mg/L (95% CI 1.19-3.20), p=0.017]. However, the proportion of subjects with concomitant HIV-RNA <50 copies/mL was higher in group 2 (78.9% versus 47.7%, p=0.028). In a multivariable model, raltegravir co-administration was independently related to a lower darunavir concentration (mean difference -0.25 log(10) mg/L, 95% CI -0.46/-0.04, p=0.020) after adjusting for time from last drug intake and concomitant drugs used. In conclusion, a potential drug interaction between darunavir and raltegravir was observed, although this did not seem virologically significant. For the distinct metabolic pathways of these drugs, its mechanism remains to be determined.

Topics: Adult; Darunavir; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

We studied seven heavily pretreated HIV-2-infected patients exhibiting a virological failure while receiving a salvage raltegravir-containing regimen. At the time of virological failure, different resistance genetic pathways were observed: T97A-Y143C, Q148K, Q148R, G140S-Q148R, E92Q-Y143R-N155H, and T97A-N155H. Thus, despite a 40% difference in integrase genes between HIV-1 and HIV-2, the genetic pathways leading to raltegravir resistance are similar.

Topics: Antiviral Agents; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV-2; Humans; Molecular Sequence Data; Pyrrolidinones; Raltegravir Potassium

Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs.. The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response.. One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1-2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively.. Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Female; HIV Infections; HIV-1; Humans; Logistic Models; Male; Middle Aged; Proportional Hazards Models; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy

The Abbott RealTime HIV-1 viral load assay uses primers and probes targeted to integrase, which is also the target of integrase inhibitors such as raltegravir. Viral loads of 42 raltegravir-susceptible and 40 raltegravir-resistant specimens were determined using RealTime HIV-1 and Roche Monitor (v1.5). The differences in viral load measurements between assays were comparable in the two groups, demonstrating that the RealTime HIV-1 assay can tolerate raltegravir-selected mutations.

Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV-1; Humans; Molecular Diagnostic Techniques; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Reagent Kits, Diagnostic; Sensitivity and Specificity; Viral Load

The emergence of integrase strand-transfer inhibitor (INSTI) resistance-associated mutations was examined in patients with low-level viremia after switching from enfuvirtide to raltegravir in the ANRS 138-Easier trial.. Integrase genes of plasma virus from raltegravir-treated patients in the Easier trial with low-level viremia (50-500 copies/ml) were sequenced to determine INSTI resistance-associated mutations. Baseline viral load, baseline and nadir CD4 cell count, antiretroviral treatment, genotypic susceptibility score, level of viremia and degree of treatment adherence during the study period were also analyzed.. Forty-nine patients experienced at least one episode of low-level viremia while receiving raltegravir; integrase genotyping was successful in samples from 39 individuals (80%). Among them, three [7.7%, 95% confidence interval (CI) 1.6-20.9%] had significant INSTI resistance mutations consisting of N155H in two and P145S in one. Absence of these mutations from proviral DNA at baseline suggested selection of INSTI resistance during episodes of low-level viremia. No specific factors significantly associated with emergence of INSTI resistance mutations during low-level viremia were identified.. Emergence of INSTI resistance mutations can occur during episodes of low-level viremia in patients receiving raltegravir-containing regimens.

Topics: Adult; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Mutation; Pyrrolidinones; Raltegravir Potassium; Viremia

Non-nucleoside reverse transcriptase inhibitors and enfuvirtide are ineffective against HIV-2 replication. These considerations may have particular significance in the formulation of second-line or salvage regimens for HIV-2 infection when resistance or toxicity precludes the use of protease inhibitors (PIs) or specific nucleoside analogues. We describe a case of a treatment-experienced patient with important limitations in therapeutic options dictated by the presence of HIV-2 infection, severe HIV nephropathy (requiring haemodialysis), intolerance to PIs and clinical contraindications to the use of some nucleoside analogues (anaemia, pancreatic toxicity and high cardiovascular risk). A three-drug regimen based on raltegravir, tenofovir disoproxil fumarate and lamivudine was given, with no major toxicity, good immunological response and complete viral suppression. Our case indicates that regimens based on integrase inhibitors could represent an effective alternative in PI-resistant or PI-intolerant patients with HIV-2, and that tenofovir disoproxil fumarate may be used in patients with end-stage renal disease requiring haemodialysis who cannot take other nucleoside analogues because of treatment-limiting adverse effects.

Topics: Adenine; Adult; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV-2; Humans; Kidney Failure, Chronic; Lamivudine; Male; Organophosphonates; Protease Inhibitors; Pyrrolidinones; Raltegravir Potassium; Renal Dialysis; Salvage Therapy; Tenofovir; Treatment Outcome

Topics: Anti-HIV Agents; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Sleep Initiation and Maintenance Disorders

The Department of Health and Human Services (DHHS) HIV treatment guidelines recommend that antiretroviral regimens for treatment-naïve individuals include at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus either (1) a nonnucleoside reverse transcriptase inhibitor (NNRTI), (2) a protease inhibitor (PI), or (3) raltegravir, an integrase strand transfer inhibitor. Differences in drug-drug interaction potential may represent an important differentiating feature when choosing between these regimen types.. To identify risk factors for clinically significant drug-drug interactions (CSDDIs) among patients on NNRTI-, PI-, and raltegravir-based antiretroviral regimens; compare CSDDI risks between these regimen types; and develop a clinical prediction tool for antiretroviral CSDDIs.. In this cross-sectional study, outpatient medical records from the HIV clinic at Albany Medical Center Hospital were randomly selected to review patients' current antiretroviral regimens. Patients treated with NNRTI-, PI-, or raltegravir-based regimens were included. Drug therapies were analyzed for interactions using Lexi-Comp drug interaction software. The CSDDIs were defined as either (1) a drug combination that is contraindicated or accompanied by strong precautions per DHHS antiretroviral guidelines or (2) a drug combination that necessitates a medication dose adjustment.. Of the 500 patient records screened, 229 were included. Baseline characteristics were similar between regimen groups, with the exception of comorbidities. In multivariate analyses, variables independently associated with CSDDIs were use of >5 non-antiretroviral medications (prevalence ratio [PR] 1.86; 95% CI 1.31 to 2.64; p<0.001) and regimen type (NNRTI: PR 2.48, PI: PR 4.96, and raltegravir [referent]: PR 1.00; 95% CI 1.79 to 3.44; p<0.001).. Use of >5 non-antiretroviral medications or a non-raltegravir-based antiretroviral regimen increased the risk of a CSDDI. Our findings help clarify drug interaction risks among NNRTI-, PI-, and raltegravir-based regimen types that should be considered when prescribing antiretroviral therapy.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cross-Sectional Studies; Drug Administration Schedule; Drug Interactions; Drug Resistance, Viral; Female; Forecasting; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Risk Factors

Topics: Adult; Anti-Bacterial Agents; Anti-HIV Agents; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rifampin; Tuberculosis

To evaluate the liver safety of raltegravir-including combinations in HIV/hepatitis C virus (HCV) co-infected patients.. Grade 3-4 transaminase elevations (TEs) and grade 4 total bilirubin elevations (TBEs) were assessed during 12 months in 108 HIV/HCV co-infected patients starting antiretroviral therapy including raltegravir in a retrospective cohort study. Furthermore, the relationship between baseline fibrosis and hepatotoxic events was determined.. Eight patients (7.4%) developed grade 3 TEs and two (1.9%) patients showed grade 4 TEs. TBE grade 4 was detected in two (1.9%) patients. No patient permanently discontinued raltegravir because of hepatotoxic events. Of the patients with and without significant fibrosis, six (9.4%) and two (11.8%), respectively, showed grade 3-4 TEs (P = 0.769). Grade 3-4 TEs was observed in four (9.8%) patients in whom cirrhosis was ruled out, while none of the patients diagnosed with cirrhosis developed grade 3-4 TEs (P = 0.303). During the follow-up, the median (Q1-Q3) CD4 cell count increased from 257 (145-421) cells/mm(3) to 407 (213-587) cells/mm(3) (P < 0.0001) and the number of patients with an undetectable HIV viral load augmented from 33 (30.6%) to 73 (81.1%) (P = 0.002).. Raltegravir-containing regimens are safe in HIV/HCV co-infected patients. The incidence of severe liver toxicity of raltegravir in these individuals is in the range of boosted protease inhibitors in clinical trials. The frequencies of grade 3-4 TEs and grade 4 TBEs were similar in patients receiving raltegravir with or without significant fibrosis or cirrhosis.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bilirubin; Cohort Studies; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Transaminases

Topics: Darunavir; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Dolutegravir (S/GSK1349572) is a second-generation HIV-1 integrase inhibitor (INI) in advanced clinical development. It has shown good antiviral activity in most patients with prior raltegravir failure, although changes at the integrase codon 148, particularly when combined with other mutations, confer reduced susceptibility and may impair dolutegravir activity. Mutations believed to be associated with dolutegravir resistance at positions 92, 101, 124, 148, 153, and 193 were assessed in patients either INI-naïve or experiencing failure to raltegravir-based regimens. The integrase coding region was sequenced using an in-house nested-PCR protocol. HIV-1 subtyping was carried out using the Stanford algorithm. A total of 638 plasma samples were analyzed from 535 INI-naïve and 103 raltegravir-experienced patients. Non-B subtypes were recognized in 20.8% patients. Mutations L101I and T124A were significantly more prevalent in patients with non-B subtypes (66.9% vs. 45.7% for L101I; 61.7% vs. 25.9% for T124A; and 39.1% vs. 12.7% for L101I+T124A; p<0.001 in all cases). E92Q and Q148H/R were only seen in raltegravir-experienced patients and exclusively infected with subtype B (1.9% vs. 0%, p=0.026, for E92Q and 12.6% vs. 0%, p<0.001, for Q148H/R). On the contrary, T124A was more frequent in INI-naïve than raltegravir-experienced patients (35.1% vs. 24.3%, p=0.040). S153Y/F was absent in this dataset. Polymorphic changes L101I and T124A were more frequent in HIV-1 non-B than B subtypes. T124A was more frequent in INI-naïve patients but E92Q and Q148H/R were only seen in raltegravir-experienced individuals. Thus, both HIV-1 subtype and raltegravir exposure may influence the antiviral activity of dolutegravir.

Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

The authors report a case of an HIV type-1-infected patient concomitantly using highly active antiretroviral therapy and acenocoumarol anticoagulant for secondary prevention of recurrent venous thromboembolism. This is the first report of a possible drug interaction between efavirenz and atazanavir/ritonavir with acenocoumarol and also of the uncomplicated concurrent use of raltegravir with acenocoumarol.

Topics: Acenocoumarol; Alkynes; Anti-HIV Agents; Anticoagulants; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Venous Thrombosis

We report the case of an integrase strand-transfer inhibitor (INI)-resistant and four-drug-class-resistant HIV-1 variant infecting an antiretroviral therapy-naive man. The virus harboured INI drug resistance substitutions (Q148H and G140S) along with multiple reverse transcriptase and protease inhibitor resistance mutations. This case illustrates an emerging need to consider the possibility of acquired INI resistance among newly diagnosed treatment-naive individuals harbouring multidrug-resistant HIV-1.

Topics: Anti-HIV Agents; Drug Resistance, Multiple, Viral; Genotype; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors

Here, we describe an HIV-infected patient with pretreatment resistance to raltegravir, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors, and the ultimate ability to achieve viral suppression. Pretreatment integrase resistance testing is not routinely performed because transmitted integrase mutations conferring resistance to raltegravir are currently thought to be negligible. We suggest obtaining a pretreatment integrase genotype in patients with transmitted multiclass drug resistance in order to create an optimal first regimen and increase the chance for virological suppression.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Viral Load

To compare the frequency of previously in vitro-selected integrase mutations (T124A, T124A/S153F, S153Y, T124A/S153Y and L101I/T124A/S153Y) conferring resistance to S/GSK1349572 between HIV-1 subtype B integrase inhibitor (INI)-naive and raltegravir-treated patients.. Integrase sequences from 650 INI-naive patients and 84 raltegravir-treated patients were analysed.. The T124A mutation alone and the combination T124A/L101I were more frequent in raltegravir-failing patients than in INI-naive patients (39.3% versus 24.5%, respectively, P = 0.005 for T124A and 20.2% versus 10.0%, respectively, P = 0.008 for T124A/L101I). The S153Y/F mutations were not detected in any integrase sequence (except for S153F alone, only detected in one INI-naive patient).. T124A and T124A/L101I, more frequent in raltegravir-treated patients, could have some effect on raltegravir response and their presence could play a role in the selection of other mutations conferring S/GSK1349572 resistance. The impact of raltegravir-mediated changes such as these on the virological response to S/GSK1349572 should be studied further.

Topics: Amino Acid Substitution; Anthracenes; Anti-HIV Agents; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV-1; Humans; Mutation, Missense; Oxazines; Piperazines; Prevalence; Pyridones; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA; Viral Proteins

The SnoB study analysed the variability of the integrase (IN) gene of non-B viruses from treatment-naïve patients to determine whether non-B subtypes carry natural resistance mutations to raltegravir (RAL). Plasma viral RNA from 427 patients was gained, and IN sequences were subtyped and screened for subtype-specific highly-variable residues. Seven viruses of different subtypes were phenotypically tested for RAL susceptibility; 359/427 samples could be sequenced. One hundred and seventy samples (47%) were classified as non-B subtypes. No primary RAL resistance-associated mutations (RRAMs) were detected. Certain secondary mutations were found, mostly related to specific non-B subtypes. L74 M was significantly more prevalent in subtype 02_AG, T97A in A and 06_cpx, V151I in 06_cpx, and G163R in 12_BF. Various additional mutations were also detected and could be associated with the subtype too. While K156 N and S230 N were correlated with B subtype, V72I, L74I, T112I, T125A, V201I and T206S were more frequent in certain non-B subtypes. The resistance factors (RF) of 7 viral strains of different subtypes ranged from 1.0 to 1.9. No primary or secondary but subtype-associated additional RRAMs were present. No correlation between RF and additional RRAMs was found. The prevalence of RRAMs was higher in non-B samples. However, the RFs for the analysed non-B subtypes showed lower values to those reported relevant to clinical failure. As the role of baseline secondary and additional mutations on RAL therapy failure is actually not known, baseline IN screening is necessary.

Topics: Adolescent; Adult; Aged; Cell Line, Tumor; Child; Child, Preschool; DNA Mutational Analysis; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Phenotype; Polymorphism, Genetic; Prevalence; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Young Adult

Measurement of drug levels in plasma is currently the gold standard for pharmacological studies. However, venous sampling is not feasible in some populations (e.g., neonates) or may be difficult in certain situations, such as nonhospital-based settings. Dried blood spots (DBS) can be obtained by a simple fingerprick and the subsequent collection of blood on a filter card, allowing patient-friendly sample collection in non-hospital-based settings. Despite these advantages, thus far no clinical evaluation has been performed for the use of DBS concentrations as surrogates for plasma levels. Our purpose was to clinically evaluate DBS sampling for the determination of plasma concentrations for the novel antiretroviral drugs etravirine, darunavir/ritonavir and raltegravir.. DBS concentrations were measured in 11 HIV-infected patients using LC-MS/MS. DBS concentrations were proportional to plasma concentrations. All drug concentrations were higher in DBS than in plasma samples. The plasma:DBS ratio and the respective relative standard error of estimate (RSE) of darunavir, etravirine, raltegravir and ritonavir were 0.632 (4.97% RSE), 0.523 (4.84% RSE), 0.617 (14.9% RSE) and 0.592 (2.99% RSE), respectively. Hematocrit did not explain variability in our study.. DBS are reproducibly correlated to plasma levels and can be used for monitoring antiretroviral drug exposure in HIV-infected patients.

Topics: Blood Specimen Collection; Chromatography, High Pressure Liquid; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Male; Mass Spectrometry; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects.. In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%.. 7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir.. In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Female; Genotype; High-Throughput Nucleotide Sequencing; HIV Infections; HIV-1; Humans; Male; Mutation; Pyridines; Pyrones; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sulfonamides; Treatment Failure

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Long-Term Care; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic

CD4(+) T cells and macrophages are the primary target cells for HIV in vivo, and antiretroviral drugs can vary in their ability to inhibit the infection of these different cell types. Resistance pathways to the HIV integrase inhibitor raltegravir have previously been investigated in T cells. Primary raltegravir resistance mutations, most often at integrase amino acid position 148 or 155, afford some resistance to the drug. The acquisition of pathway-specific secondary mutations then provides higher-level resistance to viruses infecting T cells. We show here that during macrophage infection, the presence of a single primary raltegravir resistance mutation (Q148H, Q148R, N155H, or N155S) is sufficient to provide resistance to raltegravir comparable to that seen in viruses expressing both primary and secondary mutations in costimulated CD4(+) T cells. These data implicate macrophages as a potential in vivo reservoir that may facilitate the development of resistance to raltegravir. Notably, the newer integrase inhibitor MK-2048 effectively suppressed the infection of all raltegravir-resistant viruses in both T cells and macrophages, indicating that more recently developed integrase inhibitors are capable of inhibiting infection in both major HIV cellular reservoirs, even in patients harboring raltegravir-resistant viruses.

Topics: Alkynes; Benzoxazines; CD4-Positive T-Lymphocytes; Cells, Cultured; Cyclopropanes; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Macrophages; Mutation; Pyrrolidinones; Raltegravir Potassium; Zidovudine

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cyclohexanes; Female; HIV Infections; Humans; Male; Maraviroc; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Triazoles

Topics: Adult; Anti-Retroviral Agents; Darunavir; Hemodiafiltration; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Treatment Outcome

Adequate antiretroviral therapy is essential for HIV-positive pregnant women to prevent mother-to-child transmission. We report a small case series of five women receiving raltegravir as part of their antiretroviral regimen during pregnancy.

Topics: Adult; Anti-Retroviral Agents; Chemoprevention; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Treatment Outcome

Our objective was to analyze the pathways leading to resistance of HIV to the integrase (IN) inhibitor raltegravir (RAL).. Three HIV-infected individuals exhibiting RAL resistance pathway switching were characterized using longitudinal analysis of viral samples from plasma.. 454/Roche pyrosequencing was used to generate approximately 74,000 sequence reads from the integrase coding region. Effects of error were controlled by denoising with Pyronoise, and by comparison to approximately 142,000 control reads from HIV(NL4-3). Viral lineages were modeled quantitatively using viral serial pathway analysis (vSPA).. All three patients showed transitions from the N155H pathway to the Q148H/G140S pathway. Analysis with vSPA revealed complex pathways to the final genotype, probably involving both de-novo mutation and recombination. No reads contained both the N155H and Q148H drug resistance mutations (DRMs), indicating that the double mutant is not a prominent intermediate, consistent with low fitness. To characterize possible drug-resistant variants circulating prior to therapy, we sequenced approximately 70,000 reads from samples collected prior to initiating treatment. Although some preexisting drug-resistant variants were detected, N155H, the first major DRM present after initiating RAL therapy, was not detected.. The main DRMs are present at very low levels if at all prior to initiating therapy. We also outline general methods for deep sequence analysis of DRMs in longitudinal HIV samples.

Topics: Algorithms; Drug Resistance, Viral; Female; Genotype; High-Throughput Nucleotide Sequencing; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Longitudinal Studies; Male; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, RNA

Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). In recent years our research group has been engaged in the stucture-function study of this enzyme and in the development of some three-dimensional pharmacophore models which have led to the identification of a large series of potent HIV-1 integrase strand-transfer inhibitors (INSTIs) bearing an indole core. To gain a better understanding of the structure-activity relationships (SARs), herein we report the design and microwave-assisted synthesis of a novel series of 1-H-benzylindole derivatives.

Topics: Green Chemistry Technology; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Indoles; Kinetics; Magnetic Resonance Spectroscopy; Microwaves; Models, Molecular; Molecular Structure; Pyrrolidinones; Quinolones; Raltegravir Potassium; Small Molecule Libraries; Structure-Activity Relationship

HIV-2 is endemic in West Africa and has spread throughout Europe. However, the alternatives for HIV-2-infected patients are more limited than for HIV-1. Raltegravir, an integrase inhibitor, is active against wild-type HIV-2, with a susceptibility to this drug similar to that of HIV-1, and is therefore a promising option for use in the treatment of HIV-2-infected patients. Recent studies have shown that HIV-2 resistance to raltegravir involves one of three resistance mutations, N155H, Q148R/H and Y143C, previously identified as resistance determinants in the HIV-1 integrase coding sequence. The resistance of HIV-1 IN has been confirmed in vitro for mutated enzymes harboring these mutations, but no such confirmation has yet been obtained for HIV-2.. The integrase coding sequence was amplified from plasma samples collected from ten patients infected with HIV-2 viruses, of whom three RAL-naïve and seven on RAL-based treatment at the time of virological failure. The genomes of the resistant strains were cloned and three patterns involving N155H, G140S/Q148R or Y143C mutations were identified. Study of the susceptibility of integrases, either amplified from clinical isolates or obtained by mutagenesis demonstrated that mutations at positions 155 and 148 render the integrase resistant to RAL. The G140S mutation conferred little resistance, but compensated for the catalytic defect due to the Q148R mutation. Conversely, Y143C alone did not confer resistance to RAL unless E92Q is also present. Furthermore, the introduction of the Y143C mutation into the N155H resistant background decreased the resistance level of enzymes containing the N155H mutation.. This study confirms that HIV-2 resistance to RAL is due to the N155H, G140S/Q148R or E92Q/Y143C mutations. The N155H and G140S/Q148R mutations make similar contributions to resistance in both HIV-1 and HIV-2, but Y143C is not sufficient to account for the resistance of HIV-2 genomes harboring this mutation. For Y143C to confer resistance in vitro, it must be accompanied by E92Q, which therefore plays a more important role in the HIV-2 context than in the HIV-1 context. Finally, the Y143C mutation counteracts the resistance conferred by the N155H mutation, probably accounting for the lack of detection of these mutations together in a single genome.

Topics: Amino Acid Motifs; Amino Acid Sequence; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-2; Humans; Molecular Sequence Data; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium

Eradication of HIV-1 is prevented by the formation of viral reservoirs in peripheral blood, lymphoid tissues and other sanctuary sites. In most patients, rebound upon treatment cessation is prompt. We assessed whether early treatment with raltegravir can impact on the formation of the viral reservoir.. We conducted an open-label, nonrandomized study, and assessed in detail the decay characteristics of HIV-1 RNA in plasma, HIV DNA in CD4 T cells and colon tissue biopies (CTBs) in 16 treatment-naive patients during either primary (PHI, n = 8) or chronic (CHI, n = 8) HIV-1 infection after treatment with raltegravir and Truvada for 52 weeks.. HIV-1 RNA decreased rapidly with treatment in all patients; first and second phase levels were lower in PHI patients with no appreciable difference in residual viremia between the two groups at 52 weeks. Episomal HIV-1 DNA increased sharply in both groups with peak levels at 3-4 weeks. Total HIV-1 DNA levels were reduced in both groups with similar kinetics, but were markedly lower in PHI patients after 52 weeks. Integrated HIV-1 DNA levels were significantly lower at baseline in PHI patients and this difference widened on treatment. Finally, total HIV-1 DNA decayed substantially in both groups in CTB.. Treatment with raltegravir resulted in a large number of abrogated integration events, reflected by the increase of episomal HIV-1 DNA after treatment initiation. Levels of total and integrated HIV-1 DNA were lower in PHI patients at the end of the study period.

Topics: Adult; Anti-HIV Agents; Australia; CD4 Lymphocyte Count; Colon; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pilot Projects; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Sequence Analysis, RNA; Viral Load; Virus Latency; Virus Replication

Raltegravir is the first approved antiretroviral able to prevent HIV genome integration into the host chromosomes. The aim of the study is to test if raltegravir plasma concentrations can be associated with proviral DNA decline during raltegravir-based salvage therapy.. A total of 33 multidrug-resistant HIV-infected patients were enrolled in a longitudinal open-label pilot study and completed a 24-week follow-up. The CD4(+) T-cell count, plasma viral load, proviral HIV DNA and two-long-terminal repeat (2-LTR) circular forms were assessed at baseline, day 14, 30, 60, 90 and 180. The raltegravir trough concentration (C (trough)) was measured by HPLC-ultraviolet and patients were divided into two groups according to the median raltegravir C (trough).. The mean±SD values of baseline HIV RNA, CD4(+) T-cell count and HIV DNA were 4.4±0.82 log copies/ml, 256±177 cells/mm(3) , and 2,668±4,721 copies/10(6) peripheral blood mononuclear cells, respectively. Despite a transient increase of total DNA at week 2, a marked proviral DNA decay (P=0.01) with an increase of the 2-LTR unintegrated/total DNA ratio (P=0.06) over time was observed. At univariate analysis, no correlation between raltegravir C(trough) and classical virological parameters was observed. Nevertheless, the decay of proviral HIV DNA was more pronounced in patients displaying C(trough)<158 ng/ml with respect to those with C(trough)>158 ng/ml (P=0.046).. Successful raltegravir-based therapy produces a significant decline in proviral DNA and is associated with an increase of the unintegrated/total DNA ratio. Further studies are necessary to define the possible role of pharmacokinetic raltegravir monitoring and the biological meaning of unintegrated proviral DNA.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Proviruses; Pyrrolidinones; Raltegravir Potassium; Viral Load; Virus Integration

Little is known in HIV-2 infection about the kinetics of disappearance of raltegravir (RAL)-resistant virus after RAL withdrawal.. RAL was interrupted in four highly antiretroviral-experienced HIV-2-infected patients exhibiting a virological failure when receiving RAL. Integrase gene was sequenced from plasma samples collected at the time of RAL failure and at further time points following RAL withdrawal.. At the time of RAL withdrawal, virus exhibited different integrase resistance pathways: G140S/Q148R, E92Q/N155H, T97A/N155H and T97A/Y143C. In patient 1, the G140S/Q148R double-mutant was still detected at month (M)7 and at M11 after stopping RAL, but was no longer detected at M15. Regarding patient 2, the double-mutant E92Q/N155H was still present at M2 and M8 after stopping RAL, and was no longer detected at M12. In patient 3, RAL-resistant virus with T97A/N155H mutations were still present 1 month after stopping RAL, and were no longer detected at M14. Regarding patient 4, the mutant T97A/Y143C was still detected at M1 and M3 following RAL withdrawal. At M18 after RAL stop, integrase genotypic pattern evolved to T97A/Y143G.. Persistence of HIV-2 RAL-resistant mutants was observed in all the key genetic RAL resistance pathways. These findings have clinical implications especially in HIV-2-infected patients for whom therapeutic arsenal is limited compared to HIV-1, since the persistence of resistant mutants might compromise the possible efficacy of upcoming second-generation integrase inhibitors.

Topics: Drug Resistance, Viral; Follow-Up Studies; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV Reverse Transcriptase; HIV-2; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Viral Load; Withholding Treatment

Topics: Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium

Most of the previous studies that explored the molecular basis of raltegravir resistance were conducted studying the HIV-1 B subtype. It has been shown that the CRF02_AG subtype in relation to its natural integrase (IN) sequence could develop different genetic pathways associated with raltegravir resistance. The aim of this study was to explore resistance pathways preferably used by CRF02_AG viruses compared with subtype B.. Twenty-five HIV-1 CRF02_AG-infected patients failing a raltegravir-containing regimen were studied. IN gene sequences were examined for the presence of previously described IN inhibitor (raltegravir, elvitegravir, dolutegravir and MK-2048) resistance mutations at 20 amino acid positions.. Among the 25 studied patients, 7 showed viruses harbouring major raltegravir resistance mutations mainly associated with the 155 genetic pathways and 18 showed viruses harbouring none of them; however, for 1 patient, we found a 118R mutation, associated with MK-2048 in vitro resistance, in a 74M background. For this patient, the phenotypic analysis showed that addition of only the G118R mutation conferred a high level of resistance to raltegravir (fold change = 25.5) and elvitegravir (fold change = 9.2).. This study confirmed that mutation pathways for raltegravir resistance could be different between the two subtypes CRF02_AG and B with a preferential use of the 155 mutation in non-B subtypes. A new genetic pathway associated with raltegravir resistance, including the 118R mutation, has also been identified. This new genetic pathway, never described in subtype B, should be further evaluated for phenotypic susceptibility to dolutegravir and MK-2048.

Topics: Amino Acid Substitution; Anti-HIV Agents; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV-1; Humans; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Sequence Analysis, DNA; Treatment Failure

Raltegravir is the first integrase strand transfer inhibitor approved for treating HIV-1 infection. Although emerging data suggest that raltegravir may also be useful for HIV-2 treatment, studies addressing the in-vitro susceptibility of HIV-2 to raltegravir are scarce, and the genetic pathways leading to raltegravir resistance in HIV-2 have not been adequately characterized. Our objectives were to directly compare the susceptibilities of HIV-1 and HIV-2 to raltegravir and to examine the role of mutations in HIV-2 integrase in emergent raltegravir resistance.. Single-cycle and spreading infection assays were used to quantify the sensitivities of wild-type HIV-1 and HIV-2 strains to raltegravir. HIV-2 integrase mutants were constructed by site-directed mutagenesis, and the replication capacities and raltegravir susceptibilities of the resultant variants were analyzed in single-cycle assays.. Raltegravir showed comparable activity against wild-type HIV-1 and HIV-2 in both single-cycle and spreading infections, with EC(50) values in the low nanomolar range. Amino acid changes Q148R and N155H individually conferred resistance to raltegravir (14-fold and seven-fold, respectively), whereas the Y143C replacement had no statistically significant effect on raltegravir sensitivity. The combination of Q148R with N155H resulted in high-level raltegravir resistance (>1000-fold). In addition, all HIV-2 integrase variants tested showed impairments in replication capacity.. Our data support clinical studies of raltegravir for treating HIV-2 infection and show that the Q148R and N155H changes alone are sufficient for raltegravir resistance in HIV-2. Further efforts are needed to improve access to HIV-2-active antiretrovirals, including raltegravir, in resource-limited areas where HIV-2 is endemic.

Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; HIV-2; Humans; Mutagenesis, Site-Directed; Pyrrolidinones; Raltegravir Potassium

A HIV positive patient who received a cadaveric renal transplantation developed tacrolimus toxicity as manifest by renal failure and decreased consciousness. This was due to atazanavir and ritonavir therapy for her HIV inhibiting the CYP3A4 hepatic enzyme resulting in accumulation of tacrolimus. Her HIV treatment was switched to raltegravir which is metabolized by UGT1A1 which does not affect tacrolimus. Tacrolimus was then reintroduced, and follow-up at 1 year demonstrated successful immunosuppression and undetectable HIV viral loads.

Topics: Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Tacrolimus

Novel integrase inhibitors are in advanced clinical development, and cross-resistance data are needed to consider the possibility to plan a sequential usage within this class of antiretroviral drugs. Ex vivo phenotypic assays were conducted on 11 wild-type and 27 fully replicating recombinant viruses obtained from 11 patients failing previous raltegravir-containing regimens. Dolutegravir maintained its activity in vitro on viruses with mutations in position 143 and 155. However, viruses with mutation Q148R associated with secondary mutations and the combination Q148H+G140S were instead associated with a reduced level of susceptibility to dolutegravir in vitro.

Topics: Amino Acid Substitution; Anti-HIV Agents; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Mutation; Oxazines; Phenotype; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium

The pharmacokinetic interaction of etravirine and raltegravir is reviewed, with discussion of implications for clinical practice.. Etravirine (a second-generation nonnucleoside reverse transcriptase inhibitor) and raltegravir (an integrase strand- transfer inhibitor) are two agents approved by the Federal Food and Drug Administration for use in human immunodeficiency virus (HIV) treatment-resistant patients. Minimal data exist on the concurrent use of raltegravir with etravirine. This combination would offer treatment-experienced HIV patients a novel pharmacotherapy plan including two new fully active agents. Etravirine induces uridine diphosphate- glucuronosyltransferase 1A1 and reduces the raltegravir minimum concentration (C(min)) by 34% when administered concurrently in healthy volunteers. In a case series of four HIV treatment-resistant patients initiated on an antiretroviral regimen including standard doses of etravirine and raltegravir, poor virological control was demonstrated. Two of these four patients had a raltegravir C(min) below the 95% minimum inhibitory concentration. In a larger study (n = 103), sustained virological control (viral loads of <50 copies/mL) resulted when HIV treatment-resistant patients received standard doses of darunavir, ritonavir, etravirine, raltegravir, and nucleoside analogs with or without enfuvirtide. Debate exists regarding the best raltegravir pharmacokinetic parameter to evaluate (C(min) or the area under the concentration curve/50% effective concentration). Recent data in HIV treatment-naive patients support a negative association between a low raltegravir C(min) (≤43 ng/mL) and virological suppression.. The need to adjust the dosage of raltegravir in HIV-infected patients who are also receiving etravirine is unclear. In such patients who have an extensive history of HIV disease treatment, prescribing raltegravir 1200 mg/day, rather than the standard 800 mg/day, may be prudent to prevent the development of treatment-resistant virus and to achieve an optimal virological response.

Topics: Anti-HIV Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Glucuronosyltransferase; HIV Infections; HIV Integrase Inhibitors; Humans; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Viral Load

In order to design strategies for eradication of HIV-1 from infected individuals, detailed insight into the HIV-1 reservoirs that persist in patients on suppressive antiretroviral therapy (ART) is required. In this regard, most studies have focused on integrated (proviral) HIV-1 DNA forms in cells circulating in blood. However, the majority of proviral DNA is replication-defective and archival, and as such, has limited ability to reveal the dynamics of the viral population that persists in patients on suppressive ART. In contrast, extrachromosomal (episomal) viral DNA is labile and as a consequence is a better surrogate for recent infection events and is able to inform on the extent to which residual replication contributes to viral reservoir maintenance. To gain insight into the diversity and compartmentalization of HIV-1 under suppressive ART, we extensively analyzed longitudinal peripheral blood mononuclear cells (PBMC) samples by deep sequencing of episomal and integrated HIV-1 DNA from patients undergoing raltegravir intensification. Reverse-transcriptase genes selectively amplified from episomal and proviral HIV-1 DNA were analyzed by deep sequencing 0, 2, 4, 12, 24 and 48 weeks after raltegravir intensification. We used maximum likelihood phylogenies and statistical tests (AMOVA and Slatkin-Maddison (SM)) in order to determine molecular compartmentalization. We observed low molecular variance (mean variability ≤0.042). Although phylogenies showed that both DNA forms were intermingled within the phylogenetic tree, we found a statistically significant compartmentalization between episomal and proviral DNA samples (P<10(-6) AMOVA test; P = 0.001 SM test), suggesting that they belong to different viral populations. In addition, longitudinal analysis of episomal and proviral DNA by phylogeny and AMOVA showed signs of non-chronological temporal compartmentalization (all comparisons P<10(-6)) suggesting that episomal and proviral DNA forms originated from different anatomical compartments. Collectively, this suggests the presence of a chronic viral reservoir in which there is stochastic release of infectious virus and in which there are limited rounds of de novo infection. This could be explained by the existence of different reservoirs with unique pharmacological accessibility properties, which will require strategies that improve drug penetration/retention within these reservoirs in order to minimise maintenance of the viral reservoir by de novo infecti

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Disease Reservoirs; DNA, Circular; DNA, Viral; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Leukocytes, Mononuclear; Phylogeny; Plasmids; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA; Viral Load

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV Protease Inhibitors; HIV-2; Humans; Lopinavir; Male; Middle Aged; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Salvage Therapy; Tenofovir; Treatment Outcome; Viral Load

In the modern era of highly active antiretroviral therapy (HAART), reluctance to perform transplantation (Tx) in HIV-infected individuals is no longer justified. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs), the current first line regimens of HAART, are metabolized by the cytochrome P450 family (CYP3A4). Most NNRTIs induce CYP3A4, whereas PIs inhibit it. Calcinuerin inhibitors (CNIs), which are mandatory for Tx, need the same enzyme complex for their clearance. Therefore, a significant drug-drug interaction (DDI) is encountered between current HAART and CNIs. This results in extreme difficulty in adjusting the optimal dose of CNIs, for which the therapeutic range is narrow. Of interest, integrase inhibitors (INIs) - novel, potent anti-HIV drugs - are mainly metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and do not induce or inhibit CYP3A4. DDI is presumably absent when NNTRIs or PIs are replaced by INIs. Raltegravir (RAL), a first generation INI, has been introduced into kidney and liver Tx. There is increasing evidence that rejection is well controlled without renal impairment due to CNI over-exposure while persistent, robust suppression of HIV is achieved. Global phase III clinical trials of dolutegravir (DTG), a second generation INI, are currently in progress. In vitro data has suggested that DTG may be less prone to resistance than RAL (referred to as having a higher genetic barrier). The time has come to extensively discuss the implications of INIs in Tx for HIV positive patients.

Topics: Antiretroviral Therapy, Highly Active; Calcineurin; Calcineurin Inhibitors; Clinical Trials as Topic; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Integrase Inhibitors; Oxazines; Piperazines; Pyridones; Pyrrolidinones; Raltegravir Potassium; Transplantation

: Resistance to raltegravir is associated with three genetic pathways defined by the mutations Y143R/C, Q148H/R/K or N155H in integrase, which also infer a viral fitness cost. Additionally, the three major HIV-1 drug-targeted enzymes protease, reverse transcriptase and integrase mature from the same polyprotein, suggesting the potential for interaction between them. This study aims to elucidate the relative contribution of protease-reverse transcriptase, integrase and the rest of the HIV-1 genome to viral fitness and susceptibility to raltegravir.. : Recombinant viruses included integrase, protease-reverse transcriptase or the complete pol-coding region from three patients whose raltegravir-containing regimen had failed. The first had the mutations G140S+Q148H+S230N, the second had Y143R+G163R and the third had no evidence of genotypic resistance in integrase. Primary virus isolates were obtained from peripheral blood mononuclear cells. In-vitro phenotypic resistance and changes in replication capacity were assessed.. : Virus isolates, and integrase-recombinant and pol-recombinant viruses from the patients harboring integrase resistance mutations showed a decrease in raltegravir susceptibility, with no differences between them. Defects in viral fitness were modulated by resistance mutations within protease, reverse transcriptase and integrase, which were further compensated by regions outside pol. Moreover, protease-reverse transcriptase rescued replication capacity of viruses containing integrase resistance mutations, although integrase was unable to compensate defects in replication capacity caused by protease-reverse transcriptase resistance mutations.. : Susceptibility to raltegravir is driven by resistance mutations in integrase, whereas other viral genes are involved in restoring defects in viral fitness in patients whose raltegravir-containing regimen fails, suggesting the existence of epistatic effects on replication capacity.

Topics: Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium; Virus Replication

Raltegravir (RAL) achieved remarkable virologic suppression rates in randomized-clinical trials, but today efficacy data and factors for treatment failures in a routine clinical care setting are limited.. First, factors associated with a switch to RAL were identified with a logistic regression including patients from the Swiss HIV Cohort Study with a history of 3 class failure (n = 423). Second, predictors for virologic outcome were identified in an intent-to-treat analysis including all patients who received RAL. Last observation carried forward imputation was used to determine week 24 response rate (HIV-1 RNA >or= 50 copies/mL).. The predominant factor associated with a switch to RAL in patients with suppressed baseline RNA was a regimen containing enfuvirtide [odds ratio 41.9 (95% confidence interval: 11.6-151.6)]. Efficacy analysis showed an overall response rate of 80.9% (152/188), whereas 71.8% (84/117) and 95.8% (68/71) showed viral suppression when stratified for detectable and undetectable RNA at baseline, respectively. Overall CD4 cell counts increased significantly by 42 cells/microL (P < 0.001). Characteristics of failures were a genotypic sensitivity score of the background regimen

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load

Integrase (IN), the HIV-1 enzyme responsible for the integration of the viral genome into the chromosomes of infected cells, is the target of the recently approved antiviral raltegravir (RAL). Despite this drug's activity against viruses resistant to other antiretrovirals, failures of raltegravir therapy were observed, in association with the emergence of resistance due to mutations in the integrase coding region. Two pathways involving primary mutations on residues N155 and Q148 have been characterized. It was suggested that mutations at residue Y143 might constitute a third primary pathway for resistance. The aims of this study were to investigate the susceptibility of HIV-1 Y143R/C mutants to raltegravir and to determine the effects of these mutations on the IN-mediated reactions. Our observations demonstrate that Y143R/C mutants are strongly impaired for both of these activities in vitro. However, Y143R/C activity can be kinetically restored, thereby reproducing the effect of the secondary G140S mutation that rescues the defect associated with the Q148R/H mutants. A molecular modeling study confirmed that Y143R/C mutations play a role similar to that determined for Q148R/H mutations. In the viral replicative context, this defect leads to a partial block of integration responsible for a weak replicative capacity. Nevertheless, the Y143 mutant presented a high level of resistance to raltegravir. Furthermore, the 50% effective concentration (EC(50)) determined for Y143R/C mutants was significantly higher than that obtained with G140S/Q148R mutants. Altogether our results not only show that the mutation at position Y143 is one of the mechanisms conferring resistance to RAL but also explain the delayed emergence of this mutation.

Topics: Anisotropy; Cell Line; DNA, Viral; Drug Resistance, Viral; HeLa Cells; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Models, Molecular; Mutation; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction

We created an HIV-1 cloning vector, pNL4.3DeltaIN, to generate recombinant infectious molecular clones for analysis of patient-derived HIV-1 integrase coding regions. Using this vector, we constructed a panel of clinically derived viruses with the canonical patterns of raltegravir resistance mutations and submitted the panel to the NIH AIDS Research and Reference Reagent Program. Investigational integrase inhibitors with activity against these clones are likely to retain activity against the most clinically relevant raltegravir-resistant variants.

Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Sequence Data; Mutation; Pyrrolidinones; Raltegravir Potassium

The emergence of drug-resistance mutations in HIV-1 integrase of patients receiving HAART salvage regimens including raltegravir was investigated in 11 heavily pretreated patients (median number of treatment failures 12, range 5-22) within an expanded access program in Pavia, Italy. HIV-1 RNA levels in plasma, CD4(+) T-cell counts and sequencing of HIV-1 reverse transcriptase (RT), protease (PR), gp41, and integrase genes were performed at baseline and after 1, 2, 3, 6, and 12 months. The treatment baseline median HIV-1 RNA levels in plasma decreased from 7,510 (range 118-407,107) to <50 copies/ml (range <50-7,562), while median CD4(+) T-cell counts remained unchanged (from 212 cells/microl, range 10-764 to 262 cells/microl, range 13-760). Mutations at positions involved in raltegravir resistance (E92G, G140S, Q148H, and N155H) were detected in 4 of 11 (36.3%) patients as early as 1 month after initiating salvage HAART. Of note, the E --> G change at codon 92 was not reported previously. In two patients with raltegravir resistance, the simultaneous appearance of additional mutations (Y143R and E170A) with an unclear impact on susceptibility to raltegravir or on integrase activity was observed. It is concluded that raltegravir resistant HIV-1 strains may emerge as early as 1 month after initiating HAART salvage regimens. A new mutation associated with the emergence of raltegravir resistance is described, and the simultaneous appearance of primary and secondary mutations was observed. The effect of single and multiple mutations on integrase activity, raltegravir susceptibility, and on the capacity of viral replication remains to be elucidated.

Topics: Adult; Amino Acid Sequence; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sequence Alignment; Time Factors

Topics: Hemophilia A; Hepatitis; HIV Infections; Humans; Middle Aged; Peritonitis; Pyrrolidinones; Radiography; Raltegravir Potassium

Patients with chronic hepatitis C virus (HCV) infection experience antiretroviral-associated liver toxicity more frequently than HIV mono-infected persons. Herein, we report the hepatic safety profile of raltegravir in a relatively large group of HIV/HCV co-infected patients, a population that was poorly represented in the registrational studies.. Prospective, observational study of all antiretroviral-experienced HIV-infected patients who initiated raltegravir from January 2006 to January 2009 at a reference HIV clinic. Clinical data, laboratory parameters and liver stiffness measured at baseline, week 4 and every 3 months thereafter were collected. Chronic hepatitis C was defined as positive serum HCV-RNA. Grade 1-4 hepatotoxicity was defined following the AIDS Clinical Trials Group definition for liver enzyme elevations (LEEs). A control group of patients who initiated protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) was examined similarly.. Data from 218 HIV-infected patients on raltegravir were analysed, 126 HIV mono-infected and 92 HIV/HCV co-infected patients. Any degree of LEEs occurred in 10 (7.9%) HIV mono-infected and 23 (25%) co-infected patients (relative risk 3.1; 95% confidence interval 2.9-3.4; P = 0.002). Severe hepatotoxicity (grade 3-4), however, was only seen in 3 (1.4%) patients, all co-infected with HCV. It occurred at months 1, 15 and 15, respectively. In all three subjects other reasons than raltegravir exposure most likely explained LEEs. Multivariate analysis revealed HCV co-infection as the only independent variable associated with any degree of hepatotoxicity on raltegravir (P = 0.03). Finally, the rate of LEEs in patients on raltegravir was lower than in those who were treated with PIs or NNRTIs.. LEEs are less frequent in patients treated with raltegravir than with other antiretroviral drug classes. However, HIV/HCV co-infected patients treated with raltegravir experienced LEEs more frequently than HIV mono-infected persons. In this series, LEEs in patients treated with raltegravir were uniformly mild and no cases of grade 3-4 hepatotoxicity could be directly attributed to the drug. These results reinforce the overall hepatic safety profile of raltegravir.

Topics: Adult; Anti-HIV Agents; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver; Liver Function Tests; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Severity of Illness Index

Our aim was to analyse the evolution of HIV-1 2-long terminal repeat (2-LTR) circular DNA in vitro and ex vivo in the presence of raltegravir.. Twenty-five patients starting a raltegravir-based regimen were included. Total HIV-1 DNA and 2-LTR DNA were quantified at baseline and in follow-up samples up to month 12. The effect of raltegravir on the formation of 2-LTR circles was evaluated in HeLa P4 cells. The effect of raltegravir was also investigated by sequence analysis of the 2-LTR circle junctions.. Among 21 patients with undetectable 2-LTR DNA at baseline, 7 had detectable 2-LTR DNA during the follow-up. Three of four patients with detectable 2-LTR DNA at baseline had undetectable 2-LTR DNA during the follow-up (P = 0.27). The mean 2-LTR level increased significantly (+0.07 log(10)/month, P = 0.02) in raltegravir-treated patients, and a 2-LTR increase was also observed in raltegravir-treated HeLa P4 cells, with a peak at 3 days post-infection. 2-LTR DNA showed a high prevalence of deletions ex vivo (64.5%) and in vitro (50%) in the presence of raltegravir, which was not statistically different from the prevalence in untreated patients or cells.. In antiretroviral-experienced patients receiving raltegravir, 2-LTR DNA increased while total HIV-1 DNA decreased over time. The frequent rearrangements found in 2-LTR sequences warrant further investigations to determine the dynamics of evolution of unintegrated HIV-1 DNA.

Topics: Anti-HIV Agents; DNA, Circular; DNA, Viral; Evolution, Molecular; HeLa Cells; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; In Vitro Techniques; Plasmids; Pyrrolidinones; Raltegravir Potassium; Recombination, Genetic; Sequence Analysis, DNA; Viral Load

To understand the dynamic viral evolution observed during failure on raltegravir-containing regimens, we studied the genotypic and phenotypic patterns of resistance to raltegravir and the residual replication capacity (rRC) of HIV-1 variants selected in vivo.. Clonal genotypic analyses were performed on sequential HIV-1 integrase sequences amplified from 11 failing patients and sampled every 4-24 weeks for up to 64 weeks. Fully replicating recombinant viruses were generated using modified vectors in which selected viral integrase genes amplified from patients' plasma were cloned. rRC was measured by a novel multiple cycle competition assay. Resistance to raltegravir and the rRC of resistant HIV-1 variants selected in vivo were evaluated in purified CD4+ T cells.. In all of the patients but one, failure was associated with selection of mutations in positions 143, 148 or 155. Unlike mutations at position 143 (Y143S/K/R), identified alone or in combination with others, mutations at position 148 and 155 were always found in combination. A wide range of resistance levels to raltegravir [from 10- to 770-fold change in 50% inhibitory concentration (IC(50)) compared with baseline] was observed using recombinant viral clones. Finally, rRC was not significantly altered in highly resistant variants.. Two patterns of viral evolution were observed in the resistant viral populations, driving the variants towards a fast (most of them with G140S + Q148H mutations) or progressive increase in resistance to raltegravir. These results may have implications either for the evaluation of genotypic results, or for the correct clinical use of the compound.

Topics: Amino Acid Substitution; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Cells, Cultured; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV-1; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Mutation, Missense; Phenotype; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA; Virus Replication

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; HIV; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Viral Load

* Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV-1 integrase inhibitor. * Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs. * As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them.. * Relative to individual monotherapy, co-administration resulted in a 20% and 33% decrease in mean C(max), and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively. * Co-administration was generally safe and well tolerated in healthy subjects. * These changes are not likely to be clinically relevant, thus no dose adjustment is necessary.. To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir.. In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1-3 raltegravir 400 mg q12h, days 4-5 washout, days 6-11 maraviroc 300 mg q12h, and days 12-14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters.. For maraviroc, the test/reference % ratio (95% CI) for AUC(tau) was 85.8 (78.7, 93.5), for C(max) was 79.5 (64.8, 97.5) and for C(min) was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC(tau) was 63.3 (41.0, 97.6), for C(max) was 66.8 (37.1, 120.0) and for C(min) was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC(tau) divided by 12) were >100 ng ml(-1), the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C(min) decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance.. Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.

Topics: Adult; Area Under Curve; Chromatography, Liquid; Cyclohexanes; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; HIV Fusion Inhibitors; HIV Infections; HIV Seronegativity; Humans; Male; Maraviroc; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Tandem Mass Spectrometry; Triazoles

In patients with virological failure during highly active antiretroviral therapy (HAART) and drug resistance, guidelines recommend the achievement of maximal virological suppression by the use of a new regimen with at least 2 active drugs. We describe the clinical outcome of a heavily antiretroviral-experienced patient who experienced early failure to raltegravir.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Treatment Failure

Topics: Aged; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Rhabdomyolysis

Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short-course (28-day) intensification of standard antiretroviral combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma HIV-1 RNA levels in patients receiving suppressive antiretroviral therapy.. Subjects (n = 10) with long-term HIV-1 suppression receiving combination antiretroviral regimens had their regimens intensified for 4 weeks with raltegravir. Plasma HIV-1 RNA level was determined before, during, and after the 4-week intensification period, using a sensitive assay (limit of detection, 0.2 copies of HIV-1 RNA/mL of plasma). A 4-week intensification course was chosen to investigate potential HIV-1 replication in cells with relatively short (approximately 1-14-day) half-lives.. There was no evidence in any subject of a decline in HIV-1 RNA level during the period of raltegravir intensification or of rebound after discontinuation. Median levels of HIV-1 RNA before (0.17 log10 copies/mL), during (0.04 log10 copies/mL), and after (0.04 log10 copies/mL) raltegravir intensification were not significantly different (P > .1 for all comparisons in parametric analyses). High-performance liquid chromatography and mass spectroscopy experiments confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification.. Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects receiving suppressive regimens, indicating that rapidly cycling cells infected with HIV-1 were not present. Eradication of HIV-1 from infected persons will require new therapeutic approaches.. ClinicalTrials.gov identifier: NCT00618371.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load; Viremia

The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir-boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation.. We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels.. Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohn's disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged.. Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction.

Topics: Adult; Anti-HIV Agents; Drug Interactions; HIV Infections; HIV-1; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Ritonavir; Serum; Tacrolimus

Therapy for infection with HIV-2 remains limited. We report an HIV-2-infected patient in whom genotyping demonstrated PI, NRTI and NNRTI resistance, with a subsequent response to raltegravir- and maraviroc-based therapy. Further studies are required to assess the clinical efficacy of maraviroc in HIV-2 infection.

Topics: Anti-HIV Agents; Cyclohexanes; Drug Resistance, Viral; Genotype; HIV Infections; HIV-2; Humans; Maraviroc; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Outcome; Triazoles

Topics: Adult; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; HIV; HIV Infections; HIV-1; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Time Factors; Treatment Outcome

The objective of this study was to evaluate the development of resistance to raltegravir (RAL) in patients with viraemia between 40 and 400 copies/ml. All HIV-1-infected patients with multidrug-resistant virus, plasma HIV-1 RNA >1000 copies/ml and starting RAL were enrolled in this observational study and followed up until week 48. Sixty-seven patients with median plasma HIV-1 RNA at 4.3 log(10) copies/ml and CD4 at 177 cells/mm(3) were included. At week 24, 43 achieved full viral suppression (FVS; plasma HIV-1 RNA <40 copies/ml), 18 had incomplete viral suppression (IVS; plasma HIV-1 RNA 40-400 copies/ml). At week 48, all the FVS were sustained, 16 of the IVS patients retained a plasma HIV-1 RNA <400 copies/ml and only 2 of the IVS at week 24 experienced VF. No RAL resistance was detected in the persistent low viraemia. In contrast, integrase mutation was detected in 6 of the patients with VF. A genotypic sensitivity score equal to 0 was associated with plasma HIV-1 RNA >40 copies/ml at week 24 (OR 20.9, 95% CI 2.0-215.1) and with RAL resistance (OR 14.2, 95% CI 2.1-94.7). This study confirmed the high efficacy of a RAL-containing regimen under routine clinical conditions in infections caused by multidrug-resistant virus. If persistent low viraemia is observed over more than 48 weeks without the emergence of resistance, RAL should never be given as functional monotherapy, as it is associated with a maximal risk of VF and the emergence of RAL resistance.

Topics: Adult; Aged; Analysis of Variance; Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Predictive Value of Tests; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Treatment Failure; Viral Load

Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.

Topics: Antiretroviral Therapy, Highly Active; DNA, Complementary; DNA, Viral; HIV Infections; HIV Integrase Inhibitors; HIV Long Terminal Repeat; HIV-1; Humans; Polymerase Chain Reaction; Pyrrolidinones; Raltegravir Potassium; Virus Integration; Virus Replication

Topics: Adult; AIDS Dementia Complex; CD4 Lymphocyte Count; Chromatography, Liquid; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Spinal Puncture; Young Adult

Resistance to raltegravir (RAL), the first HIV-1 integrase (IN) inhibitor approved by the FDA, involves three genetic pathways: IN mutations N155H, Q148H/R/K, and Y143H/R/C. Those mutations are generally associated with secondary point mutations. The resulting mutant viruses show a high degree of resistance against RAL but somehow are affected in their replication capacity. Clinical and virological data indicate the high relevance of the combination G140S + Q148H because of its limited impact on HIV replication and very high resistance to RAL. Here, we report how mutations at the amino acid residues 140, 148, and 155 affect IN enzymatic activity and RAL resistance. We show that single mutations at position 140 have limited impact on 3'-processing (3'-P) but severely inactivate strand transfer (ST). On the other hand, single mutations at position 148 have a more profound effect and inactivate both 3'-P and ST. By examining systematically all of the double mutants at the 140 and 148 positions, we demonstrate that only the combination G140S + Q148H is able to restore the catalytic properties of IN. This rescue only operates in cis when both the 140S and 148H mutations are in the same IN polypeptide flexible loop. Finally, we show that the G140S-Q148H double mutant exhibits the highest resistance to RAL. It also confers cross-resistance to elvitegravir but less to G-quadraduplex inhibitors such as zintevir. Our results demonstrate that IN mutations at positions 140 and 148 in the IN flexible loop can account for the phenotype of RAL-resistant viruses.

Topics: Amino Acid Sequence; Amino Acid Substitution; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Sequence Data; Oligonucleotides; Point Mutation; Pyrrolidinones; Raltegravir Potassium; Sequence Homology, Amino Acid; Virus Replication

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Female; HIV; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy

Topics: Anti-HIV Agents; DNA, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Plasmids; Pyrrolidinones; Raltegravir Potassium; Virus Integration; Virus Latency

An HIV-1 subtype C specific assay was established for integrase genotyping from 51 integrase inhibitor-naive patient plasma samples and 22 antiretroviral drug-naive primary viral isolates from South Africa. Seventy-one of the 73 samples were classified as HIV-1 subtype C and two samples were unique AC and CG recombinants in integrase. Amino acid sequence analysis revealed there were no primary mutations (Y143R/C/H, Q148H/R/K, and N155H/S) associated with reduced susceptibility to the integrase inhibitors raltegravir and elvitegravir. However, one sample had the T97A mutation, three samples had the E157Q and V165I mutations, and the majority of samples contained the polymorphic mutation V72I. The expected finding of no major integrase mutations conferring resistance to integrase inhibitors suggests that this new antiretroviral drug class will be effective in our region where HIV-1 subtype C predominates. However, the impact of E157Q and other naturally occurring polymorphisms warrants further phenotypic investigation.

Topics: Amino Acid Sequence; Drug Resistance, Multiple, Viral; Genetic Variation; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Sequence Data; Phylogeny; Polymorphism, Single Nucleotide; Pyrrolidinones; Quinolones; Raltegravir Potassium; RNA, Viral; South Africa

Our aim was to study the in vivo viral genetic pathways for resistance to raltegravir, in antiretroviral-experienced patients with virological failure (VF) on raltegravir-containing regimens.. We set up a prospective study including antiretroviral-experienced patients receiving raltegravir-based regimens. Integrase (IN) genotypic resistance analysis was performed at baseline. IN was also sequenced at follow-up points in the case of VF, i.e. plasma HIV-1 RNA>400 copies/mL at month 3 and/or >50 copies/mL at month 6. For phenotyping, the IN region was recombined with an IN-deleted HXB2-based HIV-1 backbone. A titrated amount of IN recombinant viruses was used for antiviral testing against raltegravir and elvitegravir.. Among 51 patients, 11 (21.6%) had VF. Four different patterns of IN mutations were observed: (i) emergence of Q148H/R with secondary mutations (n=5 patients); (ii) emergence of N155H, then replaced by a pattern including Y143C/H/R (n=3); (iii) selection of S230N (n=1); and (iv) no evidence of selection of IN mutations (n=2). The median raltegravir and elvitegravir fold changes (FCs) were 244 (154-647) and 793 (339-892), respectively, for the Q148H/R pattern, while the median raltegravir and elvitegravir FCs were 21 (6-52) and 3 (2-3), respectively, with Y143C/H/R. The median plasma raltegravir Cmin was lower in patients with selection of the N155H mutation followed by Y143C/H/R compared with patients with Q148H/R and with patients without emerging mutations or without VF.. Diverse genetic profiles can be associated with VF on raltegravir-containing regimens, including the dynamics of replacement of mutational profiles. Pharmacokinetic parameters could be involved in this genetic evolution.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Mutation, Missense; Prospective Studies; Pyrrolidinones; Quinolones; Raltegravir Potassium; RNA, Viral; Sequence Analysis, DNA; Treatment Failure; Viral Load

Resistance to HIV-1 integrase (IN) inhibitor raltegravir (RAL), is encoded by mutations in the IN region of the pol gene. The emergence of the N155H mutation was replaced by a pattern including the Y143R/C/H mutations in three patients with anti-HIV treatment failure. Cloning analysis of the IN gene showed an independent selection of the mutations at loci 155 and 143. Characterization of the phenotypic evolution showed that the switch from N155H to Y143C/R was linked to an increase in resistance to RAL. Wild-type (WT) IN and IN with mutations Y143C or Y143R were assayed in vitro in 3'end-processing, strand transfer and concerted integration assays. Activities of mutants were moderately impaired for 3'end-processing and severely affected for strand transfer. Concerted integration assay demonstrated a decrease in mutant activities using an uncleaved substrate. With 3'end-processing assay, IC(50) were 0.4 microM, 0.9 microM (FC = 2.25) and 1.2 microM (FC = 3) for WT, IN Y143C and IN Y143R, respectively. An FC of 2 was observed only for IN Y143R in the strand transfer assay. In concerted integration, integrases were less sensitive to RAL than in ST or 3'P but mutants were more resistant to RAL than WT.

Topics: Drug Resistance; HIV Infections; HIV Integrase; Humans; Inhibitory Concentration 50; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Treatment Failure

Little is known about raltegravir removal by hemodialysis in patients with end-stage renal disease (ESRD). We therefore measured raltegravir concentrations in plasma in pre- and postdialyzer blood samples from 2 ESRD HIV-infected patients. The hemodialysis extraction ratio and raltegravir hemodialysis clearance were 5.5% and 9.1 ml/min in patient 1 and 9.5% and 19.1 ml/min in patient 2, respectively. Our results suggest minimal raltegravir removal by hemodialysis with no specific raltegravir dosage adjustments required in HIV-infected patients undergoing hemodialysis.

Topics: HIV Infections; HIV Integrase Inhibitors; Humans; Kidney Failure, Chronic; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Renal Dialysis

Topics: Acute Kidney Injury; Adult; Antiviral Agents; Hepatitis C, Chronic; HIV Infections; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Rhabdomyolysis

In HIV-infected patients with HCV-related chronic hepatitis, liver impairment and drug toxicity may substantially reduce the number of possible therapeutic options.. we here describe the case of an HCV-HIV coinfected woman who had repeated severe episodes of drug-related liver toxicity with indinavir, saquinavir, fosamprenavir, and darunavir, with minimal further therapeutic options left in this class. Previous treatment-limiting side effects with efavirenz and nevirapine also precluded use of non-nucleoside reverse transcriptase inhibitors. Introduction of an integrase-inhibitor regimen based on raltegravir, tenofovir, and emtricitabine allowed a prompt achievement of undetectable viral load and a substantial rise of CD4 count to high levels, with no subsequent episodes of hepatic toxicity, and no other side effects.. given the relatively common prevalence of HCV-related chronic hepatitis among people with HIV, raltegravir might represent an important alternative option for a substantial number of patients who cannot be treated with protease inhibitors or NNRTI because of drug-related hepatic toxicity.

Topics: Adenine; Adult; Antiviral Agents; CD4-Positive T-Lymphocytes; Chemical and Drug Induced Liver Injury; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver; Lymphocyte Count; Organophosphonates; Protease Inhibitors; Pyrrolidinones; Raltegravir Potassium; Tenofovir; Treatment Outcome; Viral Load

Topics: Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Topics: Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Although antiretroviral therapy during pregnancy is associated with significant reductions in the risk of vertical transmission of HIV, attainment of this outcome in highly treatment-experienced pregnant women might be complicated by the lack of active drugs available to assemble a potent regimen. The recent licensing and availability of darunavir, etravirine and raltegravir has broadened management options available for highly treatment-experienced patients. However, data on their safety and efficacy in preventing vertical transmission are limited.. A retrospective chart review of two cases describing obstetrical, infant and treatment outcomes associated with the use of regimens that include darunavir and etravirine with or without raltegravir during pregnancy was conducted.. We document two cases of pregnant HIV-positive women treated with antiretroviral therapy including darunavir, etravirine and raltegravir. Vertical transmission was averted and no congenital anomalies were observed.. In the absence of human development toxicity data for these agents, these cases provide preliminary anecdotal data on their safety during pregnancy. Although the outcomes of these cases are reassuring, additional studies and registries are required to establish the safety and efficacy of these agents during pregnancy.

Topics: Adolescent; Adult; Anti-HIV Agents; Darunavir; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Nitriles; Pregnancy; Pregnancy Complications, Infectious; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Sulfonamides; Treatment Outcome; Young Adult

Topics: HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium; Viral Load

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; Humans; Organophosphonates; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Tenofovir; Viral Load; Viremia

to analyze the long-term immunovirological effect and tolerability of a maraviroc-containing antiretroviral therapy in viraemic and pretreated HIV-infected patients with a high prevalence of hepatitis C virus (HCV) coinfection.. forty-six R5 HIV-infected patients (48% HCV-coinfected) started a maraviroc-containing antiretroviral regimen, including patients with multidrug resistant virus and patients after first virologic failure. A retrospective study was performed, analysing percentage of patients with undetectable viral load, mean CD4+ gain, liver enzymes, clinical events and treatment modification up to week 48.. Raltegravir plus a boosted protease inhibitor was combined with maraviroc in 65.2% of the patients (mainly patients with multidrug resistant virus), while the coformulation lamivudine/abacavir was combined with maraviroc in 26.1% (all of them patients after first virologic failure). After 48 weeks on maraviroc-containing regimen, 96.3% of the patients had achieved undetectability and a mean CD4+ count increase of 151 cells/mm3 was observed. Liver enzymes did not increase along the follow up. One patient died after 24 weeks follow up due to heroin overdose. One patient developed a non-Hodgkin lymphoma after 36 weeks follow up, despite undetectable viral load and significant CD4+ increase was achieved (the only AIDS-defining event observed). Treatment modification was performed in 19.6% of the patients: 77.7% of them experienced a treatment simplification and only 1/46 suspended maraviroc.. maraviroc-containing regimen is long-term effective and well tolerated in HIV-infected patients in routine clinical practice and in different clinical scenarios.

Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cyclohexanes; Female; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Maraviroc; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Spain; Time; Triazoles; Viral Load

Because of high intersubtype HIV-1 genetic variability, it has been shown that subtype-specific patterns of resistance to antiretroviral drugs exist. We wished to ascertain whether this might be true for integrase inhibitors.. We compared the susceptibility of subtype B and C HIV-1 integrase enzymes, harboring the previously reported resistance mutations E92Q, N155H, and E92Q/N155H, to clinically relevant integrase inhibitors. This was performed biochemically using a microtiter plate system.. Subtype C integrase enzymes bearing the resistance mutations E92Q/N155H were approximately 10-fold more susceptible to each of two integrase inhibitors, raltegravir and elvitegravir, than were subtype B recombinant integrase containing the same mutations.. Polymorphic differences within the subtype B and C integrase genes likely cause variations in the contribution of N155H alone or in combination with E92Q to drug resistance. It is possible that different viral subtypes may favor different mutational pathways, potentially leading to varying levels of drug resistance among different subtypes.

Topics: Cells, Cultured; DNA, Viral; Drug Resistance, Viral; Genetic Variation; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA

Topics: Adult; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyrrolidinones; Raltegravir Potassium

To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut.. Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml.. Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers.. Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum.. Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible.

Topics: Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-1; Humans; Lymphocyte Activation; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; T-Lymphocyte Subsets; Viral Load; Young Adult

Natural polymorphisms of HIV-1, often associated with drug resistance, are widely described in protease and reverse transcriptase regions but data on their presence in the integrase region, especially in non-B subtypes, are still very limited. We aimed to characterize naturally occurring polymorphisms in the integrase region in 104 treatment-naive and 10 treatment-experienced patients infected predominantly with HIV-1 CRF06_cpx and its recombinant with subtype A1 and/or CRF03_AB viruses. No primary drug resistance mutations against integrase inhibitors were found, but resistance-associated polymorphisms such as V72I, L74I, V201I, and T206S were seen in more than 90% of viruses. Substitutions E157Q and E157K, associated with raltegravir resistance, were found in only two CRF06_cpx strains. We conclude that similar to other HIV-1 non-B subtypes, the CRF06_cpx and its recombinants with subtype A1 and CRF03_AB are rich in integrase region natural polymorphisms, which may impact the development of resistance against integrase inhibitors.

Topics: Adult; Drug Resistance, Multiple, Viral; Estonia; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Male; Molecular Sequence Data; Phylogeny; Polymorphism, Genetic; Pyrrolidinones; Raltegravir Potassium; Recombination, Genetic; RNA, Viral

Using quantitative deep HIV-1 sequencing in a subject who developed virological failure to deep salvage therapy with raltegravir, we found that most Q148R and N155H mutants detected at the time of virological failure originated from pre-existing minority Q148R and N155H variants through independent evolutionary clusters. Double 148R+N155H mutants were also detected in 1.7% of viruses at virological failure in association with E138K and/or G163R. Our findings illustrate the ability of HIV-1 to escape from suboptimal antiretroviral drug pressure through selection of pre-existing drug-resistant mutants, underscoring the importance of using fully active antiretroviral regimens to treat all HIV-1-infected subjects.

Topics: Adult; Amino Acid Sequence; Amino Acid Substitution; DNA Mutational Analysis; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Molecular Sequence Data; Mutation; Phylogeny; Pyrrolidinones; Raltegravir Potassium; Selection, Genetic; Treatment Failure

Raltegravir (RAL) is primarily metabolized by uridine diphosphate-glucorunosyl transferase 1A1 (UGT1A1). Atazanavir (ATV), a strong inhibitor of UGT1A1, has been shown to increase plasma concentrations of RAL by approximately 50% in healthy volunteers. However, the extent of this interaction has not been studied in HIV-infected patients. A pharmacokinetic study was performed in 22 HIV-infected adults treated with 400 mg RAL plus 300 mg ATV 300 twice a day. Both drugs showed high pharmacokinetic variability (RAL AUC 0-12 7649 ± 4862 ng*h/mL; ATV AUC 0-12 = 19237 ± 13136 ng*h/mL). Notably, RAL trough concentrations were significantly higher compared with those measured in HIV subjects (n = 24) on RAL plus nucleoside reverse transcriptase inhibitors (506 ± 411 versus 177 ± 262 ng/mL, P < 0.01). A significant correlation was found between RAL and ATV area under the curve (AUC) (r = 0.611, P = 0.005). Notably, patients with ATV AUC 0-12 above the mean or with concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had twofold higher RAL AUCs compared with patients with lower ATV exposure. Coadministration of ATV significantly increased plasma concentrations of RAL, especially in HIV-1-infected patients exposed to high concentrations of the protease inhibitor. This pharmacokinetic drug interaction could be handled by routine measurements of ATV trough concentrations and by the assessment of plasma RAL concentrations 2 to 3 hours after the morning drug intake.

Topics: Adult; Area Under Curve; Atazanavir Sulfate; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Male; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium

Viruses were sequenced from 75 antiretroviral therapy (ARV)-naïve and from 75 ARV-treated patients who subsequently received a raltegravir-containing regimen. No major integrase inhibitor (INI)-resistance mutations were present in the 150 integrase (IN) sequences. Four ARV-naïve (5.3%) and two ARV-treated patients (2.7%) had one of the following minor INI-resistance mutations: L74M, E157Q, G163R, and R263K but there was no association between baseline raltegravir genotype and subsequent response to raltegravir treatment. We also combined our sequences with 4170 previously published group M IN sequences from INI-naïve patients to assess IN sequence variability and compared our findings with those of a study we performed in 2008 using data from 1563 patients. The number of polymorphic IN positions increased from 40% to 41% between the two studies. However, none of the major INI-resistance mutations was found to be polymorphic in either study and there were no significant changes in the prevalence of any of the minor INI-resistance mutations.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Genetic Variation; HIV Infections; HIV Integrase; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA

Topics: Cerebellar Ataxia; Female; HIV Infections; HIV-1; Humans; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Because of the favourable safety and tolerability profiles of atazanavir (ATV) and raltegravir (RAL), attention has recently turned to the use of dual ATV plus RAL therapy as a nucleoside reverse transcriptase inhibitor-sparing treatment strategy in highly antiretroviral treatment (ART)-experienced HIV-infected patients.. A retrospective observational study was carried out to assess the maintenance of viral suppression and ART tolerability in 20 highly ART-experienced patients with viral suppression, who had been switched to RAL and unboosted ATV dual therapy, using data collected during standard-of-care visits.. At 6, 12 and 18 months, viral load was maintained at <400 HIV RNA copies/ml, with only one participant recording a detectable viral load (150 copies/ml) at the 6-month time point. Stable CD4(+) T-cell counts were maintained throughout the study period. Five participants changed regimen during the 18-month follow-up, with the median time to switch being 9 months (range 2-12). In three cases, patients were changed from dual therapy because of adverse events while on the regimen. These included increased fatigue (two patients), persistently increased bilirubin (one patient) and gastrointestinal side effects (one patient). Two additional patients changed therapy: one patient added lamivudine and one ceased ATV to pre-empt a potential drug-drug interaction. All five patients who switched from ATV/RAL before 12 months follow-up maintained viral suppression, implying no disadvantage from switching to dual therapy.. Dual therapy with ATV plus RAL maintained viral suppression in this small group of highly ART-experienced patients. Further investigation of this novel dual therapy regimen is warranted.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; CD4 Lymphocyte Count; Drug Interactions; Female; Follow-Up Studies; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Middle Aged; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load

Human Immunodeficiency Virus type 2 is naturally resistant to some antiretroviral drugs, restricting therapeutic options for patients infected with HIV-2. Regimens including integrase inhibitors (INI) seem to be effective, but little data on HIV-2 integrase (IN) polymorphisms and resistance pathways are available.. The integrase coding sequence from 45 HIV-2-infected, INI-naïve, patients was sequenced and aligned against the ROD (group A) or EHO (group B) reference strains and polymorphic or conserved positions were analyzed.To select for raltegravir (RAL)-resistant variants in vitro, the ROD strain was cultured under increasing sub-optimal RAL concentrations for successive rounds. The phenotype of the selected variants was assessed using an MTT assay.. We describe integrase gene polymorphisms in HIV-2 clinical isolates from 45 patients. Sixty-seven percent of the integrase residues were conserved. The HHCC Zinc coordination motif, the catalytic triad DDE motif, and AA involved in IN-DNA binding and correct positioning were highly conserved and unchanged with respect to HIV-1 whereas the connecting residues of the N-terminal domain, the dimer interface and C-terminal LEDGF binding domain were highly conserved but differed from HIV-1. The N155 H INI resistance-associated mutation (RAM) was detected in the virus population from one ARV-treated, INI-naïve patient, and the 72I and 201I polymorphisms were detected in samples from 36 and 38 patients respectively. No other known INI RAM was detected.Under RAL selective pressure in vitro, a ROD variant carrying the Q91R+I175M mutations was selected. The Q91R and I175M mutations emerged simultaneously and conferred phenotypic resistance (13-fold increase in IC50). The Q91R+I175M combination was absent from all clinical isolates. Three-dimensional modeling indicated that residue 91 lies on the enzyme surface, at the entry of a pocket containing the DDE catalytic triad and that adding a positive charge (Gln to Arg) might compromise IN-RAL affinity.. HIV-2 polymorphisms from 45 INI-naïve patients are described. Conserved regions as well as frequencies of HIV-2 IN polymorphisms were comparable to HIV-1. Two new mutations (Q91R and I175M) that conferred high resistance to RAL were selected in vitro, which might affect therapeutic outcome.

Topics: Anti-HIV Agents; Cell Line; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV-2; Humans; Molecular Sequence Data; Phylogeny; Polymorphism, Genetic; Pyrrolidinones; Raltegravir Potassium

Raltegravir (RAL), an HIV integrase inhibitor, may uncommonly induce an increase of serum creatine kinase (CK) both in naïve and antiretroviral (ARV)-experienced HIV-positive patients. We report the case of severe rhabdomyolysis requiring hospitalization in an ARV-experienced HIV/hepatitis C co-infected patient treated with a RAL-containing drug regimen. Factors favouring a severe clinical occurrence of RAL-induced rhabdomyolysis from cases reported in literature are described.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Creatine Kinase; Female; HIV Infections; HIV Integrase Inhibitors; Humans; L-Lactate Dehydrogenase; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rhabdomyolysis

Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.

Topics: Administration, Oral; Animals; Anti-HIV Agents; Cyclohexanes; Disease Models, Animal; Female; Flow Cytometry; HIV Infections; HIV-1; Humans; Maraviroc; Mice; Mice, Transgenic; Post-Exposure Prophylaxis; Pyrrolidinones; Raltegravir Potassium; Triazoles; Vagina

Integrase inhibitor-resistant HIV-1 was detected in the cerebrospinal fluid, but not in the plasma of a 42-year-old man with HIV encephalopathy treated with a raltegravir (RAL)-containing regimen. Raltegravir resistance may develop in the central nervous system when the virus is already multi-drug resistant because of different penetration into cerebrospinal fluid of individual antiretroviral agents.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Central Nervous System; Cerebrospinal Fluid; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Male; Plasma; Pyrrolidinones; Raltegravir Potassium

For the quantification of the HIV-integrase inhibitor raltegravir in human plasma, dried blood spots and peripheral blood mononuclear cell (PBMC) lysate, an assay was developed and validated, using liquid chromatography coupled with tandem mass spectrometry. The assay also allowed detection, but no quantification due to absence of reference substance, of the main metabolite, raltegravir-glucuronide. Raltegravir was extracted from plasma by means of protein precipitation with a mixture of methanol and acetonitrile using only 50microL plasma. Extraction from dried blood spots was performed with a simple one-step extraction with a mixture of methanol, acetonitrile and 0.2M zincsulphate in water (1:1:2, v/v/v) and extraction from cell lysate was performed in 50% methanol in water. Chromatographic separation was performed on a reversed phase C18 column (150mmx2.0mm, particle size 5microm) with a quick stepwise gradient using an acetate buffer (pH 5) and methanol, at a flow rate of 0.25mL/min. The analytical run time was 10min. The triple quadrupole mass spectrometer was operated in the positive ion-mode and multiple reaction monitoring was used for drug quantification. The method was validated over a range of 50-10,000ng/mL in plasma and dried blood spots and a range of 1-500ng/mL in PBMC lysate. Dibenzepine was used as the internal standard. The method was proven to be specific, accurate, precise and robust. Accuracies ranged from 104% to 105% in plasma, from 93% to 105% in dried blood spots and from 82% to 113% in PBMC lysate. Precision over the complete concentration range was less than 6%, 11% and 13% in plasma, dried blood spots and PBMC lysate, respectively. The method is now applied for therapeutic drug monitoring and pharmacological research in HIV-infected patients treated with raltegravir.

Topics: Acetonitriles; Antiviral Agents; Biological Assay; Calibration; Chromatography, High Pressure Liquid; Desiccation; Drug Monitoring; Drug Stability; Drug Storage; Freezing; HIV Infections; HIV Integrase Inhibitors; Humans; Leukocytes, Mononuclear; Methanol; Molecular Structure; Particle Size; Pyrrolidinones; Raltegravir Potassium; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Solutions; Tandem Mass Spectrometry; Water; Zinc Sulfate

Raltegravir (MK-0518) is the first integrase (IN) inhibitor to be approved by the US FDA and is currently used in clinical treatment of viruses resistant to other antiretroviral compounds. Virological failure of Raltegravir treatment is associated with mutations in the IN gene following two main distinct genetic pathways involving either the N155 or Q148 residue. Importantly, in most cases, an additional mutation at the position G140 is associated with the Q148 pathway. Here, we investigated the viral DNA kinetics for mutants identified in Raltegravir-resistant patients. We found that (i) integration is impaired for Q148H when compared with the wild-type, G140S and G140S/Q148H mutants; and (ii) the N155H and G140S mutations confer lower levels of resistance than the Q148H mutation. We also characterized the corresponding recombinant INs properties. Enzymatic performances closely parallel ex vivo studies. The Q148H mutation 'freezes' IN into a catalytically inactive state. By contrast, the conformational transition converting the inactive form into an active form is rescued by the G140S/Q148H double mutation. In conclusion, the Q148H mutation is responsible for resistance to Raltegravir whereas the G140S mutation increases viral fitness in the G140S/Q148H context. Altogether, these results account for the predominance of G140S/Q148H mutants in clinical trials using Raltegravir.

Topics: Amino Acid Substitution; Catalysis; Cell Line; DNA, Viral; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Point Mutation; Pyrrolidinones; Raltegravir Potassium; Virus Replication

Raltegravir, a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has pH-dependent solubility. Raltegravir plasma concentration increases with omeprazole coadministration in healthy subjects; this is likely secondary to an increase in bioavailability attributable to increased gastric pH. Increased gastric pH has been reported in HIV-1-infected individuals, and the effects of omeprazole in this intended population may be diminished. Further investigation is necessary.

Topics: Adolescent; Adult; Anti-HIV Agents; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Omeprazole; Plasma; Pyrrolidinones; Raltegravir Potassium; Young Adult

Topics: Adult; Aged; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sulfonamides; Treatment Outcome

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Cyclopropanes; HIV Infections; Humans; Liver Failure, Acute; Liver Transplantation; Pyrrolidinones; Raltegravir Potassium

: Evaluate HIV-1 subtype B integrase gene evolution in patients failing raltegravir (RAL)-based savage regimens by clonal analysis of the replicating viral quasispecies.. : Seven triple class failure HIV-1 (subtype B)-infected patients, followed at San Raffaele Hospital and enrolled in the RAL Expanded Access Program (MK0518-023), were evaluated. Patients were followed up for 24-48 weeks and due to the absence of other active drugs, RAL was maintained in their regimens even if resistance mutations were detected.. : Immunologic and virologic parameters were recorded every 4 weeks, and amplification and clonal analysis of viral populations were performed at baseline and every 4-12 weeks in all patients.. : Resistance to RAL appeared initially associated with selection of single variants (Y143R, Q148R N155H) in the majority of patients; however, in three patients, complex patterns of viral mutations were observed. The clonal analysis of viral quasispecies allowed to describe the evolution of each viral population and the progressive accumulation of RAL resistance-associated mutations and polymorphisms associated with therapy failure.. : The complex patterns of resistance mutations observed, including novel variants evolved under continuous RAL pressure, suggesting that they are the result of the equilibrium between drug resistance and enzyme function. Despite the efficacy of this compound, our data discourage its use in a functional monotherapy and maintaining RAL even in presence of RAL resistance-associated mutations may lead to the progressive formation of viral reservoirs with multiple integrase inhibitor-resistant variants that may limit the future efficacy of other integrase inhibitors due to cross-resistance.

Topics: CD4 Lymphocyte Count; Drug Resistance, Viral; Evolution, Molecular; Follow-Up Studies; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium; Viral Load

Raltegravir is the first approved inhibitor of HIV-1 integrase (IN). In most patients, raltegravir failure is associated with mutations in the IN gene, through two different genetic pathways: 155 (N155H) or 148 (Q148K/R/H). The objective of this study was to characterize the dynamics of HIV-1 quasispecies variant populations in patients who failed to respond to raltegravir treatment.. Bulk genotyping and clonal analysis were performed during the follow-up of 10 patients who failed to respond to raltegravir treatment.. Treatment failed through the 155 pathway in six patients and through the 148 pathway in two patients; two further patients switched from the 155 to the 148 pathway. In the two patients switching from the 155 to the 148 pathway, clonal analysis showed that Q148R/H and N155H mutations were present on different strands, suggesting that these two pathways are independent. This was consistent with our finding that each genetic profile was associated with different secondary mutations. We observed a greater variability among quasispecies associated with the 155 pathway, and IC(50) determinations showed that the fold resistance to raltegravir, relative to wild-type, was 10 for the N155H mutant and 50 for the G140S+Q148H mutant.. Clonal analysis strongly suggests that the two main genetic pathways, 155 and 148, involved in the development of resistance to raltegravir are independent and exclusive. Moreover, the switch of the resistance profile from 155 to 148 may be related to the higher level of resistance to raltegravir conferred by the 148 pathway and also to the higher instability of the 155 pathway.

Topics: Amino Acid Substitution; Anti-HIV Agents; Cluster Analysis; Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV-1; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA

Abstract The activity of raltegravir and etravirine was assessed in vitro in HIV-1 group O isolates. Despite the presence of some natural polymorphisms associated with resistance to raltegravir (V72I, L74I, S153A, V201I, and T206S) and etravirine (G190A), both drugs showed significant antiviral activity. Subsequently, the clinical benefit was shown in an HIV-1 group O-infected individual in whom enfuvirtide was replaced by raltegravir. Therefore, individuals infected with HIV-1 group O might benefit from raltegravir and/or etravirine therapy.

Topics: Amino Acid Substitution; Anti-HIV Agents; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Middle Aged; Mutation, Missense; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Viral Load

Topics: Anti-HIV Agents; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Topics: Adult; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Middle Aged; Preoperative Care; Pyrrolidinones; Raltegravir Potassium; Viral Load

HIV type-1 (HIV-1) integrase (IN) inhibitor resistance is the consequence of mutations that are selected in the viral IN gene targeted by antiretroviral drugs, such as raltegravir (RAL) and elvitegravir (EVG). The genetic barrier, defined as the number of viral mutations required to overcome the drug-selective pressure, is one of the important factors in the development of drug resistance. The genetic barrier for IN inhibitor resistance was compared between HIV-1 subtype B and HIV-1 subtype CRF02_AG, which is highly prevalent in West Africa and becoming more frequent in developed countries.. IN nucleotide sequences from 73 HIV-1 subtype B and 77 HIV-1 subtype CRF02_AG antiretroviral-naive patients were examined at 19 IN amino acid positions implicated in RAL and EVG resistance.. The majority (14/19) of the studied positions showed a high degree of conservation of the predominant codon sequences leading to a similar genetic barrier between subtypes B and CRF02_AG. Nevertheless, at positions 140 and 151, the variability between subtypes affected the genetic barrier for the mutations G140C, G140S and V1511 with a higher genetic barrier being calculated for subtype CRF02_AG.. The major IN mutations E92Q, Q148K/R/H, N155H and E157Q (implicated in the resistance of IN inhibitors RAL and EVG) are highly conserved between subtypes B and CRF02_AG and display a similar genetic barrier. However, subtype CRFO2_AG showed a higher genetic barrier to acquire mutations 6140S, 6140C and V1511 as compared with subtype B, which could play a role in the resistance to RAL and/or EV6.

Topics: DNA, Viral; Drug Resistance, Viral; Genetic Variation; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Quinolones; Raltegravir Potassium; Sequence Analysis, DNA

Topics: Anti-HIV Agents; Drug Interactions; HIV Infections; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Viral Load

The integrase inhibitor (INI) raltegravir has shown promising results in clinical trials to date, reducing second phase HIV RNA levels by 70% in comparison with standard regimens. These trial results have been limited by the 50 copies/ml detection limit of the HIV RNA assay and have not investigated the effect of an INI regimen on levels of latently infected cells. Mathematical models that duplicated previous raltegravir results were extended to estimate effects of an INI regimen on HIV RNA beyond second phase and on HIV DNA levels. Depending on assumptions underlying later phase HIV RNA generation and its interaction with latently infected cells, HIV RNA in later phases can be lower or show no difference with an INI, and similarly for HIV DNA. If latent infection is maintained by differentiation of stem cells with integrated HIV DNA, then an INI regimen will eventually have no added benefit. Other hypotheses that allow ongoing replication predict continually lower HIV RNA levels with an INI regimen, but this differential effect need not translate to a reduction in latent infection. Investigation of HIV RNA and HIV DNA levels with an INI will provide better understanding of how these components are generated and maintained under antiretroviral therapy.

Topics: DNA, Viral; HIV; HIV Infections; Humans; Integrase Inhibitors; Models, Biological; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Virus Latency

Topics: Anti-HIV Agents; Area Under Curve; Drug Interactions; Hepatitis B; Hepatitis C; HIV Infections; Humans; Product Surveillance, Postmarketing; Pyrrolidinones; Raltegravir Potassium; United States; United States Food and Drug Administration

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Dideoxynucleosides; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Cardiovascular Diseases; Dideoxynucleosides; Drug Interactions; HIV Infections; Humans; Interleukin-2; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium

Raltegravir is the first publicly released HIV integrase inhibitor. In clinical trials, patients on a raltegravir-based highly active antiretroviral therapy (HAART) regimen were observed to have 70% less viraemia in the second-phase decay of viraemia than patients on an efavirenz-based HAART regimen. Because of this accelerated decay of viraemia, raltegravir has been speculated to have greater antiretroviral activity than efavirenz. Alternative explanations for this phenomenon are also possible. For example, the stage in the viral life cycle at which raltegravir acts might explain the distinct viral dynamics produced by this drug.. In this report, we use a mathematical model of HIV viral dynamics to explore several hypotheses for why raltegravir causes different viral dynamics than efavirenz. Using the experimentally observed viral dynamics of raltegravir, we calculated constraints on the mechanisms possibly responsible for the unique viral dynamics produced by raltegravir.. We predicted that the dominant mechanism for the 70% reduction in the second-phase viraemia is not antiviral efficacy but the stage of the HIV viral life cycle at which raltegravir acts. Furthermore, we found that the kinetic constraints placed on the identity of the virus-producing cells of the second phase were most consistent with monocytes/macrophages.. Our model predictions have important implications for the motivation behind the use of raltegravir and our understanding of the virus-producing cells of the second-phase viraemia. Our results also highlight that the viral dynamics produced by different antiretroviral drugs should not be directly compared with each other.

Topics: CD4-Positive T-Lymphocytes; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Models, Biological; Pyrrolidinones; Raltegravir Potassium; Viremia; Virus Integration; Virus Replication

Since the discovery of MK-0518 (raltegravir, the first FDA-approved integrase inhibitor) in October 2007, Merck Co. researchers have continued to patent original new heterocycles related to raltegravir as powerful strand transfer inhibitors. Among the most recent patented works hexahydrodiazocino-naphthyridinetriones present the particularity to possess two different sources of chirality, that is, an asymmetric carbon and a heterocyclic eight-membered ring presenting atropisomerism. The different synthesized isomers claimed in this patent are described and their biological properties commented on in relation to stereoisomerism.

Topics: Drug Design; HIV Infections; HIV Integrase Inhibitors; Humans; Naphthyridines; Patents as Topic; Pyrrolidinones; Raltegravir Potassium; Stereoisomerism

We investigated the prevalence of raltegravir resistance-associated mutations at baseline and their evolution during raltegravir therapy in patients infected with different HIV-1 subtypes.. At pre-treatment screening, the integrase gene from plasma samples from patients infected with subtype B and non-B viruses was analysed. Raltegravir resistance evolution was further evaluated in 10 heavily pre-treated patients.. Two hundred and nine plasma samples from 94 subtype B and 115 non-B patients were sequenced. No signature/primary raltegravir resistance mutations were detected at baseline. The secondary mutations L74M, T97A, V151I and G163R were observed with a frequency of <4%. The primary mutations N155H, Q148R/H or Q143R were observed during raltegravir therapy. The Q148R/H was detected only in subtype B. A switch of the primary mutation during raltegravir treatment was not restricted to the subtype B viruses. The prevalence of each primary mutation varied depending on the length of the raltegravir therapy. The Q148R/H was mostly detected after short exposure to raltegravir, while the Y143R was observed only after prolonged raltegravir exposure. We detected an association between the presence of the T206S in the baseline genotype and the absence of the primary Q148R/H mutation or any secondary mutation accompanying the N155H following raltegravir failure.. A number of secondary and additional mutations were found in baseline genotypes. During therapy, when the virus was not optimally suppressed, resistance mutations developed, which were dependent on subtype and time on raltegravir.

Topics: Amino Acid Substitution; DNA Mutational Analysis; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV-1; Humans; Molecular Sequence Data; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, DNA

Topics: Amino Acid Substitution; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV-1; Humans; Male; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Selection, Genetic

Clinical trials of the first approved integrase inhibitor (INI), raltegravir, have demonstrated a drop in the human immunodeficiency virus type 1 (HIV-1) RNA loads of infected patients that was unexpectedly more rapid than that with a potent reverse transcriptase inhibitor, and apparently dose independent. These clinical outcomes are not understood. In tissue culture, although their inhibition of integration is well documented, the effects of INIs on levels of unintegrated HIV-1 cDNAs have been variable. Furthermore, there has been no report to date on an INI's effect on these episomal species in vivo. Here, we show that prophylactic treatment of transgenic rats with the strand transfer INI GSK501015 reduced levels of viral integrants in the spleen by up to 99.7%. Episomal two-long-terminal-repeat (LTR) circles accumulated up to sevenfold in this secondary lymphoid organ, and this inversely correlated with the impact on the proviral burden. Contrasting raltegravir's dose-ranging study with HIV patients, titration of GSK501015 in HIV-infected animals demonstrated dependence of the INI's antiviral effect on its serum concentration. Furthermore, the in vivo 50% effective concentration calculated from these data best matched GSK501015's in vitro potency when serum protein binding was accounted for. Collectively, this study demonstrates a titratable, antipodal impact of an INI on integrated and episomal HIV-1 cDNAs in vivo. Based on these findings and known biological characteristics of viral episomes, we discuss how integrase inhibition may result in additional indirect antiviral effects that contribute to more rapid HIV-1 decay in HIV/AIDS patients.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Line; DNA, Complementary; DNA, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrones; Pyrrolidinones; Raltegravir Potassium; Rats; Rats, Transgenic; Virus Integration

To evaluate 24-week virologic effectiveness of novel antiretroviral regimens for treatment of three-class experienced adult patients in a clinical practice setting following the US Food and Drug Administration approval of darunavir (DRV) for this population.. A prospective cohort study.. A single-center, academic HIV clinic.. Three-class antiretroviral-experienced patients changing regimens between July 2006 and May 2008. Sociodemographic, psychosocial, and clinical characteristics were collected at baseline and during prospective follow-up.. Plasma HIV viral load below 50 copies/ml and change in CD4 cell count at 24 weeks following regimen change. The Stanford Genotype Database was used to analyze HIV genotype resistance results and determine the number of active drugs in each regimen. Multivariate models and propensity score methods were employed to assess outcome measures.. Among 109 three-class experienced patients, who previously received an average of 10.5 prior antiretrovirals, 55% achieved viral load below 50 copies/ml at 24 weeks. Treatment strategy was classified as nonprotease inhibitor (n = 25), DRV/ritonavir (DRV/r) (n = 51), or other protease inhibitor (n = 33). The number of active drugs was not significantly different across strategies (P = 0.24). In multivariate analysis, patients treated with DRV/r (65%, odds ratio = 4.24 vs. nonprotease inhibitor strategy, 95% confidence interval = 1.28-14.06), raltegravir (65%, odds ratio = 3.10, 95% confidence interval = 1.12-8.62), or both were more likely to achieve viral load below 50 copies/ml.. Among antiretroviral-experienced patients changing regimens, those treated with DRV/r, raltegravir, or both were more likely to achieve a viral load below 50 copies/ml at 24 weeks. The effectiveness of these agents in routine clinical care mirrors their efficacy in clinical trials and has ushered in a new era in the therapy of three-class experienced patients.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Treatment Outcome; Viral Load

Topics: CD4 Lymphocyte Count; HIV; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Viral Load

Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug-drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176-890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6-14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT.

Topics: Adult; Anti-Retroviral Agents; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Interactions; Female; Graft Rejection; HIV Infections; HIV Integrase; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: CD4 Lymphocyte Count; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium; Viral Load

Raltegravir, a novel HIV-1 integrase inhibitor, has superior efficacy with optimized background treatment (OBT) vs. placebo + OBT in treatment-experienced HIV-1 patients. This study assessed the long-term cost effectiveness of raltegravir from a Spanish National Healthcare System perspective. A cohort-state-transition model was used to estimate clinical and economic outcomes associated with raltegravir + OBT vs. OBT alone. Subjects were stratified into health states according to HIV RNA level, CD4 count, and opportunistic infection (OI) history, and could transition into different health states over time based on projected long-term efficacy. Each health state was associated with a distinct treatment cost and utility (QoL) score. Model inputs for mortality, resource utilization, unit costs, OI risk, and long-term durability of viral suppression were obtained from clinical trials, published studies, and database analyses. Model outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2007 Euros per quality-adjusted life-year (euro/QALY) gained. Costs and QALYs were discounted at 6% per year based on Spanish cost-effectiveness guidelines. Extensive sensitivity analyses were conducted. Five years of treatment with raltegravir + OBT resulted in an additional 4.5 years of undiscounted life expectancy vs. OBT alone. The ICER of raltegravir + OBT vs. OBT alone was euro22,908/QALY and euro31,431/QALY for 3- and 5-year use, respectively. Lower ICERs were observed with lower discount rates (3%) for costs and benefits, lower raltegravir price (20%), and shorter treatment duration (3 years). ICER was also sensitive to analytical time horizon and alternative sources of QoL scores. In treatment-experienced Spanish patients, raltegravir was projected to provide survival benefits and be cost effective.

Topics: Adult; Cost-Benefit Analysis; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Life Expectancy; Male; Middle Aged; Models, Statistical; National Health Programs; Pyrrolidinones; Quality of Life; Raltegravir Potassium; Spain

Topics: Adult; Canada; CD4 Lymphocyte Count; Cohort Studies; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Viral Load

With the approval of the first HIV-1 integrase inhibitor raltegravir and a second one in phase III clinical development (elvitegravir), genotypic and phenotypic resistance assays are required to guide antiretroviral therapy and to investigate treatment failure. In this study, a genotypic and phenotypic recombinant virus assay was validated for determining resistance against integrase inhibitors. The assays are based on the amplification of a region encompassing not only HIV-1 integrase, but also reverse transcriptase and RNAseH. The overall amplification success was 85% (433/513) and increased to 93% (120/129) for samples with a viral load above 3 log(10) copies/ml. Both B and non-B HIV-1 subtypes could be genotyped successfully (93%; 52/56 and 100%; 49/49, respectively) and reproducibly. The phenotypic assay showed a high success rate (96.5%; 139/144) for subtype B (100%; 19/19) and non-B subtypes (92%; 45/49), and was found to be accurate and reproducible as assessed using well-characterized integrase mutants. Using both assays, baseline resistance to raltegravir and elvitegravir in subtype B and non-B HIV-1 strains selected at random was not observed, although integrase polymorphisms were present at varying prevalence. Biological cutoff values were found to be 2.1 and 2.0 for raltegravir and elvitegravir, respectively. In summary, a genotypic and phenotypic integrase resistance assay was validated successfully for accuracy, reproducibility, analytical and clinical sensitivity, and dynamic range.

Topics: Drug Resistance, Multiple, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Polymorphism, Genetic; Pyrrolidinones; Quinolones; Raltegravir Potassium; Reproducibility of Results; Ribonuclease H, Human Immunodeficiency Virus; RNA, Viral; Sensitivity and Specificity; Sequence Analysis, DNA

To monitor HIV-1 integrase resistance mutations during raltegravir (RAL) therapy, including the impact of RAL interruption.. An analysis of viral load and the HIV-1 integrase gene evolution in 26 HIV-1 treatment-experienced patients undergoing RAL therapy.. Initial suppression of viral load was observed in all patients; however, four patients failed to maintain suppression and subsequently developed resistance at viral load rebound. Mutations Q148R (2 months) followed by G140A/Q148R and then G140A/Y143CHR/Q148R/G163R were detected in the virus from one patient, and these reverted to wild type when treatment was withdrawn, although clonal analysis identified maintenance of RAL resistance minority species at this time point. RAL treatment was restarted after 6 months, and 2 weeks later, Y143CY/G163RG mutations appeared. In three other patients, viruses with N155H emerged at viral rebound either alone (2 months), followed by V151I (8 months) or alone (10 months), or together with V151I/G163RG (7 months). Loss of virus with the N155H mutation occurred in these patients when RAL therapy was terminated, despite maintenance of reverse transcriptase/polymerase resistance mutations.. Complete viral suppression was important in order to prevent resistance emerging. RAL-resistance mutations were detected in the presence of other antiviral treatments, and the reverse of these mutations following RAL cessation suggests that a fitness deficit was conferred by these mutants. The observation that following RAL interruption virus rebound was with previously existing reverse transcriptase/polymerase mutations in the absence of integrase mutations implies that it is pre-RAL-archived viruses that re-emerge.

Topics: Adult; Aged; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Integrase; HIV-1; Humans; Male; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Sequence Analysis, RNA; Treatment Failure; Viral Load

The emergence of human immunodeficiency virus type 1 resistance to raltegravir, an integrase strand transfer inhibitor, follows distinct and independent genetic pathways, among which the N155H and Q148HKR pathways are the most frequently encountered in treated patients. After prolonged viral escape, mutants of the N155H pathway are replaced by mutants of the Q148HKR pathway. We have examined the mechanisms driving this evolutionary pattern using an approach that assesses the selective advantage of site-directed mutant viruses as a function of drug concentration. These selective-advantage curves revealed that among single mutants, N155H had the highest and the widest (1 to 500 nM) selective-advantage profile. Despite the higher 50% inhibitory concentration, Q148H displayed a lower and narrower (10 to 100 nM) selective-advantage profile. Among double mutants, the highest and widest selective-advantage profile was seen with G140S+Q148H. This finding likely explains why N155H can be selected early in the course of RAL resistance evolution in vivo but is later replaced by genotypes that include Q148HKR.

Topics: Dose-Response Relationship, Drug; Drug Resistance, Viral; Genome, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Inhibitory Concentration 50; Mutagenesis, Site-Directed; Mutation; Pyrrolidinones; Raltegravir Potassium

The evolutionary dynamics of RAL resistance in the HIV-2 virus were examined through population and clonal sequence analysis of the IN from baseline, during treatment, and after stopping RAL therapy. The treatment failure of an RAL regimen in the HIV-2 patient studied was associated with the emergence of mutations via the N155H resistance pathway and subsequent switching to the Y143C mutational route. This study has also identified four novel secondary mutations, Q91R, S147G, A153G, and M183I, not previously reported in HIV-1 patients failing RAL therapy. Resistant variants involving the Y143C pathway were noted to have persisted beyond 4 weeks following the cessation of RAL therapy. All resistance-associated mutations were lost at 20 weeks after stopping RAL therapy. Our findings provide evidence supporting the supposition that substantial cross-resistance between strand transfer IN-Is is likely in HIV-2 as shown in HIV-1.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Evolution, Molecular; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-2; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Sequence Analysis, RNA; Treatment Failure

Raltegravir has been shown to be active against wildtype HIV-2 with a phenotypic susceptibility similar to HIV-1. Due to the recent introduction of these novel inhibitors, information on the selection of resistance mutations and its phenotypic effect in this population is scarce.. To explore in vitro the effect of raltegravir resistance in one individual with HIV-2 infection who failed raltegravir-HAART.. A 20-year-old man with HIV-2 infection received a raltegravir-based HAART regimen. Drug resistance mutations were examined in the integrase gene by sequence analysis. Phenotypic analyses were performed in two HIV-2 isolates from the patient (wildtype isolate: SP-2p2-175 and mutant isolate: SP-2p2-189) and a laboratory reference strain (HIV-2 ROD). Susceptibility to raltegravir was assessed in a PBMC culture assay. Furthermore, a replicative capacity assay was performed.. After introduction of raltegravir, patient's HIV-2 viremia dropped 1 log but did not reach undetectability. Genotypic analysis at month 8 with raltegravir, revealed the development of N155H resistant mutation along with other changes in the HIV-2 integrase: V72I, I84V, A153G, N160K and S163S/G. These changes resulted in a 37-fold increase in phenotypic resistance to raltegravir. Wildtype HIV-2 integrase (SP-2p2-175) had an IC(50) of 21.5nM and HIV-2 mutant virus (SP-2p2-189) showed an IC(50) of 789nM. SP-2p2-189 virus presented also lower replicative capacity in the absence of raltegravir than wildtype.. A continued low HIV-2 viral load seems to be enough to select the N155H mutation, which despite significantly impairing viral replication, shows a level of resistance sufficient to give a selective advantage to the virus that maintains this pathway of resistance to raltegravir overtime.

Topics: Amino Acid Sequence; Anti-Retroviral Agents; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV-2; Humans; Male; Molecular Sequence Data; Mutation; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Sequence Alignment; Viral Load; Virus Replication; Young Adult

Topics: Anti-HIV Agents; Cyclosporine; Drug Interactions; HIV Infections; Humans; Immunosuppressive Agents; Liver Transplantation; Pyrrolidinones; Raltegravir Potassium; Serum; Transplantation

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Approval; Drug Evaluation; HIV Infections; Humans; Life Expectancy; Patient Selection; Prognosis; Pyrrolidinones; Raltegravir Potassium

Topics: Drug Approval; Drug Labeling; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium; United States; United States Food and Drug Administration

Emergence of major resistance mutations has already been associated with raltegravir regimen failure. Because of few remaining therapeutic options, the maintenance of raltegravir in the salvage regimen is often considered despite the risk of worsening resistance to integrase inhibitors. We determined whether raltegravir retains residual antiretroviral activity in vivo against viruses harbouring raltegravir mutations, and thus whether the drug can contribute to the subsequent regimen.. This retrospective observational study reports the changes in the viral load (VL) after the withdrawal of raltegravir from patients carrying virus with resistance mutations. We selected patients under stable treatment and with stable VL during at least the previous 2 months before the withdrawal.. Five patients (A-E) were selected. The median changes in VL and CD4 counts at the end of the raltegravir interruption were -0.04 log copies/mL (range, -0.20 to +0.19) and +58 cells/mm(3) (range, -56 to +252), respectively.. All VL changes were well below the clinically relevant variation of 0.5 log copies/mL at the end of the interruption. Thus, this study indicates that, for viruses harbouring one of the two main resistance pathways described for raltegravir, no relevant antiviral activity seems to persist in vivo. Even if further observations would be useful to reinforce this conclusion, the cost/benefit and risk/benefit of maintaining raltegravir as part of a salvage regimen in the presence of raltegravir mutations seem debatable, especially in the absence of relevant antiretroviral activity in this context.

Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Mutation, Missense; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Viral Load

Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug.. Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma.. Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations.. Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

Topics: Adult; Albumins; Anti-HIV Agents; Chromatography, Liquid; Female; HIV Infections; HIV-1; Humans; Male; Mass Spectrometry; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Reproducibility of Results

The human immunodeficiency virus type 1 (HIV-1) integrase mutations N155H and Q148R(H)(K) that reduce susceptibility to the integrase inhibitor raltegravir have been identified in patients failing treatment regimens containing raltegravir. Whether these resistance mutations occur individually or in combination within a single virus genome has not been defined, nor do we fully understand the impact of these primary mutations and other secondary mutations on raltegravir susceptibility and viral replication capacity. To address these important questions, we investigated the raltegravir susceptibility and replication capacity of viruses containing mutations at positions 155 and 148 separately or in combination with secondary mutations selected in subjects failing treatment regimens containing raltegravir. Clonal analysis demonstrated that N155H and Q148R(H)(K) occur independently, not in combination. Viruses containing a Q148R(H)(K) mutation generally displayed larger reductions in raltegravir susceptibility than viruses with an N155H mutation. Analysis of site-directed mutants indicated that E92Q in combination with N155H resulted in a higher level of resistance to raltegravir than N155H alone. Viruses containing a Q148R(H) mutation together with a G140S mutation were more resistant to raltegravir than viruses containing a Q148R(H) mutation alone; however, viruses containing G140S and Q148K were more susceptible to raltegravir than viruses containing a Q148K mutation alone. Both N155H and Q148R(H)(K) mutations reduced the replication capacity, while the addition of secondary mutations either improved or reduced the replication capacity depending on the primary mutation. This study demonstrates distinct genetic pathways to resistance in subjects failing raltegravir regimens and defines the effects of primary and secondary resistance mutations on raltegravir susceptibility and replication capacity.

Topics: Drug Resistance, Viral; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutagenesis, Site-Directed; Pyrrolidinones; Raltegravir Potassium

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Deoxycytidine; Drug Combinations; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; HIV-1; Humans; Long-Term Care; Lopinavir; Oligopeptides; Organophosphonates; Oxazines; Pyridines; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Maraviroc; Piperazines; Pyrimidines; Pyrrolidinones; Quinolones; Raltegravir Potassium; Succinates; Triazoles; Triterpenes; Viral Load

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium

Raltegravir is a potential treatment option for virologically suppressed HIV-1 infected patients on enfuvirtide with injection site reactions.. To characterize safety and efficacy of an enfuvirtide to raltegravir switch including changes in T-cells, quality of life, and residual viremia.. In patients with viral load <50 copies/mL and injection site reactions, enfuvirtide was switched to raltegravir without additional changes to the antiretroviral regimen. Virologic failure was defined as a viral load >1000 copies/mL or two consecutive viral load measurements between 50 and 1000 copies/mL (low-level viremia). Over the 24 week study, we compared changes in T-cells, injection site reactions, quality of life, and residual viremia, as measured through the single-copy assay which can detect plasma virus down to a single copy, using paired t-tests.. Fourteen patients with a median CD4+ T-cell count of 420 cells/microL were enrolled. After the switch, two patients experienced virologic failure due to confirmed low-level viremia. However, both patients subsequently were re-suppressed, one without any changes to his regimen. There was no change in CD4+ T-cell count. Injection site reactions resolved. However, there was little reported change in quality of life. The baseline median level of residual viremia was 6 copies/mL and did not change after the switch to raltegravir.. A switch to raltegravir in virologically suppressed patients on enfuvirtide is effective in maintaining immunologic and virologic control at 24 weeks but did not result in a change in residual viremia.

Topics: CD4 Lymphocyte Count; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Pyrrolidinones; Quality of Life; Raltegravir Potassium; Treatment Outcome; Viral Load; Viremia

Twelve heavily pretreated, perinatally infected adolescents in virological failure were treated with a combination of raltegravir, r-darunavir and etravirine, as part of an expanded access program in France. After a 12-month median follow-up, viral load was <400 copies/ml in 11 (<50 in six). No grade > 2 side effects were recorded. Additional data and marketing authorizations are awaited, but preliminary results in adolescents with extensive multidrug resistant virus are encouraging.

Topics: Adolescent; Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; France; HIV Infections; HIV-1; Humans; Male; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Treatment Outcome; Viral Load

A new drug combination regimen, consisting of raltegravir, emtricitabine and tenofovir disoproxil fumarate (TDF), is described for the treatment of HIV-1 infection. This new drug combination regimen is applicable to the treatment of drug-naïve HIV-1-infected patients. It extends the use of the drug combinations to a new class of anti-HIV drugs, i.e. raltegravir, targeted at a new site in the HIV-1 replicative cycle, namely the HIV-1 integrase. This opens new perspectives for the design of multiple drug combination regimens targeting different enzymes involved in HIV-1 replication, i.e. integrase and reverse transcriptase. These multiple (triple or quadruple) drug combinations should be aimed at once daily dosing.

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Organophosphonates; Pyrrolidinones; Raltegravir Potassium; Tenofovir

Topics: Adult; Anti-HIV Agents; Drug Approval; HIV Infections; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; United States; United States Food and Drug Administration

Protease inhibitors potently suppress HIV viral load but are often associated with metabolic disturbances such as dyslipidemias and lipodystrophy. In addition to exercise, diet modification and anti-lipid therapies, one potential management strategy for HIV-positive patients with dyslipidemia is to switch any antiretrovirals that may be exacerbating the condition to more lipid-neutral drugs. The SWITCHMRK studies examined the effects of substituting lopinavir/ritonavir, a protease inhibitor known to cause dyslipidemias, with the integrase inhibitor raltegravir. Participants who switched from lopinavir/ritonavir to raltegravir experienced an improvement in cholesterol and triglycerides at 12 weeks; however, a large proportion of patients in the raltegravir arms did not maintain HIV virologic suppression at less than 50 copies/ml at week 24. Further analyses are underway to determine why more patients in the raltegravir arms experienced increased virologic failure and to determine whether switching lopinavir/ritonavir with raltegravir may be appropriate for specific subgroups of patients.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; Darunavir; Drug Discovery; Drug Therapy, Combination; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium; Sulfonamides

Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.

Topics: Administration, Oral; Area Under Curve; Biological Availability; Half-Life; HIV Infections; HIV Integrase Inhibitors; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Pyrrolidinones; Raltegravir Potassium

Topics: Adult; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-2; Humans; Male; Pyrrolidinones; Raltegravir Potassium; Viral Load

Enfuvirtide has been a cornerstone of salvage therapy for multidrug-resistant HIV. Raltegravir provides another novel class option, with the advantages of easier administration and improved tolerability. Thirty-five adults electively replaced enfuvirtide with raltegravir while the rest of their regimen was unchanged. All maintained virologic suppression after a median of 7 months except one who experienced a transiently detectable viral load after 5 months. The new regimen was well tolerated with no apparent new drug-related adverse clinical or laboratory events.

Topics: Adult; Aged; Drug Resistance, Multiple, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Topics: Antiretroviral Therapy, Highly Active; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rhabdomyolysis

Topics: Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Recent data showed the selection of mutations in the integrase gene, mainly involving position 148 or 155, in patients displaying virological failure (VF) on raltegravir (RAL) therapy. Here, we describe the development of RAL resistance, in both plasmatic and cellular compartments, in three heavily pretreated HIV-infected patients failing RAL-containing regimens.. Three of 17 patients receiving RAL displayed VF. The entire integrase gene, isolated from plasma and peripheral blood mononuclear cells (PBMC), was sequenced. A clonal analysis was performed in one patient at the time of VF.. At the time of VF, RAL-resistance mutations were selected: (i) Q148R in patients 1 and 3; (ii) T66A and E92Q in patient 2. A gradual accumulation of new mutations was observed in all patients, including G140S, Q148H and N155H in patient 1, L74I in patient 2, and G140S in patient 3. Clonal analysis showed the coexistence, in patient 1, of the two common resistance pathways (mutations Q148R/H and N155H) found in distinct quasi-species. In addition, RAL-resistance mutations were detected in HIV DNA in all patients.. Having rapidly established, resistance to RAL evolves and diversifies, and is likely to impact the efficacy of subsequently used second-generation integrase inhibitors. Moreover, RAL-resistance mutations can be archived early in PBMC.

Topics: CD4 Lymphocyte Count; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Mutation; Paris; Pyrrolidinones; Raltegravir Potassium; Salvage Therapy; Sequence Analysis, RNA; Treatment Failure; Viral Load

Raltegravir belongs to a new class of antiretrovirals acting for a human immunodeficiency virus (HIV)-1 integrase inhibition. Clinical trials of this drug have demonstrated potent antiviral activity in both therapy naïve and experienced patients. Thus, raltegravir has become an important component of combination treatment regimens used to treat patients with multidrug-resistant HIV-1. The quantification of raltegravir in human plasma is important to support clinical studies and determine pharmacokinetic parameters of raltegravir in HIV-1 infected patients. Recently, the LC-MS/MS superfine system was developed to determine plasma concentration of raltegravir; however, the system needs to be delicately set and the equipment is very expensive. Therefore, we developed a conventional LC-MS method to overcome these difficulties. Subsequently the method was validated by estimating the precision and accuracy for inter- and intraday analysis in the concentration range of 0.010-7.680 microg/ml. The calibration curve was linear in this range. Average accuracy ranged from 97.2 to 103.4%. Relative standard deviations of both inter- and intraday assays were less than 10.4%. Recovery of raltegravir was more than 80.6%. This novel LC-MS method is accurate and precise enough to determine raltegravir levels in human plasma samples.

Topics: Administration, Oral; Chromatography, Liquid; HIV Infections; HIV Integrase Inhibitors; Humans; Indicators and Reagents; Mass Spectrometry; Pyrrolidinones; Raltegravir Potassium; Reproducibility of Results

We investigated the in vitro phenotypic susceptibility of HIV-2 isolates from integrase inhibitor (INI)-naive patients to INIs and its relation to HIV-2 integrase gene polymorphism.. We determined the phenotypic susceptibility to raltegravir and elvitegravir of co-cultured isolates obtained from the HIV-2 ROD reference strain and from 14 clinical isolates. IC(50) values were compared with those for HIV-1 reference strains. HIV-2 integrase gene polymorphism was assessed in isolates from 52 INI-naive patients enrolled in the French HIV-2 cohort.. Median raltegravir and elvitegravir IC(50) values for the 14 clinical HIV-2 isolates were 2.4 and 0.7 nM, respectively, and were similar to those observed for HIV-2 ROD and HIV-1 reference strains. Overall, 38% of HIV-2 integrase amino acids were polymorphic. The catalytic triad DDE and the HHCC and RKK motifs were fully conserved, at the same genomic positions as described in HIV-1. In subtype B isolates, the total length of the integrase gene varied, owing to the presence of stop codons at positions 288, 294, 297 and 302. Fourteen of the positions associated with substitutions conferring INI resistance in HIV-1 were polymorphic in HIV-2.. Despite 40% heterogeneity between the HIV-1 and HIV-2 integrase genes, the phenotypic susceptibility of clinical HIV-2 isolates to INIs was similar to that of HIV-1. This new class of antiretroviral drugs thus represents a novel therapeutic possibility for HIV-2-infected patients who otherwise have few treatment options.

Topics: Amino Acid Sequence; Amino Acid Substitution; Catalytic Domain; Codon, Nonsense; Cohort Studies; Conserved Sequence; Drug Resistance, Viral; France; HIV Infections; HIV Integrase; HIV-1; HIV-2; Humans; Inhibitory Concentration 50; Integrase Inhibitors; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation, Missense; Polymorphism, Genetic; Pyrrolidinones; Quinolones; Raltegravir Potassium

Topics: Adult; Depression; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium

The contribution of clade-specific polymorphisms in the HIV-1 integrase gene towards integrase inhibitor phenotypic susceptibility was tested on 137 clinical isolates, of which 60 were non-clade B strains. Control Q148R mutant virus showed fold change values of 17.85 +/- 2.77 and 88.94 +/- 9.02 for raltegravir and elvitegravir, respectively, whereas the average fold change for the clinical samples was 0.91 +/- 0.40, and 0.84 +/- 0.37. Phenotypic testing proved that clade-specific integrase polymorphisms do not contribute to reduced susceptibility towards integrase inhibitors.

Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Polymorphism, Genetic; Pyrrolidinones; Quinolones; Raltegravir Potassium

Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-2; Humans; Male; Middle Aged; Mutation; Pyrrolidinones; Raltegravir Potassium; Treatment Failure

A new method using high-performance liquid chromatography coupled with photo diode array detection was developed and validated for the quantification of plasma concentrations of the human immunodeficiency syndrome integrase inhibitor raltegravir (RGV), the new nonnucleoside reverse transcriptase inhibitor etravirine (ETV), and 11 other antiretroviral agents: ritonavir, atazanavir, lopinavir, nevirapine, efavirenz, saquinavir, indinavir, nelfinavir, and its metabolite M-8, amprenavir, and darunavir. A simple solid phase extraction procedure was applied to 500 microL aliquots of plasma, and chromatographic separation of the drugs and internal standard (quinoxaline) was achieved with a gradient (acetonitrile and phosphate buffer) on an C-18 reverse-phase analytical column with a 28-minute analytical run time. Calibration curves were optimized according to expected ranges of drug concentrations in patients, and the coefficient of determination (r) was higher than 0.998 for all analytes. Mean intraday and interday precisions (percent relative SD) for all compounds were 3.67% and 6.39%, respectively, and mean accuracy (percent deviation from nominal concentration) was -1.17%. Extraction recovery ranged within 75% and 83% for all drugs analyzed. The solid phase extraction and high-performance liquid chromatography coupled with photo diode array method described allow a specific, sensitive, and reliable simultaneous determination of RGV, ETV, and 11 antiretroviral agents in plasma by a single assay. Good extraction efficiency and low limit of quantification make this a suitable method for use in clinical trials and for therapeutic drug monitoring of RGV, protease inhibitors, and nonnucleoside reverse transcriptase inhibitors, including ETV.

Topics: Anti-Retroviral Agents; Chromatography, High Pressure Liquid; Drug Therapy, Combination; HIV Infections; Humans; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sensitivity and Specificity

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Infectious Disease Transmission, Patient-to-Professional; Male; Occupational Exposure; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Topics: Adult; Anti-HIV Agents; Darunavir; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Salvage Therapy; Sulfonamides; Treatment Outcome

Topics: Benchmarking; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Pyrrolidinones; Raltegravir Potassium; Retreatment; Viral Load

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Clinical Trials, Phase III as Topic; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Multicenter Studies as Topic; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Deoxycytidine; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; HIV Integrase Inhibitors; Humans; Multicenter Studies as Topic; Organophosphorus Compounds; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; RNA, Viral

Topics: Clinical Trials, Phase II as Topic; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

HIV type-1 (HIV-1) protease (PR), reverse transcriptase (RT) and integrase (IN) share the same precursor polyprotein and there is much evidence to suggest functional interactions between IN and RT. We aimed to elucidate whether long-term highly active antiretroviral therapy (HAART) targeting PR and RT could influence raltegravir susceptibility and the fitness of IN.. HIV-1 IN sequences from 45 heavily antiretroviral-experienced patients with longitudinal samples separated by a median of 10 years were obtained to estimate the rate of nucleotide substitution. IN recombinant viruses were generated from five selected patients. Phenotypic susceptibility to raltegravir was tested in vitro. Changes in viral replication capacity were assayed by growth kinetics and competition of intrapatient IN recombinant viruses.. The amino acid substitution rate within IN was 0.06% per year during long-term antiretroviral treatment. Some substitutions had previously been associated with resistance to different IN inhibitors. Despite this, neither the early- nor late-derived IN recombinant viruses showed an increase in phenotypic susceptibility to raltegravir. Moreover, IN recombinant viruses corresponding to IN samples after 10 years of HAART had a replication capacity that was similar to or better than IN recombinant viruses from baseline samples.. HIV-1 IN from longitudinal samples taken from patients treated with IN inhibitor-sparing regimens showed no evidence of genotypic or phenotypic resistance to raltegravir. Additionally, long-term pressure with PR and RT inhibitors did not impair the fitness of HIV-1 IN. These data suggest that current antiretroviral regimens do not diminish the fitness of IN or influence raltegravir efficacy.

Topics: Amino Acid Substitution; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Evolution, Molecular; Genotype; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Phenotype; Pyrrolidinones; Raltegravir Potassium; Recombination, Genetic; Time Factors; Virus Replication

Topics: Anti-HIV Agents; Cardiovascular Diseases; CCR5 Receptor Antagonists; Cyclohexanes; HIV Infections; HIV Integrase Inhibitors; Humans; Maraviroc; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Triazoles

Topics: Drug Resistance, Viral; HIV; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium; United States; United States Food and Drug Administration; Virus Replication

Topics: CD4 Lymphocyte Count; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Viral Load

Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; Humans; Pyrrolidinones; Raltegravir Potassium

Topics: Clinical Trials as Topic; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Proviruses; Pyrrolidinones; Raltegravir Potassium; Virus Integration

* Raltegravir, the first in a new class of orally administered HIV type-1 (HIV-1) integrase inhibitors, selectively inhibits the strand transfer activity of HIV-1 and its integration into human DNA, a key stage in retroviral propagation, thereby limiting viral replication and the infection of new cells. * In two randomized, double-blind (with in-house blinding), placebo-controlled, multicentre, ongoing phase III trials, the proportion of patients achieving HIV-1 RNA loads of <400 copies/mL (primary endpoint) was significantly greater in raltegravir plus optimized background therapy (OBT) recipients than in placebo plus OBT recipients (preliminary 24-week results). * The proportion of patients achieving viral loads of <50 copies/mL was significantly greater with raltegravir plus OBT than with placebo plus OBT in the two studies. * In addition, mean CD4+ cell counts (secondary endpoint) were significantly increased from baseline in patients receiving raltegravir plus OBT relative to those receiving placebo plus OBT. * Raltegravir therapy was well tolerated overall. The incidence of mild to moderate adverse events was similar in the raltegravir and placebo arms of the two randomized trials.

Topics: Administration, Oral; Drug Administration Schedule; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome

Topics: Administration, Oral; CCR5 Receptor Antagonists; Cyclohexanes; Drug Administration Schedule; Drug Costs; Drug Interactions; Drug Resistance, Viral; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Maraviroc; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Triazoles

Raltegravir (MK-0518) is a potent inhibitor of human immunodeficiency virus (HIV) integrase and is clinically effective against viruses resistant to other classes of antiretroviral agents. However, it can select mutations in the HIV integrase gene. Nine heavily pretreated patients who received salvage therapy including raltegravir and who subsequently developed virological failure under raltegravir therapy were studied. For each patient, the sequences of the integrase-coding region were determined and compared to that at the beginning of the treatment. Four different mutation profiles were identified in these nine patients: E92Q, G140S Q148H, N155H, and E157Q mutations. For four patients, each harboring a different profile, the wild-type and mutated integrases were produced, purified, and assayed in vitro. All the mutations identified altered the activities of integrase protein: both 3' processing and strand transfer activities were moderately affected in the E92Q mutant; strand transfer was markedly impaired in the N155H mutant; both activities were strongly impaired in the G140S Q148H mutant; and the E157Q mutant was almost completely inactive. The sensitivities of wild-type and mutant integrases to raltegravir were compared. The E92Q and G140S Q148H profiles were each associated with a 7- to 8-fold decrease in sensitivity, and the N155H mutant was more than 14-fold less sensitive to raltegravir. At least four genetic profiles (E92Q, G140S Q148H, N155H, and E157Q) can be associated with in vivo treatment failure and resistance to raltegravir. These mutations led to strong impairment of enzymes in vitro in the absence of raltegravir: strand transfer activity was affected, and in some cases 3' processing was also impaired.

Topics: Amino Acid Sequence; Amino Acid Substitution; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Mutation; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Treatment Failure; Viral Load

Topics: Acidosis, Renal Tubular; Acute Kidney Injury; Drug Therapy, Combination; Glomerular Filtration Rate; Hepatitis C, Chronic; HIV Infections; HIV Integrase Inhibitors; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Sirolimus

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Male; Nitriles; Organic Chemicals; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Salvage Therapy; Treatment Outcome

Topics: Anti-HIV Agents; Contraindications; Cyclohexanes; Darunavir; Drug Monitoring; HIV Infections; Humans; Maraviroc; Nitriles; Organic Chemicals; Patient Education as Topic; Patient Selection; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Sulfonamides; Triazoles

Topics: Anti-HIV Agents; Cyclohexanes; Drug Resistance, Viral; Drugs, Investigational; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Maraviroc; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Triazoles

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Cyclohexanes; Cyclopropanes; HIV Infections; HIV Integrase Inhibitors; Humans; Lipodystrophy; Maraviroc; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Triazoles; Viral Load

Topics: CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Viral Load

Topics: Health Services Accessibility; HIV Infections; HIV Integrase Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Topics: HIV Infections; Humans; Multicenter Studies as Topic; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors

Topics: Anti-Retroviral Agents; Clinical Trials as Topic; Congresses as Topic; Cyclohexanes; HIV Fusion Inhibitors; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Maraviroc; Multicenter Studies as Topic; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Triazoles; United States

Topics: Acyclovir; Anti-HIV Agents; Circumcision, Male; Cyclohexanes; Dideoxynucleosides; Drug Interactions; Female; Hepatitis C; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Maraviroc; Multicenter Studies as Topic; Nitriles; Organic Chemicals; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Triazoles

Topics: Antiretroviral Therapy, Highly Active; Clinical Trials, Phase II as Topic; DNA, Viral; HIV Infections; HIV Integrase Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Topics: Anti-HIV Agents; Drug Approval; HIV Infections; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

(19)F-nuclear magnetic resonance (NMR) has been extensively used in a drug-discovery programme to support the selection of candidates for further development. Data on an early lead compound, N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (compound A (+)), and MK-0518 (N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide), a potent inhibitor of this series currently in phase III clinical trials, are described. The metabolic fate and excretion balance of compound A (+) and MK-0518 were investigated in rats and dogs following intravenous and oral dosing using a combination of (19)F-NMR-monitored enzyme hydrolysis and solid-phase extraction chromatography and NMR spectroscopy (SPEC-NMR). Dosing with the (3)H-labelled compound A (+) enabled the comparison of standard radiochemical analysis with (19)F-NMR spectroscopy to obtain quantitative metabolism and excretion data. Both compounds were eliminated mainly by metabolism. The major metabolite identified in rat urine and bile and in dog urine was the 5-O-glucuronide.

Topics: Animals; Biotransformation; Dogs; Drug Design; Fluorine; Glucuronides; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Magnetic Resonance Spectroscopy; Male; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Rats; Rats, Sprague-Dawley; Solid Phase Extraction

Topics: Drug Approval; HIV Infections; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; United States; United States Food and Drug Administration

Topics: DNA, Viral; Drug Approval; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; United States; United States Food and Drug Administration

Topics: Clinical Trials as Topic; HIV Infections; HIV Integrase Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Topics: Adult; Drug Approval; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; United States

Because raltegravir inhibits a novel viral target, even HIV that is resistant to other antiretroviral-medication classes is sensitive to this drug.

Topics: Drug Costs; HIV Infections; HIV Integrase Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Topics: Double-Blind Method; Drug Approval; HIV Infections; HIV Integrase Inhibitors; Humans; Organic Chemicals; Placebos; Pyrrolidinones; Raltegravir Potassium; Tablets; United States; United States Food and Drug Administration

Topics: Adenine; Animals; Anti-HIV Agents; Evolution, Molecular; HIV Infections; HIV-1; Humans; Organic Chemicals; Organophosphonates; Primates; Pyrrolidinones; Raltegravir Potassium; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Tenofovir

Topics: Drug Therapy, Combination; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Viral Load

Topics: Dose-Response Relationship, Drug; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Topics: Acquired Immunodeficiency Syndrome; CCR5 Receptor Antagonists; Clinical Trials as Topic; Darunavir; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Ritonavir; Salvage Therapy; Sulfonamides

The XVI International AIDS Conference (AIDS 2006), organized by the International AIDS Society (IAS), took place August 12-18 in Toronto, Canada. It was attended by over 26,000 participants from more than 170 countries and featured more than 4,500 abstracts as well as an array of community and cultural activities. The theme of the meeting was "Time to deliver", emphasizing the continued need and urgency in bringing effective HIV prevention and treatment strategies to those living with and affected by HIV/AIDS. The meeting's agenda was broad and included policy and programmatic topics as well as scientific research. This report focuses on reports presented at the conference that directly deal with antiretroviral therapy. This is primarily because of the nature of the venue where it is intended to be published (Drug News & Perspectives) as well as the expertise of the author. It is not a lack of recognition of the other equally important topics and discussions that took place at AIDS 2006. The author is solely responsible for the selection of topics and presentations to be included in this report.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Antibodies, Monoclonal; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drugs, Investigational; HIV Infections; HIV-1; Humans; Maraviroc; Nitriles; Organic Chemicals; Piperazines; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Receptors, Chemokine; Sulfonamides; Treatment Outcome; Triazoles

Topics: Clinical Trials, Phase II as Topic; HIV Infections; Humans; Lipid Metabolism; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium

Topics: Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Organic Chemicals; Peptide Fragments; Pyrrolidinones; Raltegravir Potassium; Viral Load

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Carbamates; Cyclopropanes; Furans; HIV Infections; Humans; Oligopeptides; Organic Chemicals; Organophosphates; Oxazines; Patient Compliance; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Viral Load

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Organic Chemicals; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5