ritonavir and efavirenz

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

Efavirenz, a non-nucleoside reverse-transcriptase inhibitor (NNRTI) is one of the most commonly prescribed antiretroviral drugs. The present article provides a systematic overview and meta-analysis of clinical trials comparing efavirenz and other active drugs currently recommended for treatment of HIV-infected, antiretroviral-naive patients. Electronic databases (Pubmed, Embase, the Cochrane Library, Trip Database) were searched up till 23 December 2013 for randomized controlled clinical trials published as a peer-reviewed papers, and concerning efavirenz-based regimens used as initial treatment for HIV infection. Thirty-four studies were included in the systematic review, while twenty-six trials were suitable for the meta-analysis. Efavirenz was compared with drugs from four different classes: NNRTIs other than efavirenz (nevirapine or rilpivirine), integrase strand transfer inhibitors (InSTIs), ritonavir-boosted protease inhibitors (bPI) and chemokine (C-C motif) receptor 5 (CCR5) antagonists (maraviroc), all of them were added to the background regimen. Results of the current meta-analysis showed that efavirenz-based regimens were equally effective as other recommended regimens based on NNRTI, ritonavir-boosted PI or CCR5 antagonist in terms of efficacy outcomes (disease progression and/or death, plasma viral HIV RNA <50 copies/ml) while statistically significant more patients treated with InSTI achieved plasma viral load <50 copies/ml at week 48. In comparison with both InSTI-based and CCR5-based therapy, efavirenz-based treatment was associated with a higher risk of therapy discontinuation due to adverse events. However, comparisons of efevirenz-based treatment with InSTI-based and CCR5-based therapy were based on a limited number of trials, therefore, conclusions from these two comparisons must be confirmed in further reliable randomized controlled studies. Results of our meta-analysis support the present clinical guidelines for antiretroviral-naive, HIV-infected patients, in which efavirenz is one of the most preferred regimens in the analyzed population. Beneficial safety profile of InSTI-based and CCR5-based therapy over efavirenz-based treatment needs further studies.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; HIV Infections; HIV Protease Inhibitors; Humans; Randomized Controlled Trials as Topic; Receptors, CCR5; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

Abacavir is one of the recommended nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infections among children and adolescents. However, there are concerns that the antiviral efficacy of abacavir might be low when compared to other NRTIs especially among children. There are also concerns that abacavir use may lead to serious adverse events such as hypersensitivity reactions and has potential predisposition to developing cardiovascular diseases. We searched four electronic databases, four conference proceedings and two clinical trial registries in August 2014, without language restrictions. Experimental and observational studies with control groups that examined the efficacy and safety of abacavir-containing regimens in comparison with other NRTIs as first-line treatment for HIV-infected children and adolescents aged between one month and eighteen years were eligible. Two authors independently screened search results, extracted data and assessed the risk of bias of included studies using a pre-specified, standardised data extraction form and validated risk of bias tools. We also assessed the quality of evidence per outcome with the GRADE tool.. We included two randomised controlled trials (RCTs) and two analytical cohort studies with a total of 10,595 participants. Among the RCTs we detected no difference in virologic suppression after a mean duration of 48 weeks between abacavir- and stavudine-containing regimens (2 trials; n = 326: RR 1.28; 95 % CI 0.67-2.42) with significant heterogeneity (P = 0.02; I(2) = 81 %). We also found no significant differences between the two groups for adverse events and death. After five years of follow-up, virologic suppression improved with abacavir (1 trial; n = 69: RR 1.96; 95 % CI 1.11-3.44). For cohort studies, we detected that the virologic suppression activity of abacavir was less effective than stavudine in both the lopinavir/ritonavir (1 study, n = 2165: RR 0.79, 95 % CI 0.67-0.92) and efavirenz sub-groups (1 study, n = 3204: RR 0.79, 95 % CI 0.67-0.92) respectively. The quality of evidence from RCTs was moderate for virologic suppression but low for death and adverse events, while that of cohort studies was low for all three these outcomes.. Available evidence showed little or no difference between abacavir-containing regimen and other NRTIs regarding efficacy and safety when given to children and adolescents as a first-line antiretroviral therapy.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Lopinavir; Male; Ritonavir; Stavudine

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

Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide.. Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations.. Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echinocandins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-Retroviral Agents; Antifungal Agents; Benzoxazines; Carbamates; Cyclopropanes; Drug Interactions; Drug Monitoring; Echinocandins; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Mycoses; Organophosphates; Pyrimidines; Ritonavir; Sulfonamides; Triazoles; Voriconazole

Significant advances in antiretroviral therapy have transformed HIV into a chronic manageable disease, and millions of women living with HIV now have the opportunity to reconsider their reproductive choices, be it contraception or pregnancy planning. Hormonal contraceptives are metabolized by cytochrome P450 isoenzymes and sulfate and glucuronide conjugation in the liver. Many antiretrovirals have inducing or inhibiting effects on the cytochrome P450 system. As such, the pharmacokinetics of hormonal contraceptives can be affected by antiretroviral therapy with potential for significant clinical impact.. This article presents the pharmacology and metabolism of selected antiretrovirals and hormonal contraceptives, and highlights the potential interactions between these two classes of drugs. Furthermore, the authors present the pharmacokinetic evidence of interactions from available clinical trials, product monographs, and international conference abstracts.. Drugs most likely to interact with combined oral contraceptives, transdermal and implant contraceptives include protease inhibitors, the NNRTIs efavirenz and nevirapine, and cobicistat-boosted elvitegravir. There do not appear to be significant pharmacokinetic interactions with depo-medroxyprogesterone or intrauterine systems and antiretrovirals, although further study is needed. Clinicians working with HIV-positive women need to know the significance of these interactions in order to properly counsel patients and prevent unplanned pregnancies.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Contraceptive Agents, Female; Cyclopropanes; Drug Interactions; Female; HIV Seropositivity; Humans; Medroxyprogesterone Acetate; Nevirapine; Pregnancy; Pregnancy, Unplanned; Protease Inhibitors; Ritonavir

Nevirapine belongs to the group of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and is commonly administered in first-line treatment of HIV infection.. Systematic review and meta-analysis was undertaken to compare effectiveness of nevirapine-based regimens with other antiretroviral schedules used as an initial treatment of HIV-infected antiretroviral-naive subjects.. Electronic databases (PubMed, EMBASE, the Cochrane Library, Trip Database) were searched up to 28 December 2012 for randomized controlled trials (RCTs) published as a full text and regarding nevirapine-based regimens used as a initial treatment for HIV infection. Meta-analysis was performed with RevMan(®) V 5.2 software.. Twelve RCTs were included in the systematic review and all of them were suitable for meta-analysis. Results of the meta-analysis have shown that nevirapine, efavirenz, and ritonavir-boosted protease inhibitor, added to the background regimens, were equally effective in terms of reaching undetectable plasma HIV RNA level as well as risk of disease progression or death. Compared with ritonavir-boosted protease inhibitor-based regimens, nevirapine-based regimens statistically significantly increased the risk of discontinuation of assigned treatment (RR=3.10; 95% CI: 1.14-8.41; p<0.05).. Despite limited RCTs data available for particular comparisons, our results suggest that nevirapine-based regimens may be considered for first-line treatment of HIV-infected adults, due to their comparable efficacy to the other currently recommended initial antiretroviral therapies.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Nevirapine; Randomized Controlled Trials as Topic; Ritonavir; Treatment Outcome

HIV-positive children are at high risk of drug resistance, which is of particular concern in settings where antiretroviral options are limited. In this Review we explore resistance rates and patterns among children in developing countries in whom antiretroviral treatment has failed. We did a systematic search of online databases and conference abstracts and included studies reporting HIV-1 drug resistance after failure of first-line paediatric regimens in children (<18 years) in resource-poor regions (Latin America, Africa, and Asia). We retrieved 1312 citations, of which 30 studies reporting outcomes in 3241 children were eligible. Viruses with resistance-associated mutations were isolated from 90% (95% CI 88-93%) of children. The prevalence of mutations associated with nucleoside reverse transcriptase inhibitors was 80%, with non-nucleoside reverse transcriptase inhibitors was 88%, and with protease inhibitors was 54%. Methods to prevent treatment failure, including adequate paediatric formulations and affordable salvage treatment options are urgently needed.

Topics: Adolescent; Africa; Alkynes; Anti-HIV Agents; Asia; Benzoxazines; Child; Child, Preschool; Cross-Sectional Studies; Cyclopropanes; Developing Countries; Drug Resistance, Viral; Female; Health Resources; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Latin America; Lopinavir; Male; Mutation; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Treatment Failure; Viral Load; Zidovudine

HIV infection is a serious but treatable disease, yet current treatment is limited by development of resistance and high rates of adverse drug reactions. Antiretroviral therapy is especially suitable for pharmacogenomic investigation as both drug exposure and treatment response can be reliably measured. Increasing knowledge about genes implicated in pharmacokinetics, mode of action, efficacy, and toxicity of drugs has already provided relevant results for clinical practice, for example: The strong association of the abacavir hypersensitivity reaction with HLA-B*5701 permits testing patients for the allele, and if present avoiding the drug and therefore preventing the reaction. Persons with the allele CYP2B6*6 present higher efavirenz "area under the curve" and have increased risk of neuropsychological toxicity. Additional gene variants are being discovered that influence the action of antiretroviral drugs. And, moreover, it is expected that larger-scale comprehensive genome approaches will profoundly improve the landscape of knowledge of HIV therapy in the future. The present article shows some recent patents related to the treatment of viral infections.

Topics: Alkynes; Anti-Retroviral Agents; Aryl Hydrocarbon Hydroxylases; Atazanavir Sulfate; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Cytochrome P-450 CYP2B6; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Viral; Dyslipidemias; Genetic Predisposition to Disease; Genetic Testing; Glucuronosyltransferase; HLA Antigens; Humans; Hyperbilirubinemia; Nevirapine; Oligopeptides; Oxidoreductases, N-Demethylating; Patents as Topic; Patient Selection; Pharmacogenetics; Pyridines; Ritonavir

The strategy of induction-maintenance therapy with lopinavir-ritonavir (LPV7r) consists of initiating antiretroviral therapy in a treatment-naïve patient with two nucleosides plus LPV/r. When the patient has achieved an undetectable HIV RNA viral load of < 50 copies/mL for a specified time period, the nucleosides are withdrawn and the patient continues to receive antiretroviral therapy with LPV/r monotherapy. The induction-maintenance strategy with LPV/r has been analyzed in the M03-613 clinical trial. In this trial, antiretroviral-naïve patients were randomized to receive zidovudine/lamivudine plus LPV/r (n = 104) or efavirenz (n = 51). In patients randomized to receive LPV/r who achieved an HIV RNA viral load of < 50 copies/mL for 3 consecutive months, nucleoside therapy was suspended. In an intention-to-treat analysis (missing equals failure), 60% of the patients randomized to receive LPV/r and 63% of those randomized to receive efavirenz maintained an HIV RNA viral load of < 50 copies/mL at 96 weeks of follow-up (p = 0.73; 95% confidence interval for the difference -19% to 13%). Moreover, this study showed that patients randomized to LPV/r experienced less lipoatrophy than those randomized to efavirenz. The M03-613 trial suggests that the induction-maintenance strategy with LPV/r is safe in most patients. However, rates of virological efficacy are lower than those achieved with the simplification strategy. Moreover, this trial demonstrates that LPV/r monotherapy may have major benefits in peripheral fat preservation.

Topics: Adipose Tissue; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Lopinavir; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load; Virus Replication; Zidovudine

The efficacy of HIV-1 protease inhibitors (PIs) as part of highly active antiretroviral therapy is now well established and has provided benefits to many patients with HIV infection. Atazanavir is a new azapeptide PI compound that was recently approved in the US and Europe. Atazanavir is recommended in combination with other antiretroviral agents for the treatment of HIV-1 infection. Atazanavir is rapidly absorbed and administration of a single dose of atazanavir with a light meal resulted in a 70% increase in area under the plasma concentration-time curve (AUC); therefore atazanavir should be taken with food. Atazanavir is 86% bound to human serum protein independently of concentration. Concentration in body fluids appeared to be lower than plasma concentration. Like other PIs, atazanavir is extensively metabolised by hepatic cytochrome P450 (CYP) 3A isoenzymes. The mean terminal elimination half-life in healthy volunteers was approximately 7 hours at steady state following administration of atazanavir 400 mg daily with a light meal. When atazanavir 300 mg was coadministered with ritonavir 100 mg on a once-daily dosage regimen, atazanavir AUC from 0 to 24 hours and minimum plasma concentration were increased by 3- to 4-fold and approximately 10-fold, respectively, compared with atazanavir 300 mg alone. Therefore, ritonavir boosted atazanavir regimen (ritonavir 100 mg and atazanavir 300 mg once daily) is increasingly favoured in some patients. Efavirenz, a potent CYP3A inducer, decreased atazanavir concentrations by 75% and, unexpectedly, tenofovir, a nucleotide reverse transcriptase inhibitor, decreased atazanavir concentrations by 25%. Average predose concentrations in HIV-infected patients who received atazanavir 400mg once daily were 273 ng/mL, which was believed to be several-fold higher than protein-binding corrected 50% inhibitory concentration of wild-type viruses. In HIV-infected patients who received once-daily ritonavir (100mg) boosted atazanavir (300 mg), mean (+/-SD) trough concentration was 862 (+/-838) ng/mL. Several clinical trials showed the efficacy of atazanavir 400 mg once daily with a nucleoside analogue backbone in antiretroviral-naive patients. The atazanavir 300/ritonavir 100 mg once-daily combination coadministered with other antiretrovirals showed the efficacy of this strategy in patients receiving efavirenz or in moderately antiretroviral-experienced HIV-infected patients. Recommended once-daily doses of atazanavir taken with fo

Topics: Adenine; Age Factors; Alkynes; Atazanavir Sulfate; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver; Oligopeptides; Organophosphonates; Oxazines; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Sex Factors; Tenofovir

Although the reduction in HIV-1-related deaths with highly active antiretroviral therapy (HAART) is similar in adults and children, the extent of the changes in two important surrogate markers HIV-1 RNA levels and CD4+ T cell counts, differs widely. In most paediatric studies virological response rates to HAART are inferior to those in adults. This review provides an overview of the paediatric clinical studies using HAART and seeks to improve the understanding of factors that may contribute to success or failure of HAART in children. An overview of all current articles on paediatric clinical trials using HAART is provided. 23 papers were available. HIV-1 RNA loads and CD4+ T cell counts were used as primary outcome measures. Virological response rates were highly variable, both among the different antiretroviral drugs but also among different studies using the same medication. Four studies in which dosages of the administrated protease inhibitor (PI) were adjusted after pharmacokinetic evaluation had superior virological response rates compared with those in which fixed dosages were used. Immunological response rates were more uniform than virological responses. In almost all studies increases of CD4+ T cell counts are reported independent of the extent of the virological response. Side-effects of HAART were generally mild, transient, and of gastrointestinal origin. Significant percentages of patients with serum lipid abnormalities were reported in three paediatric studies. However, signs of clinical lipodystrophy were not observed. The inferior virological response rates, which have been reported in HIV-1 infected children treated with HAART form a reflection of the challenges that are encountered in the treatment of these children. Difficulties with adherence and with the pharmacokinetics of PIs in children require an intensive, child-adjusted approach. A practical approach to therapy in institutions without tertiary care facilities may be induction therapy with a lopinavir containing regimen (lacking a need for therapeutic drug monitoring), to reduce high viral load levels followed by an easily tolerated maintenance regimen, for example containing abacavir or nevirapine.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Sulfonamides; Zalcitabine; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine

Hypertension (HTN) is a common comorbidity among people with HIV and associated with an increased risk for atherosclerotic cardiovascular disease and chronic kidney disease. The relationship of antiretroviral therapy (ART) initiation to incident HTN remains a clinical question. We determined HTN incidence at 48 weeks of follow-up among ART-naive participants without HTN and not taking antihypertensive medications at ART initiation through randomized clinical trials through the AIDS Clinical Trial Group between 1999 and 2011. We assessed the association of baseline characteristics, including randomized ART agents with HTN incidence at 48 weeks using Poisson regression models. Incident HTN was defined as blood pressure ≥130/80 mmHg, or use of antihypertensive medication. Among 2,614 participants, mean age was 37 ± 10 years, 79% male sex, and 36% African American race. After 48 weeks, 839 participants (32%) developed HTN. Receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI) was associated with an increased relative risk (RR) of incident HTN, while the risk was lower for protease inhibitor use. Stavudine and efavirenz were associated with an increased RR of developing HTN, while tenofovir disoproxil fumarate, darunavir/ritonavir, and atazanavir/ritonavir were associated with a decreased risk of developing HTN. Additionally, older age, higher body mass index (BMI), and having hepatitis C were associated with an increased risk for developing HTN, while women and participants with a higher baseline CD4 count were at a decreased risk of developing HTN at 48 weeks. One third of these ART naive participants developed HTN after ART initiation. NNRTIs, notably efavirenz, and stavudine were associated with an increased risk of HTN. Additional factors associated with HTN included traditional factors like older age and higher BMI, and advanced HIV disease (lower CD4 count). (Clinicaltrials.gov: NCT00001137).

Topics: Adult; Alkynes; Anti-HIV Agents; Antihypertensive Agents; Benzoxazines; Cyclopropanes; Female; HIV Infections; Humans; Hypertension; Male; Middle Aged; Risk Factors; Ritonavir; Stavudine

In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions.. In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 μg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed.. The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers.. CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Contraceptive Agents, Female; Contraceptive Agents, Hormonal; Contraceptive Devices, Female; Cyclopropanes; Cytochrome P-450 CYP2B6; Desogestrel; Drug Interactions; Ethinyl Estradiol; Female; Genetic Association Studies; Genotype; HIV Infections; Humans; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Ritonavir; Vagina

Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART.. Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay.. Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases.. Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority.. NCT00993031.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Estradiol; Female; HIV Infections; HIV-1; Humans; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Progesterone; Ritonavir; Uganda

In this study, we evaluated the relationships between immune activation, bone turnover, and bone mass in virally suppressed HIV-infected children and HIV-uninfected children in South Africa. We found that decreased bone mass may occur or persist independent of immune activation and altered bone turnover.. HIV-infected children and adolescents have deficits in skeletal growth which include decreases in bone mass and alterations in bone microarchitecture. However, the mechanism by which HIV infection compromises bone accrual in children and adolescents is unclear. The goal of this study was to evaluate the relationships between immune activation, bone turnover, and bone mass in a group of pre-pubertal HIV-infected children randomized to remain on ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy (ART) or switch to efavirenz-based ART in South Africa virally suppressed at the time of this study.. This cross-sectional analysis included 219 HIV-infected and 180 HIV-uninfected children enrolled in the CHANGES Bone Study conducted in Johannesburg, South Africa. Whole body (WB) bone mineral content (BMC) was assessed by dual x-ray absorptiometry and WB BMC Z-scores adjusted for sex, age, and height were generated. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx) and procollagen type I N-terminal propeptide (P1NP), were analyzed. Markers of immune activation were also measured, including cytokines IL-6 and TNF-alpha, as well as soluble CD14 and high-sensitivity C-reactive protein (CRP).. Compared to uninfected controls, HIV-infected children had lower WB BMC Z-scores, similar IL-6 and TNF-alpha, higher soluble CD14 and high-sensitivity CRP, and lower markers of bone resorption (CTX) and bone formation (P1NP). Bone turnover markers were not different in those remaining on LPV/r or switched to efavirenz.. Our findings suggest that in HIV-infected children with viral suppression, decreased bone accrual may occur or persist independent of immune activation and altered bone turnover.

Topics: Absorptiometry, Photon; Alkynes; Benzoxazines; Bone Density; Bone Remodeling; Child; Child, Preschool; Collagen Type I; Cross-Sectional Studies; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Peptides; Ritonavir; South Africa

The aim of this study was to compare the differential effects of first-line efavirenz (EFV)-based vs. boosted lopinavir-based antiretroviral regimens on cholesterol metabolism.. Multicentre, open-label, randomized clinical trial.. Forty-nine naive HIV-infected patients were randomized (1 : 1) to receive either ritonavir-boosted lopinavir (LPV/r) or EFV both in combination with tenofovir and emtricitabine (ClinicalTrials.gov: NCT00759070). Lipid profile and serum phytosterols and cholesterol precursors were determined at baseline and after 16 weeks.. After 16 weeks of intervention, total and non-HDL cholesterol as well as triglyceride levels significantly increased in the LPV/r-group (+1.0 ± 0.8; +0.8 ± 0.7 and +0.8 ± 1.5 mmol/l, respectively), but not in the EFV-group (+0.4 ± 0.7; +0.4 ± 0.6 and 0.2 ± 0.5 mmol/l, respectively). Markers of cholesterol absorption (campesterol-to-cholesterol and sitosterol-to-cholesterol ratios) significantly increased in the LPV/r-group, but not in the EFV-group, whereas there were no changes in either group of the lathosterol-to-cholesterol ratio, a marker of cholesterol synthesis.. Treatment with an LPV/r-based therapy increased total cholesterol relative to EFV-based therapy. Our data suggest that absorption rather than synthesis is the mechanism involved in LPV/r-associated increased total cholesterol.

Topics: Adolescent; Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Blood Chemical Analysis; Cholesterol; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Young Adult

We previously demonstrated the noninferiority of switching to efavirenz (EFV) versus remaining on ritonavir-boosted lopinavir (LPV/r) for virologic control in children infected with human immunodeficiency virus (HIV) and exposed to nevirapine (NVP) for prevention of mother-to-child transmission. Here we assess outcomes up to 4 years post-randomization.. From 2010-2013, 298 NVP-exposed HIV-infected children ≥3 years of age were randomized to switch to EFV or remain on LPV/r in Johannesburg, South Africa (Clinicaltrials.gov NCT01146873). After trial completion, participants were invited to enroll into observational follow-up. We compared HIV RNA levels, CD4 counts and percentages, lipids, and growth across groups through four years post-randomization.. HIV RNA levels 51-1000 copies/mL were less frequently observed in the EFV group than the LPV/r group (odds ratio [OR] 0.67, 95% confidence interval [CI]: 0.51-0.88, P = .004), as was HIV RNA >1000 copies/mL (OR 0.52 95% CI: 0.28-0.98, P = .04). The probability of confirmed HIV RNA >1000 copies/mL by 48 months was 0.07 and 0.12 in the EFV and LPV/r groups, respectively (P = .21). Children randomized to EFV had a reduced risk of elevated total cholesterol (OR 0.45 95% CI: 0.27-0.75, P = .002) and a reduced risk of abnormal triglycerides (OR 0.42, 95% CI 0.29-0.62, P < .001).. Our results indicate that the benefits of switching virologically suppressed NVP-exposed HIV-infected children ≥3 years of age from LPV/r to EFV are sustained long-term. This approach has several advantages, including improved palatability, reduced metabolic toxicity, simplified cotreatment for tuberculosis, and preservation of second line options.. NCT01146873.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Child, Preschool; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Infant; Lipids; Lopinavir; Male; Nevirapine; Ritonavir; RNA, Viral; Treatment Outcome

The 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.. The MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12-15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).. Between May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12-15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), -11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, -13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.. At the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.. ClinicalTrial.gov registry n° NCT01127204 , 19 May 2010.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Burkina Faso; Child, Preschool; Cote d'Ivoire; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Lamivudine; Lopinavir; Male; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load

The contribution of specific antiretroviral drugs to cognitive function in HIV-infected people remains poorly understood. Efavirenz (EFV) may plausibly cause cognitive impairment. The objective of this study was therefore to determine whether chronic EFV therapy is a modifier of neurocognitive and neurometabolic function in the setting of suppressive highly active antiretroviral therapy.. We performed an open-label phase IV controlled trial. Adult subjects who were stable on suppressive EFV therapy for at least 6 months were switched to ritonavir-boosted lopinavir (LPV/r) with no change in the nucleoside reverse transcriptase inhibitor (NRTI) backbone. The following parameters were assessed before and 10 weeks after therapy switch: cognitive function (by CogState. Sixteen subjects completed the study. Despite most subjects (81%) self-reporting memory problems at baseline, cognitive function, brain metabolites, and brain activity showed no change at 10 weeks after switch. Sleep quality improved on switch off EFV [mean PSQI (standard deviation): EFV, 8.5 (6.5); LPV/r, 5.8 (5.5); mean difference -0.4; 95% confidence interval -6.0 to -0.7].. This is the first study to assess the effects of chronic EFV therapy on neurological function in a controlled setting. We conclude that EFV withdrawal is unlikely to result in significant modification of neurocognitive function in otherwise stable HIV-infected people.

Topics: Adult; Alkynes; Benzoxazines; Brain Chemistry; Cognition; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Neuropsychological Tests; Proton Magnetic Resonance Spectroscopy; Ritonavir; Treatment Outcome; Young Adult

The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone.. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCτ) and average concentration (C avg) were calculated and compared using an unpaired t test.. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCτ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P≤ .01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone C avg>15 µg/mL, which has previously been associated with successful treatment of Pneumocystis jirovecipneumonia. AUCτ and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C avg>18.5 µg/mL, a concentration that has previously been associated with successful treatment of Toxoplasmaencephalitis (TE).. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.. NCT01479361.

Topics: Administration, Oral; Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Anti-Infective Agents; Atazanavir Sulfate; Atovaquone; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Encephalitis; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Reverse Transcriptase Inhibitors; Ritonavir; Toxoplasmosis, Cerebral; Young Adult

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

To assess whether changes in antiretroviral drugs other than thymidine nucleoside reverse transcriptase inhibitors (NRTI) may have a body fat impact in HIV-infected patients with lipoatrophy.. Ninety-six-week phase IV, open-label, multicentre, pilot randomized trial. HIV-infected patients with moderate/severe lipoatrophy at one or more body sites despite long-term thymidine NRTI-free therapy were randomized to continue their efavirenz (EFV)-based antiretroviral regimen or to switch from EFV to lopinavir/ritonavir (LPV/r). The primary endpoint was the absolute change in limb fat mass measured by dual X-ray absorptiometry from baseline to 96 weeks. Changes in other body fat measurements, subjective perception of lipoatrophy, subcutaneous fat gene expression and plasma lipids were also assessed.. Thirty-three patients (73% men, median age 52 years) were recruited. At 96 weeks, absolute limb fat mass increased in the LPV/r arm vs. the EFV arm (estimated difference +1082.1 g; 95% CI +63.7 to +2103.5; P = 0.04); this difference remained significant after adjustment by gender, age, fat mass, body mass index and CD4 cell count at baseline. Subjective lipoatrophy perception scores also improved in the LPV/r arm relative to the EFV arm. Adipogenesis, glucose and lipid metabolism, and mitochondrial gene expression increased in the LPV/r arm compared with the EFV arm at 96 weeks. HDL cholesterol decreased in the LPV/r arm relative to the EFV arm.. Switching from EFV to LPV/r in HIV-infected patients with lipoatrophy may offer further limb fat gain beyond thymidine NRTI discontinuation, although this strategy decreased plasma HDL cholesterol and caused changes in subcutaneous fat gene expression that may be associated with increased insulin resistance.

Topics: Adipogenesis; Adipose Tissue; Alkynes; Anti-Retroviral Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Combinations; Extremities; Female; Gene Expression Regulation; HIV Infections; Humans; Lipid Metabolism; Lipids; Lopinavir; Male; Middle Aged; Pilot Projects; Ritonavir; Treatment Outcome

The use of progestogen-only contraceptives may cause a change in bleeding pattern, which is a common cause of discontinuation of these methods. Co-administration with some antiretroviral therapies (ART) changes the bioavailability of the etonogestrel (ENG)-releasing contraceptive implant, possibly affecting the bleeding pattern. Bleeding patterns were evaluated in HIV-positive users of the ENG implant co-administered with two common ART regimens.. Forty-five HIV-positive women who wished to use an ENG implant were included in this study: 15 had received zidovudine/lamivudine (AZT/3TC) + lopinavir/ritonavir (LPV/r) for ≥3 months (LPV/r-based ART group), 15 had received AZT/3TC + efavirenz (EFV) for ≥3 months (EFV-based ART group), and 15 had not received ART (non-ART group). Bleeding patterns were evaluated at 3 and 6 months after implant placement using a standard bleeding calendar.. Amenorrhoea and infrequent bleeding rates were higher in the LPV/r-based ART group (50% and 36%, respectively) than in the other groups (non-ART group, 36% and 29%, respectively; EFV-based ART group, 7% and 14.5%, respectively; p = 0.01). The EFV-based ART group more frequently had regular bleeding (71.5%) compared with the other groups (LPV/r-based ART group, 7%; non-ART group, 21%; p = 0.01). The proportions of women with frequent and prolonged bleeding were similar (p > 0.05) in the three groups.. The co-administration of EFV-based or LPV/r-based ART with the ENG implant affected the expected bleeding patterns during use of the implant, although unfavourable bleeding (frequent and prolonged) was not associated with the medications under evaluation.

Topics: Adolescent; Adult; Alkynes; Amenorrhea; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Desogestrel; Drug Combinations; Drug Implants; Drug Interactions; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Metrorrhagia; Prospective Studies; Ritonavir; Young Adult; Zidovudine

We investigate if switching from a ritonavir-boosted lopinavir (LPV/r)-based to an efavirenz-based antiretroviral therapy (ART) regimen is associated with beneficial bone development.. The CHANGES Bone Study follows HIV-infected children who participated in a noninferiority randomized trial in Johannesburg, South Africa evaluating the safety and efficacy of preemptive switching to efavirenz (n = 106) compared with remaining on LPV/r (n = 113). HIV-uninfected children were also recruited. Whole-body and lumbar spine bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry at a cross-sectional visit. BMC Z-scores adjusted for sex, age, and height were generated. Physical activity and dietary intake were assessed. CD4 percentage and viral load were measured. We compared bone indices of HIV-infected with HIV-uninfected children and LPV/r with efavirenz by intent-to-treat.. The 219 HIV-infected (52% boys) and 219 HIV-uninfected (55% boys) children were 6.4 and 7.0 years of age, respectively. Mean ART duration for HIV-infected children was 5.7 years. Whole-body BMC Z-score was 0.17 lower for HIV-infected children compared with HIV-uninfected children after adjustment for physical activity, dietary vitamin D and calcium (P = 0.03). Whole-body BMC Z-score was 0.55 higher for HIV-infected children switched to efavirenz compared with those remaining on LPV/r after adjustment for physical activity, dietary vitamin D and calcium, CD4 percentage, and viral load (P < 0.0001).. South African HIV-infected children receiving ART have lower bone mass compared with HIV-uninfected controls. Accrued bone mass is positively associated with switching to efavirenz-based ART compared with remaining on LPV/r, providing additional rationale for limiting LPV/r exposure once viral suppression has been achieved.

Topics: Absorptiometry, Photon; Alkynes; Anti-Retroviral Agents; Benzoxazines; Bone and Bones; Bone Development; CD4 Lymphocyte Count; Child; Cross-Sectional Studies; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Ritonavir; South Africa; Treatment Outcome; Viral Load

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

Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4⁺ cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda.. Randomized clinical trial.. We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ≤400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduce placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naive pregnant women at 12-28 weeks gestation and any CD4⁺ cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum.. The median age of the 389 study participants was 29 years; median CD4⁺ cell count was 370 cells/μl. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P < 0.001). At 48 weeks postpartum, 91.0% of women on efavirenz and 88.4% on lopinavir/ritonavir had viral suppression (P = 0.49). Grade 1 or 2 gastrointestinal adverse events were higher among women on lopinavir/ritonavir versus efavirenz. Only two infants acquired HIV (both in the lopinavir/ritonavir arm), and HIV-free infant survival was similar between study arms: 92.9% (lopinavir/ritonavir) versus 97.2% (efavirenz) (P = 0.10).. Virologic suppression at delivery was higher with an efavirenz versus lopinavir/ritonavir-based regimen. However, women in both arms achieved high levels of virologic suppression through 1 year postpartum and the risk of transmission to infants was low.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Breast Feeding; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lopinavir; Malaria; Pregnancy; Pregnancy Complications, Infectious; Ritonavir; Uganda; Viral Load

Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naive, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens.. Randomized, controlled, open-label, multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naive patients with <100 CD4 cells per cubic millimeter were randomly assigned in a 1:1:1 ratio to efavirenz (n = 29), atazanavir/ritonavir (n = 30), or lopinavir/ritonavir (n = 30) combined with tenofovir plus emtricitabine. The primary outcome was median increase in CD4 cell count at week 48. Secondary end points were the proportion of patients with HIV-1 RNA <50 copies per milliliter, adverse events, disease progression, and death.. In the on-treatment analysis, the median (interquartile range) increase in the CD4 count after 48 weeks was +193 (129-349) cells per microliter in the efavirenz arm, +197 (146-238) cells per microliter in the ritonavir-boosted atazanavir arm, and +205 (178-327) cells per microliter in the ritonavir-boosted lopinavir arm (P = 0.73). The percentage of patients achieving viral suppression was similar in all 3 treatment arms at 48 weeks {efavirenz, 85.71% [95% confidence interval (CI): 68.5 to 94.3]; atazanavir, 80% [95% CI: 62.7 to 90.5]; and lopinavir, 82.8% [95% CI: 65.5 to 92.4]; P = 0.88}. Bacterial translocation, inflammation, immune activation, and apoptotic markers, but not D-dimer, declined significantly and similarly in the 3 treatment arms. Adverse events had a similar incidence in all 3 antiretroviral regimens. No patients died.. The immune reconstitution induced by an efavirenz-based regimen in very advanced HIV-1-infected patients was similar to that induced by a ritonavir-boosted protease inhibitor-based regimen (ClinicalTrials.gov registration number: NCT00532168).

Topics: Adult; Aged; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Plasma; Ritonavir; RNA, Viral; Survival Analysis; Treatment Outcome; Viral Load; Young Adult

Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202.. Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms.. Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10).. Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Creatinine; Cyclopropanes; Dideoxynucleosides; Female; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; Ritonavir; Tenofovir

Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK), adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo, Uganda. In 2011, 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women, 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure, 26% lost weight ante-partum, and median BMI post-partum was only 20.2 kg/m(2) . Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall, drug exposure was reduced (LPV -33%, EFV -15%, ritonavir -17%) compared to well-nourished controls (P < 0.001), attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% (P < 0.001), whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure (P < 0.001), explaining 29% PK-variability. In conclusion, pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women, compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Biological Availability; Breast Feeding; Cyclopropanes; Dried Blood Spot Testing; Drug Combinations; Drug Therapy, Combination; Female; Hair; HIV Infections; Humans; Lopinavir; Malnutrition; Medication Adherence; Middle Aged; Nutritional Status; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Ritonavir; Uganda; Young Adult

CD4(+) count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function parameters and the relationship with the gain of CD4(+) count have not been assessed in a randomized clinical trial. Fifty antiretroviral treatment (cART) naïve HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine for 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, interleukin (IL)-7-receptor/IL-7 system, thymic volume, and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Both groups experienced a CD4(+) count increase that was higher in the EFV group (ΔCD4(+) 88 vs. 315 cells/μl LPV/r vs. EFV, respectively, p<0.001). Despite this difference in CD4(+) gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion, and apoptosis on CD4(+) and CD8(+) T cells (p<0.001 for all) and a significant increase in markers of thymic function, IL-7 receptor, and in the levels of central memory CD4(+) T cells and naive subsets of CD8(+) T cells (p<0.001 for all) with respect to baseline values were observed without any difference between groups. These data indicate that the differences in CD4(+) gain with different cART regimens are not immunologically meaningful and might explain the similar clinical efficacy of these regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; HIV Infections; Humans; Immune System; Lopinavir; Male; Middle Aged; Ritonavir; Time Factors; Treatment Outcome

Data on the interaction between the etonogestrel (ENG) implant and antiretroviral therapy are lacking. We evaluated the effect of 2 highly active antiretroviral therapy (HAART) regimens (1 including efavirenz and the other ritonavir-boosted lopinavir) on the pharmacokinetic (PK) parameters of an ENG-releasing implant in HIV-positive women.. Prospective nonrandomized PK study.. Forty-five HIV-positive women who desired to use ENG implants were included: 15 had received zidovudine/lamivudine + lopinavir/ritonavir for ≥3 months (LPV/r-based HAART group), 15 had received zidovudine/lamivudine + efavirenz for ≥3 months (EFV-based HAART group), and 15 had not received HAART (non-HAART group). PK parameters were measured using ultra-performance liquid chromatography-mass spectrometry at baseline and 2, 4, 6, 8, 10, 12, 16, 20, and 24 weeks after implant placement.. The EFV-based HAART regimen was associated with a reduction in the bioavailability of ENG, which showed decreases of 63.4%, 53.7%, and 70% in the area under the curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of ENG, respectively, compared with the non-HAART group. The LPV/r-based HAART regimen was associated with an increase in ENG bioavailability, which showed 52%, 60.6%, and 33.8% increases in the ENG AUC, Cmax, and Cmin, respectively, compared with the non-HAART group.. The coadministration of EFV decreased the bioavailability of ENG released from the implant, which could impair contraceptive efficacy. However, the coadministration of LPV/r increased the bioavailability of ENG released from the implant, which suggests that this antiretroviral combination does not impair the ENG implant efficacy.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Biological Availability; Contraceptive Agents, Female; Cyclopropanes; Desogestrel; Drug Combinations; Drug Implants; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Ritonavir; Young Adult

Conflicting reports on the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r) on subcutaneous adipose tissue (SAT) have been described.. The aim was to assess the 48-week molecular and clinical effects of LPV/r and EFV, combined with tenofovir/emtricitabine (TDF/FTC), on SAT of HIV-infected, antiretroviral-naive patients.. Forty-four adults were started on LPV/r or EFV combined with TDF/FTC. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by dual x-ray absorptiometry scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) and transcripts for mtDNA-encoded proteins and genes involved in inflammation, adipocyte differentiation, and metabolism were assessed in paired SAT biopsies.. Whole-body fat and limb fat mass increased in the LPV/r and EFV groups. MtDNA and cytochrome oxidase subunit II did not change, and cytochrome b increased significantly in EFV-treated patients. Tumor necrosis factor alpha and monocyte chemotactic protein-1 gene expression did not change in the LPV/r group, but these significantly increased in the EFV group. Interleukin 18 decreased in the LPV/r group, whereas it increased in the EFV group.. Starting TDF/FTC plus EFV was associated with an increased expression of genes encoding for inflammatory cytokines in SAT in naive patients. Therapy with TDF/FTC plus LPV/r or EFV was associated with an increase in subcutaneous fat mass.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Gene Expression Regulation; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Organophosphonates; Ritonavir; Subcutaneous Fat; Tenofovir; Transcriptome

There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis drugs, is a minor (∼20%) metabolic pathway for PA-824. In a phase I clinical trial, we characterized interactions between PA-824 and efavirenz (arm 1), lopinavir/ritonavir (arm 2), and rifampin (arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in arms 1 and 2 were randomized to receive drugs via sequence 1 (PA-824 alone, washout, ARV, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated. Compared to PA-824 alone, plasma PA-824 values (based on geometric mean ratios) for maximum concentration (Cmax), area under the concentration-time curve from 0 to 24 h (AUC0-24), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz, 13%, 17%, and 21% with lopinavir-ritonavir (lopinavir/r) and 53%, 66%, and 85% with rifampin, respectively. Medications were well tolerated. In conclusion, lopinavir/r had minimal effect on PA-824 exposures, supporting PA-824 use with lopinavir/r without dose adjustment. PA-824 exposures, though, were reduced more than expected when given with efavirenz or rifampin. The clinical implications of these reductions will depend upon data from current clinical trials defining PA-824 concentration-effect relationships. (This study has been registered at ClinicalTrials.gov under registration no. NCT01571414.).

Topics: Adult; Alkynes; Antitubercular Agents; Antiviral Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Female; Humans; Lopinavir; Male; Middle Aged; Nitroimidazoles; Pharmacogenetics; Rifampin; Ritonavir; Young Adult

Human immunodeficiency virus (HIV)-infected pregnant women are at increased risk of malaria and its complications. In vitro and in vivo data suggest that the HIV protease inhibitors lopinavir/ritonavir may have potent antimalarial activity. We sought to evaluate whether lopinavir/ritonavir-based antiretroviral therapy (ART) reduced the risk of placental malaria.. HIV-infected, ART-naive pregnant women were enrolled between gestational weeks 12 and 28 and randomly assigned to receive lopinavir/ritonavir-based or efavirenz-based ART. Women received daily trimethoprim-sulfamethoxazole prophylaxis and insecticide-treated bed nets at enrollment and were followed up to 1 year after delivery. The primary outcome was placental malaria, defined by the detection of malaria parasites, using microscopy or polymerase chain reaction (PCR) analysis of placental blood specimens. Secondary outcomes included placental malaria, defined by histopathologic results; adverse birth outcomes; incidence of malaria; and prevalence of asymptomatic parasitemia. Analyses were done using an intention-to-treat approach.. Of 389 subjects randomly assigned to a treatment group, 377 were followed through to delivery. There was no significant difference in the risk of placental malaria, as defined by thick smear or PCR findings, between the lopinavir/ritonavir-based and efavirenz-based ART arms (7.4% vs 9.8%; P = .45). Similarly, there were no differences in secondary outcomes between the 2 treatment arms.. Lopinavir/ritonavir-based ART did not reduce the risk of placental or maternal malaria or improve birth outcomes, compared with efavirenz-based ART.. NCT00993031.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Antimalarials; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Female; HIV Infections; Humans; Infant, Newborn; Lopinavir; Malaria; Pregnancy; Pregnancy Complications, Infectious; Ritonavir; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

Protease inhibitor-based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART.. This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12-28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim-sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression.. Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth.. LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Female; HIV Infections; Humans; Infant, Newborn; Lopinavir; Male; Pregnancy; Premature Birth; Risk Factors; Ritonavir; Uganda; Young Adult

Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients.. In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated.. Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined.. No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).

Topics: Adenine; Adult; Alkynes; Aminoisobutyric Acids; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Coinfection; Cyclopropanes; Darunavir; Drug Interactions; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Leucine; Male; Middle Aged; Oligopeptides; Organophosphonates; Proline; Protease Inhibitors; Quinolines; Ritonavir; Sulfonamides; Tenofovir; Thiazoles; Young Adult

Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects.. The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated.. The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-τ), Cmax and Cτ, respectively.. Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Cross-Over Studies; Cyclopropanes; Drug Combinations; Drug Interactions; Female; Heterocyclic Compounds, 3-Ring; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Models, Biological; Oxazines; Piperazines; Pyridines; Pyridones; Pyrones; Ritonavir; Sulfonamides; Young Adult

Gene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here, we evaluated early changes in adipose tissue gene expression and their relationship to fat changes in ART-naive HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline and weeks 16 and 48. mRNA changes of 11 genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy, and inflammation were assessed through reverse transcription-quantitative PCR (RT-qPCR). Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (P < 0.05). After 16 weeks of exposure to the drug regimen, transcripts of CEBP/A, ADIPOQ, GLUT4, LPL, and COXIV were significantly down-regulated in the EFV arm compared to the LPV/r arm (P < 0.05). Significant correlations were observed between LPL expression change and trunk fat change at week 16 in both arms and between CEBP/A or COXIV change and trunk fat change at the same time point only in the EFV arm and not in the LPV/r arm. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV and LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm. (This was a substudy of a randomized clinical trial [LIPOTAR study] registered at ClinicalTrials.gov under identifier NCT00759070.).

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adipogenesis; Adiponectin; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Body Composition; CCAAT-Enhancer-Binding Proteins; Cyclopropanes; Deoxycytidine; Drug Combinations; Emtricitabine; Energy Metabolism; Female; Gene Expression; Glucose; Glucose Transporter Type 4; HIV-1; Humans; Inflammation; Lipid Metabolism; Lipoprotein Lipase; Lopinavir; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Ritonavir; Subcutaneous Fat; Tenofovir

The drug-drug interactions between pitavastatin and darunavir/ritonavir (DRV/r) as well as pitavastatin and efavirenz (EFV) were examined in an open-label, parallel-arm, pharmacokinetic (PK) study in HIV-uninfected healthy volunteers.. Subjects received a pitavastatin dose of 2 mg for 4 days, followed by either EFV 600 mg (n = 14) or DRV/r 800/100 mg (n = 14) daily for 10 days, and pitavastatin 2 mg coadministered with EFV 600 mg or DRV/r 800/100 mg for 4 days. Full PK profiles were determined for pitavastatin and its lactone metabolite on days 4 and 18 and for EFV or DRV on days 14 and 18.. In the EFV arm, the geometric mean area under the concentration time curve (AUC0-τ) and Cmax of pitavastatin were 85.3 ng·h·mL and 15.6 ng/mL, respectively, when given alone, versus 76 ng·h·mL and 18.8 ng/mL when coadministered with EFV. The geometric mean ratio for pitavastatin with EFV versus alone was 0.89 [90% confidence interval (CI): 0.73 to 1.09] for AUC0-τ and 1.20 (90% CI: 0.79 to 1.83) for Cmax. In the DRV/r arm, AUC0-τ and Cmax were 62.8 ng·h·mL and 24.0 ng/mL, respectively, when pitavastatin was administered alone, versus 56.9 ng·h·mL and 23.2 ng/mL when coadministered with DRV/r. The geometric mean ratio for pitavastatin with DRV/r versus alone was 0.91 (90% CI: 0.78 to 1.06) for AUC0-τ and 0.93 (90% CI: 0.72 to 1.19) for Cmax.. There were no significant PK interactions between pitavastatin and EFV or DRV/r. No significant safety issues or lipid changes were noted.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Darunavir; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Quinolines; Ritonavir; Sulfonamides; Young Adult

Rates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors, HIV-related inflammatory and immunologic changes, and effects of antiretroviral therapy (ART). This study prospectively evaluated changes in cardiovascular biomarkers in an underrepresented, racially diverse, HIV-1-infected population receiving abacavir/lamivudine as backbone therapy.. This 96-week, open-label, randomized, multicenter study compared once-daily fosamprenavir/ritonavir 1400/100 mg and efavirenz 600 mg, both with ABC/3TC 600 mg/300 mg, in antiretroviral-naïve, HLA-B*5701-negative adults without major resistance mutations to study drugs. We evaluated changes from baseline to weeks 4, 12, 24, 48, and 96 in interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), d-dimer, plasminogen, and fibrinogen. Biomarker data were log-transformed before analysis, and changes from baseline were described using geometric mean ratios.. This study enrolled 101 patients (51 receiving fosamprenavir/ritonavir; 50 receiving efavirenz): 32% female, 60% African American, and 38% Hispanic/Latino; 66% (67/101) completed 96 weeks on study. At week 96, levels of IL-6, sVCAM-1, d-dimer, fibrinogen, and plasminogen were lower than baseline in both treatment groups, and the decrease was statistically significant for sVCAM-1 (fosamprenavir/ritonavir and efavirenz), d-dimer (fosamprenavir/ritonavir and efavirenz), fibrinogen (efavirenz), and plasminogen (efavirenz). Values of hs-CRP varied over time in both groups, with a significant increase over baseline at Weeks 4 and 24 in the efavirenz group. At week 96, there was no difference between the groups in the percentage of patients with HIV-1 RNA <50 copies/mL (fosamprenavir/ritonavir 63%; efavirenz 66%) by ITT missing-equals-failure analysis. Treatment-related grade 2-4 adverse events were more common with efavirenz (32%) compared with fosamprenavir/ritonavir (20%), and median lipid concentrations increased in both groups over 96 weeks of treatment.. In this study of underrepresented patients, treatment with abacavir/lamivudine combined with either fosamprenavir/ritonavir or efavirenz over 96 weeks, produced stable or declining biomarker levels except for hs-CRP, including significant and favorable decreases in thrombotic activity (reflected by d-dimer) and endothelial activation (reflected by sVCAM-1). Our study adds to the emerging data that some cardiovascular biomarkers are decreased with initiation of ART and control of HIV viremia.. ClinicalTrials.gov identifier NCT00727597.

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Biomarkers; C-Reactive Protein; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Furans; HIV Infections; Humans; Interleukin-6; Lamivudine; Male; Middle Aged; Organophosphates; Plasminogen; Prospective Studies; Ritonavir; Sulfonamides; Vascular Cell Adhesion Molecule-1; Young Adult

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

Topics: Adult; Alkynes; Anti-Retroviral Agents; Benzoxazines; Breast Feeding; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Eruptions; Drug Substitution; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Ritonavir; Uganda; World Health Organization

Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy.. Three open-label studies were conducted in healthy subjects to assess potential interactions between the investigational first-in-class HCV NS5A replication complex inhibitor daclatasvir and representative antiretrovirals atazanavir/ritonavir, efavirenz and tenofovir disoproxil fumarate.. Target exposure was that of 60 mg daclatasvir alone. Dose-normalized (60 mg) geometric mean ratios of daclatasvir AUCτ for 20 mg ± atazanavir/ritonavir (2.10 [90% CI 1.95, 2.26]) and 120 mg ± efavirenz (0.68 [0.60, 0.78]) showed less than the three-fold elevation and two-fold reduction, respectively, in systemic exposure predicted by prior interaction studies with potent inhibitors/inducers of CYP3A4. Daclatasvir dose adjustment to 30 mg once daily with atazanavir/ritonavir and 90 mg once daily with efavirenz is predicted to normalize AUCτ relative to the target exposure (geometric mean ratios 1.05 [0.98, 1.13] and 1.03 [0.90, 1.16], respectively). Atazanavir exposure (Cmax, AUCτ and C24 trough) and efavirenz Ctrough under coadministration were similar to historical data without daclatasvir. No clinically relevant interactions between daclatasvir and tenofovir disoproxil fumarate were observed for either drug, and no dosing adjustments were indicated. Daclatasvir was well tolerated in all three studies.. The pharmacokinetic data support coadministration of daclatasvir with atazanavir/ritonavir, efavirenz and/or tenofovir. A Phase III study in HIV-HCV coinfection has commenced using the described dose modifications.

Topics: Adenine; Adolescent; Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Carbamates; Coinfection; Cyclopropanes; Drug Interactions; Female; Hepatitis C; HIV Infections; Humans; Imidazoles; Male; Middle Aged; Oligopeptides; Organophosphonates; Pyridines; Pyrrolidines; Ritonavir; Tenofovir; Valine; Viral Nonstructural Proteins; Young Adult

As efforts intensify to eliminate perinatal HIV transmission, understanding kinetics of maternal-to-child transfer of antiretrovirals during pregnancy and breastfeeding is critical. Antiretroviral levels in plasma, cord blood, and breastmilk reflect exposure over short intervals. Hair concentrations reflect cumulative exposure and can uniquely quantify in utero transfer of maternal medications to infants. We measured plasma and hair antiretroviral levels in HIV-infected Ugandan mothers and their infants at delivery and during breastfeeding to assess transfer.. HIV-infected pregnant women were randomized to lopinavir/ritonavir- or efavirenz-based therapy in a larger trial (the Prevention of Malaria and HIV disease in Tororo, PROMOTE). At 0, 8, and 12 weeks postpartum, plasma antiretroviral levels were measured in 117 mother-infant pairs; hair levels were assayed at 12 weeks. Ratios and correlations of infant:maternal concentrations were calculated.. By 12 weeks, 90.4% of mothers reported exclusive breastfeeding. Hair and plasma levels over time suggest moderate (47%) to extensive (87%) in utero transfer of lopinavir and ritonavir, respectively, but negligible transfer of either via breastfeeding. Moderate transfer of efavirenz occurs during pregnancy and breastfeeding (40% cumulative; 15% during breastfeeding). Despite differences in exposure, no infant seroconversions or correlations between infant hair/plasma antiretroviral levels and adverse effects were observed.. Using a unique approach combining hair and plasma data, we found that different antiretrovirals have distinct kinetics of mother-to-infant transfer. Efavirenz transfers during both pregnancy and breastfeeding, whereas lopinavir and ritonavir transfer only in utero. Further study of the degree and timing of maternal-to-child transfer by antiretroviral will help optimize strategies that protect infants and minimize toxicities during periods of risk.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Female; Hair; HIV Infections; Humans; Infant; Infant, Newborn; Lopinavir; Milk, Human; Plasma; Pregnancy; Pregnancy Complications, Infectious; Ritonavir; Uganda

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

We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm(3) or stage B/C disease with CD4 counts of <200/mm(3). Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥ 200/mm(3) at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm(3), and the median HIV-1 RNA load was 5.4 log(10) copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥ 200/mm(3) at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cyclopropanes; Deoxycytidine; Drug Combinations; Emtricitabine; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Immune Tolerance; Lopinavir; Male; Organophosphonates; Peptide Fragments; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome; Viral Load

The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear.. A5202 randomized antiretroviral therapy-naive human immunodeficiency virus-infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF-emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests.. Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m(2), 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, -341 [interquartile range, -848 to 190; P = .03] and -400 [-661 to -221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, -12.45 [interquartile range, -24.70 to 2.90; P = .003] and -8.25 [-13.90 to -1.30; P < .001], optical density × 10(3)/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03).. ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels.. NCT00118898.

Topics: Adenine; Adipose Tissue; Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; DNA, Mitochondrial; Drug Combinations; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Male; Mitochondria; Oligopeptides; Organophosphonates; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome

Glomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on creatinine or cystatine C may be more accurate methods especially in patients without chronic kidney disease. There is lack of data on GFR estimated by these methods in patients on highly active antiretroviral therapy.. Antiretroviral-naive HIV-infected patients were randomized to tenofovir/emtricitabine in association with atazanavir/ritonavir (ATV/r) or efavirenz (EFV) Patients had to have an actual creatinine clearance >50 mL/minute (24-hour urine collection) and were followed for 48 weeks.. Ninety-one patients (48 ATV/r, 43 EFV) were recruited. Using the CKD-EPI creatinine formula, there was a significant decrease in GFR up to week 48 in patients receiving ATV/r (4.9 mL/minute/m(2), P = 0.02) compared with a not statistically significant increment in patients prescribed EFV. Using the cystatin C-based equation, we found greater decrease in GFR in both arms, although, in the EFV arm, the decrease was not statistically significant (5.8 mL/minute/m(2), P = 0.92). At multivariable analysis, ATV/r was a significant predictor of greater decrease in estimated glomerular filtration rate (eGFR) (P = 0.0046) only with CKD-EPI creatinine.. ATV/r plus tenofovir caused greater GFR decreases compared with EFV. The evaluation of eGFR by cystatin C confirmed this result, but this method seemed to be more stringent, probably precluding the possibility to detect a significant difference in the pattern of eGFR evolution between the two arms over time. More studies are needed to understand the clinical relevance of these alterations and whether cystatin C is a more appropriate method for monitoring GFR in clinical practice.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Creatinine; Cyclopropanes; Cystatin C; Deoxycytidine; Emtricitabine; Female; Glomerular Filtration Rate; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Organophosphonates; Pilot Projects; Pyridines; Ritonavir; Tenofovir

Improvements in neurocognitive (NC) function have been associated with commencing antiretroviral therapy in HIV-infected subjects. However, the dynamics of such improvements are poorly understood.. We assessed changes in NC function via a validated computerized battery (CogState™, Melbourne, Victoria, Australia) at baseline and after 24 and 48 weeks in a subset of therapy-naïve neuro-asymptomatic HIV-infected subjects, randomized to commence three different antiretroviral regimens.. Of 28 subjects enrolled in the study, nine, eight and 11 were randomly allocated to commence tenofovir/emtricitabine with efavirenz (arm 1), atazanavir/ritonavir (arm 2) and zidovudine/abacavir (arm 3), respectively. Overall improvements in NC function were observed at week 24 and function continued to improve at week 48 (changes in z-score for overall cognitive global score of 0.16 and 0.18 at weeks 24 and 48, respectively). Within the NC speed domains, generally greater improvements were observed in arms 2 and 3, compared with arm 1 (changes in z-score for composite speed scores at weeks 24/48 of 0.16/0.16, -0.29/-0.24 and -0.15/-0.31 in arms 1, 2 and 3, respectively; P = 0.04 for change at week 48 in arm 3 versus arm 1). Finally, improvements in executive function occurred later (only observed at week 48) and were driven by improvements in arm 3 (z-score changes of 0.23, 0.06 and -0.78 in arms 1, 2 and 3, respectively; P = 0.02 for change in arm 3 versus arm 1).. Improvements in NC function continue over the first year after initiating antiretroviral therapy in neuro-asymptomatic HIV-infected subjects.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cognition; Cognition Disorders; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; HIV Infections; Humans; Male; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Tenofovir; Zidovudine

Alcohol abuse has been associated with HIV/AIDS progression, but the effects of HIV infection and treatment on alcohol exposure have not been explored to date. This pilot study examines the relationship of untreated HIV infection to blood alcohol concentrations (BAC) relative to BAC after initiation of antiretroviral therapy (ART).. Fifteen volunteers with untreated HIV/AIDS participated in 2 sets of alcohol or alcohol placebo administration studies before and after initiation of ART. Oral alcohol (1 g/kg) or alcohol placebo was administered, participants were followed for pharmacokinetics, subjective responses, and cognitive effects over 8 hours. After initial alcohol studies, the ART regimen selected by participant clinicians was instituted. Observed ART dosing took place for at least 2 weeks. Participants then returned for a second set of alcohol/placebo administration studies while on ART.. Participants had significantly higher BAC (P < 0.001) before ART than after ART administration. Alcohol area under the curve was significantly higher in untreated HIV disease (P = 0.011) with significantly higher C(max) (P = 0.015) and C(min) (P = 0.05). The elimination rate was not different between pre-ART and post-ART conditions. Despite declines in BAC after ART initiation, no differences in subjective responses were observed with alcohol administration.. Untreated HIV infection is associated with risk for higher BAC than that observed after ART. These findings indicate that patients with untreated HIV disease who ingest alcohol are at greater risk for alcohol associated adverse events and toxicities and underscores the need for simultaneous treatment of alcohol use disorders and HIV in patients with co-occurring conditions.

Topics: Adult; Alcoholism; Alkynes; Anti-HIV Agents; Benzoxazines; Cognition; Cyclopropanes; Disease Progression; Double-Blind Method; Ethanol; Female; HIV Infections; Humans; Intestinal Absorption; Male; Middle Aged; Pilot Projects; Ritonavir

The effect of specific antiretrovirals on inflammation is unclear.. A5224s was a substudy of A5202, which randomized HIV-infected treatment-naïve patients to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r.. Analyses included 244 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/μl. TNF-α, soluble receptors of TNF-α (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 decreased significantly at weeks 24 and 96, without significant differences between components (P ≥ 0.44). At week 24, ABC/3TC had a greater high-sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [Δ] 61.5% [95% confidence interval (CI) 13.6%, 129.5%]; P = 0.008}. Similar results were seen at week 96 (P = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r [1.41 vs. 0.88; Δ = 60.2% (12.6%, 127.7%); P = 0.009]. IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components P = 0.019). At week 96, IL-6 decreased significantly in both nucleoside reverse transcriptase inhibitor components (between-components P = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (P ≥ 0.89).. Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Biomarkers; C-Reactive Protein; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; HIV-1; Humans; Inflammation; Interleukin-6; Lamivudine; Male; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Tenofovir; Tumor Necrosis Factor-alpha

There is little data on responses to combination antiretroviral therapy (cART) among HIV-infected children in the West African region. We describe treatment outcomes among HIV-1 and HIV-2 infected children initiating cART in a research clinic in The Gambia, West Africa.. All treatment naive HIV-infected children who initiated cART according to the WHO ART guidelines for children between October 2004 and December 2009 were included in the analysis. Kaplan-Meir estimates and sign-rank test were used to investigate the responses to treatment.. 65 HIV-1 and five HIV-2 infected children aged < 15 years were initiated on cART over this time period. HIV-1 infected children were treated with a combination of Zidovudine or Stavudine + Lamivudine + Nevirapine or Efavirenz while children with HIV-2 were treated with Zidovudine + Lamivudine + ritonavir-boosted Lopinavir. HIV-1 infected children were followed-up for a median (IQR) duration of 20.1 months (6.9 - 34.3), with their median (IQR) age at treatment initiation, CD4% and plasma viral load at baseline found to be 4.9 years (2.1 - 9.1), 13.0% (7.0 - 16.0) and 5.4 log10 copies/ml (4.4 - 6.0) respectively. The median age at treatment initiation of the five HIV-2 infected children was 12 years (range: 4.6 - 14.0) while their median baseline CD4+ T cell count and HIV-2 viral load were 140 cells/mm3 (Range: 40 - 570 cells/mm3) and 4.5 log10copies/mL (Range: 3.1 - 4.9 log10copies/mL) respectively.Among HIV-1 infected children <5 years of age at ART initiation, the median (IQR) increases in CD4% from baseline to 12, 24 and 36 months were 14% (8 - 19; P = 0.0004), 21% (15 - 22; P = 0.005) and 15% (15 - 25; P = 0.0422) respectively, while the median (IQR) increase in absolute CD4 T cell count from baseline to 12, 24 and 36 months for those ≥5 years at ART initiation were 470 cells/mm3 (270 - 650; P = 0.0005), 230 cells/mm3 (30 - 610; P = 0.0196) and 615 cells/mm3 (250 - 1060; P = 0.0180) respectively. The proportions of children achieving undetectable HIV-1 viral load at 6-, 12-, 24- and 36 months of treatment were 24/38 (63.2%), 20/36 (55.6%), 8/22 (36.4%) and 7/12 (58.3%) respectively. The probability of survival among HIV-1 infected children after 12 months on ART was 89.9% (95% CI 78.8 - 95.3). CD4 T cell recovery was sub-optimal in all the HIV-2 infected children and none achieved virologic suppression. Two of the HIV-2 infected children died within 6 months of starting treatment while the remaining three were lost to follow-up.. The beneficial effects of cART among HIV-1 infected children in our setting are sustained in the first 24 months of treatment with a significant improvement in survival experience up to 36 months; however the outcome was poor in the few HIV-2 infected children initiated on cART.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Drug Combinations; Female; Follow-Up Studies; Gambia; HIV Infections; HIV-1; HIV-2; Humans; Infant; Kaplan-Meier Estimate; Lamivudine; Lopinavir; Male; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load; Zidovudine

Although specific human immunodeficiency virus type 1 (HIV-1) drug resistance mutations are well studied, little is known about cumulative amino acid changes, or how regimen and participant characteristics influence these changes.. In the AIDS Clinical Trials Group randomized study A5202 of treatment-naive HIV-infected participants, cumulative HIV-1 amino acid changes from pretreatment to virologic failure were evaluated in protease and reverse transcriptase (RT) gene sequences.. Among 265 participants with virologic failure, those assigned atazanavir plus ritonavir (ATV/r) did not have significantly more protease changes compared with those assigned efavirenz (EFV) (P ≥ .13). In contrast, participants with virologic failure assigned EFV had more RT changes, including and excluding known resistance codons (P < .001). At pretreatment, lower CD4 cell count, major resistance, more amino acid mixtures (all P < .001), hepatitis C antibody negativity (P = .05), and black race/ethnicity (P = .02) were associated with more HIV-1 amino acid changes.. Virologic failure following EFV-containing treatment was associated with more HIV-1 amino acid changes compared to failure of ATV/r-containing treatment. Furthermore, we show that non-drug resistance mutations occurred more frequently among those failing EFV, the clinical relevance of which warrants further investigation. Pretreatment immunologic status may play a role in viral evolution during treatment, as evidenced by increased amino acid changes among those with lower pretreatment CD4 count.. NCT00118898.

Topics: Adult; Alkynes; Amino Acid Substitution; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Mutation, Missense; Oligopeptides; Pyridines; Ritonavir; Treatment Failure

Efavirenz is an inducer of drug metabolism enzymes. We studied the effect of efavirenz and ritonavir-boosted darunavir on serum unconjugated and conjugated bilirubin, as probes for UGT1A1 and bile transporters.. Healthy volunteers were enrolled in a clinical trial. There were 3 periods: Period 1, 10 days of darunavir 900 mg with ritonavir 100 mg once daily; Period 2, 14 days of efavirenz 600 mg with darunavir/ritonavir once daily; and Period 3, 14 days of efavirenz 600 mg once daily. Serum bilirubin (conjugated and unconjugated) concentrations were obtained at baseline, at the end of each phase and at exit.. We recruited 7 males and 5 females. One subject developed grade 3 hepatitis on efavirenz and was excluded. Mean serum unconjugated bilirubin concentrations were 6.09 μmol/L (95% confidence interval [CI], 4.99 to 7.19) at baseline, 5.82 (95% CI, 4.88 to 6.76) after darunavir/ritonavir, 4.00 (95% CI, 2.92 to 5.08) after darunavir/ritonavir with efavirenz, 3.55 (95% CI, 2.58 to 4.51) after efavirenz alone and 5.27 (95% CI, 3.10 to 7.44) at exit (P <0.01 for the efavirenz phases). Mean serum conjugated bilirubin concentrations were 3.55 μmol/L (95% CI, 2.73 to 4.36) at baseline, 3.73 (95% CI, 2.77 to 4.68) after darunavir/ritonavir, 2.91 (95% CI, 2.04 to 3.78) after darunavir/ritonavir with efavirenz, 2.64 (95% CI, 1.95 to 3.33) after efavirenz alone and 3.55 (95% CI, 2.19 to 4.90) at exit (P <0.05 for the efavirenz phases).. Efavirenz decreased unconjugated bilirubin by 42%, suggesting UGT1A1 induction. Efavirenz also decreased conjugated bilirubin by 26%, suggesting induction of bile efflux transporters. Ritonavir-boosted darunavir had no effect on bilirubin concentrations. These results indicate that efavirenz may reduce concentrations of drugs or endogenous substances metabolized by UGT1A1 or excreted by bile efflux transporters.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Biological Transport; Confidence Intervals; Cyclopropanes; Darunavir; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Induction; Female; Glucuronosyltransferase; HIV Infections; HIV Protease Inhibitors; Humans; Incidental Findings; Male; Membrane Transport Proteins; Middle Aged; Ritonavir; Sulfonamides; Young Adult

The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART).. Sixty-three HAART-naïve patients were randomized to zidovudine/lamivudine+efavirenz or lopinavir/ritonavir+efavirenz. We performed dual energy X-ray absorptiometry (DEXA) at baseline and at weeks 24, 48, 96 and 144 to evaluate lumbar spine and femoral neck (hip) BMD.. At baseline, 33 patients (55.9%) had low BMD (T-score < -1.0) and of these eight had osteoporosis (T-score < -2.5). Spine BMD declined in both arms until week 24, before stabilizing. In the NRTI-sparing arm, the mean percentage change from baseline was -2.7% [95% confidence interval (CI) -3.9 to -1.4] at week 24 and -2.5% (95% CI -5.4 to 0.3) at week 144, compared with -3.2% (95% CI -4.4 to -2.1) and -1.9% (95% CI -3.5 to -0.3) in the protease inhibitor-sparing arm. Hip BMD declined until week 48 before stabilizing. In the NRTI-sparing arm, BMD had decreased by -5.1% (95% CI -7.1 to -3.1) at week 48 and -4.5% (95% CI -6.9 to -2.1) at week 144, compared with -6.1% (95% CI -8.2 to -4.0) and -5.0% (95% CI -6.8 to -3.1) in the protease inhibitor-sparing arm. There were no significant differences between arms. Low baseline CD4 cell count was independently associated with spine (P=0.007) and hip (P=0.04) BMD loss and low body mass index with hip BMD loss (P=0.03).. Spine and hip BMD declined rapidly 24 to 48 weeks after initiating HAART, independent of the assigned drug class, but thereafter BMD values remained stable.

Topics: Absorptiometry, Photon; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Bone Density; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; Zidovudine

Limited data compare once-daily options for initial therapy for HIV-1.. To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1.. A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898). 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico.. Antiretroviral-naive patients.. Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine.. Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels.. 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir-lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF-emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir-lamivudine or tenofovir DF-emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine.. Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug.. Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine.. National Institutes of Health.

Topics: Adolescent; Adult; Alkynes; Atazanavir Sulfate; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Medication Adherence; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Viral Load; Young Adult

The side-effects of anti-retroviral drugs are different between Japanese and Caucasian patients. Severe central nerve system (CNS) side-effects to efavirenz and low rate of hypersensitivity against abacavir characterize the Japanese.. The objective of this study was to select a once daily regimen for further non-inferior study comparing the virological efficacy and safety of the first line once daily antiretroviral treatment regimens in the current HIV/AIDS guideline.. The study design was a randomized, open label, multicenter, selection study. One arm was treated with efavirenz and the other with ritonavir-boosted atazanavir. A fixed-dose lamivudine plus abacavir were used in both arms. The primary endpoint was virologic success (viral load less than 50 copies/mL) rate at 48 weeks. Patients were followed-up to 96 weeks with safety as the secondary endpoint. Clinicaltrials.Gov (NCT00280969) and the University hospital Medical Information Network (UMIN000000243).. A total of 71 participants were enrolled. Virologic success rates in both arms were similar at week 48 [efavirenz arm 28/36 (77.8%); atazanavir arm 27/35 (77.1%)], but were decreased at week 96 to 55.6% in the efavirenz arm and 68.8% in the atazanavir arm (p=0.33). At the 96-week follow-up, 52.8% of the EFV arm and 34.3% of the ATV/r arm reached total cholesterol more than 220 mg/dL and required treatment. None of the patients developed cardiovascular complications in this study by week 96.. There was no significant difference in the efficacy of efavirenz and ritonavir-boosted atazanavir combined with lamivudine plus abacavir at 48 weeks. The evaluation of safety was extended to 96 weeks, which also showed no significant difference in both arms.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alanine Transaminase; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cholesterol; Cyclopropanes; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Japan; Lamivudine; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome

Long-term effects of abacavir (ABC)-lamivudine (3TC), compared with tenofovir (TDF)-emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed.. A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests.. Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log(10) copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/μL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components.. Compared with ABC-3TC, TDF-FTC-treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898.

Topics: Absorptiometry, Photon; Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Bone Density; CD4 Lymphocyte Count; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Emtricitabine; Female; Fractures, Bone; HIV Infections; Humans; Intention to Treat Analysis; Lamivudine; Male; Middle Aged; Oligopeptides; Organophosphonates; Osteoporosis; Pyridines; Risk Factors; Ritonavir; Tenofovir; Viral Load

HIV-infected children are treated with tenofovir in combination with other, potentially interacting, antiretroviral agents. We report the pharmacokinetic parameters of tenofovir in combination with efavirenz, darunavir-ritonavir, or atazanavir-ritonavir in HIV-infected children. HIV-infected patients 8 to 18 years of age receiving a tenofovir (300 mg)-based regimen containing efavirenz (300 or 600 mg) once daily (group 1), darunavir (300 or 600 mg)-ritonavir (100 mg) twice daily (group 2), or atazanavir (150 to 400 mg)-ritonavir (100 mg) once daily (group 3) were enrolled. Plasma samples were collected over a 24-h time interval. The 90% confidence intervals (90% CI) of the geometric means for the area under the plasma concentration-time curve (AUC) and the minimum concentration of drug in serum (C(min)) of each antiretroviral were computed and checked for overlap with intervals bracketing published values obtained in adult or pediatric studies demonstrating safety and/or efficacy. Group 1 efavirenz plasma concentrations were observed to be higher in patients receiving fixed-dose combination tablets compared with subjects receiving the individual formulation. In group 2, tenofovir and darunavir exposure was observed to be lower than expected. In group 3, tenofovir and atazanavir administered concomitantly produced exposures similar to those published for adult patients. The 90% CI of AUC and C(min) for tenofovir overlapped the target range for all combinations. Informal comparisons of treatment groups did not indicate any advantage to any combination with respect to tenofovir exposure. Further study of exposures achieved with antiretrovirals administered in combination is warranted.

Topics: Adenine; Adolescent; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Child; Cyclopropanes; Drug Administration Schedule; Female; HIV Infections; Humans; Male; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Tenofovir

Nonnucleoside reverse transcriptase inhibitor-drug resistance mutations (DRM) are increasingly reported in Africans failing their first antiretroviral regimen. The Phidisa II trial randomized treatment-naive participants to lopinavir/ritonavir or efavirenz with stavudine + lamivudine or zidovudine + didanosine. We report the prevalence of DRM in subjects who achieved HIV RNA <400 copies per milliliter at 6 months, but subsequently had 2 consecutive HIV RNA >1000 copies per milliliter. Sixty-eight participants fulfilled the inclusion criteria. nonnucleoside reverse transcriptase inhibitor-DRM were found in 17 of 36 (47.2%) efavirenz recipients, and M184V/I mutation in 14 of 40 (35.0%) lamivudine recipients. No protease inhibitor mutation was identified in 38 lopinavir/ritonavir recipients. This is one of the first studies in Africa confirming the paucity of protease inhibitor-associated DRM despite virologic failure.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Female; HIV Infections; Humans; Lopinavir; Male; Mutation; Ritonavir; RNA, Viral; South Africa; Treatment Failure; Viral Load

To evaluate the effects of sex and initial antiretroviral regimen on decay of HIV-RNA and virologic outcome.. We conducted a viral dynamics substudy of A5142, a trial comparing lopinavir (LPV)/ritonavir with efavirenz (LPV/EFV) versus LPV and two nucleoside reverse transcriptase inhibitor (NRTI) (LPV) versus EFV and two NRTI (EFV) in antiretroviral (ARV)-naive individuals. HIV-RNA was measured at days 2, 10, and 14 in the substudy and at weeks 1, 4, and 8 in A5142 participants. Two-phase viral decay was estimated in the substudy with biexponential mixed-effects modeling and compared using Wilcoxon tests. Week 1 HIV-RNA change was assessed as a predictor of virologic failure (HIV-RNA above 50 or 200  copies/ml) at weeks 24-96 using logistic regression.. Sixty-eight individuals were enrolled in the substudy (median HIV-RNA 4.9 log(10)  copies/ml). Median rates of phase 1 viral decay by treatment were 0.61(EFV/LPV), 0.53(LPV), and 0.63(EFV) per day. Phase 1 decay was significantly faster for EFV than LPV (P = 0.023); other comparisons were not significant (P > 0.11). Viral decay did not differ by sex (P = 0.10). Week 1 HIV-RNA change, calculated in 571 participants of A5142, was greater for the EFV (median -1.47 log(10)  copies/ml) than either the LPV/EFV or LPV groups (-1.21 and -1.16 log(10 ) copies/ml, respectively; P < 0.001). Week 1 HIV-RNA change was associated with virologic failure above 50  copies/ ml at weeks 24 and 48 (P < 0.018), but not above 200  copies/ml at these time points or for any value at week 96.. Phase 1 decay was faster for EFV than LPV or LPV/EFV. Week 1 HIV-RNA change predicted virologic outcome up to week 48, but not at week 96.

Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sex Factors; Treatment Outcome; Viral Load

The objective of this analysis was to compare three methods of handling HIV-RNA data below the limit of quantification (LOQ) when describing the time-course of antiretroviral drug response using a drug-disease model. Treatment naïve Scandinavian HIV-positive patients (n = 242) were randomized to one of three study arms. Two nucleoside reverse transcriptase inhibitors were administrated in combination with 400/100 mg lopinavir/ritonavir twice daily, 300/100 mg atazanavir/ritonavir once a day or 600 mg efavirenz once a day. The viral response was monitored at screening, baseline and at 1, 2, 3, 4, 12, 24, 48, 96, 120, and 144 weeks after study initiation. Data up to 400 days was fitted using a viral dynamics non-linear mixed effects drug-disease model in NONMEM. HIV-RNA data below LOQ of 50 copies/ml plasma (39%) was omitted, replaced by LOQ/2 or included in the analysis using a likelihood-based method (M3 method). Including data below LOQ using the M3 method substantially improved the model fit. The drug response parameter expressing the fractional inhibition of viral replication was on average (95% CI) estimated to 0.787 (0.721-0.864) for lopinavir and atazanavir treatment arms and 0.868 (0.796-0.923) for the efavirenz containing regimen. At 400 days after treatment initiation 90% (76-100) of the lopinavir and atazanavir treated patients were predicted to have undetectable viral levels and 96% (89-100%) for the efavirenz containing treatment. Including viral data below the LOQ rather than omitting or replacing data provides advantages such as better model predictions and less biased parameter estimates which are of importance when quantifying antiretroviral drug response.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Limit of Detection; Lopinavir; Male; Middle Aged; Nonlinear Dynamics; Oligopeptides; Pyridines; Ritonavir; RNA, Viral; Viral Load

Although efavirenz and lopinavir/ritonavir(r) are both recommended antiretroviral agents in antiretroviral-naïve HIV-infected patients, there are few randomized comparisons of their efficacy and tolerability.. A multicenter and randomized study was performed including 126 antiretroviral-naïve patients, randomly assigned to efavirenz+Kivexa (n=63) or lopinavir/r+Kivexa (n=63). Efficacy endpoints were the percentage of patients with HIV-RNA < or =50 copies/mL at week 48 and CD4 recovery. Safety was assessed by comparing toxicity and discontinuations. Statistical analyses were performed on an intention-to-treat (ITT) basis (Missing=Failure).. At week 48, 56.7% of patients in the efavirenz and 63.2% in the lopinavir/r groups showed HIV-1 RNA <50 copies/mL (P=0.770) (intention-to-treat analysis; Missing=Failure). Only 1 (1.53%) patient from each group experienced virological failure. CD4 values increased in both groups (298 cells in the efavirenz group, P=0.001; 249 cells in the lopinavir/r group, P=0.002; P=0.126 between groups). HDL-cholesterol only increased in the efavirenz group (from 39+/-12 mg/dL to 49+/-11; P=0.001). Discontinuations were more frequent in the lopinavir/r group (36.5% versus 28.5%; P=0.193), but more patients with efavirenz interrupted due to toxicity (11.1% versus 6.3%); most of them were attributed to hypersensitivity reaction.. Similar virological efficacy was observed for efavirenz and lopinavir/r, when administered with Kivexa in antiretroviral-naïve patients, while immunological improvement was slightly superior for efavirenz. The higher rate of discontinuation due to toxicity in the efavirenz group was related to a higher incidence of hypersensitivity reaction. Nowadays, the use of the new formulation of lopinavir/r and the HLA-B*5701 genotype test before starting abacavir should improve the safety profiles of these regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Withholding Treatment

To compare the efficacy of efavirenz (EFV) vs lopinavir/ritonavir (LPV/r) in combination with azidothymidine/lamivudine in antiretroviral therapy naive, HIV+ individuals presenting for care with CD4 counts <200/mm.. Prospective, randomized, open label, multicenter trial in Mexico. HIV-infected subjects with CD4 <200/mm were randomized to receive open label EFV or LPV/r plus azidothymidine/lamivudine (fixed-dose combination) for 48 weeks. Randomization was stratified by baseline CD4 cell count (< or =100 or >100/mm). The primary endpoint was the percentage of patients with plasma HIV-1 RNA <50 copies/mL at 48 weeks by intention-to-treat analysis.. A total of 189 patients (85% men) were randomized to receive EFV (95) or LPV/r (94). Median baseline CD4 were 64 and 52/mm, respectively (P = not significant). At week 48, by intention-to-treat analysis, 70% of EFV and 53% of LPV/r patients achieved HIV-1 RNA <50 copies/mL [estimated difference 17% (95% confidence interval 3.5 to 31), P = 0.013]. The proportion with HIV-1 RNA <400 copies/mL was 73% with EFV and 65% with LPV/r (P = 0.25). Virologic failure occurred in 7 patients on EFV and 17 on LPV/r. Mean CD4 count increases (cells/mm) were 234 for EFV and 239 for LPV/r. Mean change in total cholesterol and triglyceride levels were 50 and 48 mg/dL in EFV and 63 and 116 mg/dL in LPV/r (P = 0.24 and P < 0.01).. In these very advanced HIV-infected ARV-naive subjects, EFV-based highly active antiretroviral therapy had superior virologic efficacy than LPV/r-based highly active antiretroviral therapy, with a more favorable lipid profile.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Mexico; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral

Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC(50)) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC(0-24) (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC(0-24) when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC(50) for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Darunavir; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Ritonavir; Sulfonamides

The efflux transporter MRP1 actively transports antiretrovirals and reduces intracellular accumulation in peripheral blood mononuclear cells (PBMCs). We studied MRP1 expression and function in healthy volunteers treated with darunavir/ritonavir and efavirenz.. Seven healthy HIV-negative volunteers were recruited. PBMCs were collected at baseline, 9 days after administration of darunavir (900 mg) and ritonavir (100 mg) once daily, 9 days after coadministration of darunavir/ritonavir and efavirenz (600 mg) once daily and 13 days after administration of efavirenz alone. MRP1 expression was measured in PBMCs using flow cytometry with fluorescein isothiocyanate-conjugated antibody against MRP1m6. MRP1 expression was also measured in CD4(+) T-cells with a phycoerythrin-conjugated antibody against CD4. MRP1 efflux function was assessed by incubating PBMCs with carboxyfluorescein diacetate (CFDA) and comparing CFDA fluorescence with and without the modulators MK571 and probenecid.. MRP1 expression was reduced after darunavir/ritonavir administration (geometric mean ratio [GMR] 0.58, 95% confidence interval [95% CI] 0.51-0.65; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 0.74, 95% CI 0.64-0.84; P=0.001), but not after efavirenz administration alone (GMR 0.82, 95% CI 0.64-1.06; P=0.10). MRP1 protein expression was 41% higher in CD4(+) T-cells. MRP1 efflux function was increased after efavirenz administration (GMR 3.13, 95% CI 2.73-3.59; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 4.35, 95% CI 3.35-5.68; P<0.001), but not after darunavir/ritonavir administration (GMR 1.06, 95% CI 0.80-1.42; P=0.42).. Darunavir/ritonavir and efavirenz treatment exerted differential effects on MRP1 expression and function. These effects could potentially alter antiviral activity, especially in CD4(+) T-cells.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Darunavir; Drug Therapy, Combination; Female; Gene Expression Regulation; HIV Seronegativity; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Multidrug Resistance-Associated Proteins; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Young Adult

We evaluated the pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) in Ugandan adults. The study design was a three-period crossover study (3 tablets [600 mg of lopinavir/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n = 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n = 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n = 20), nevirapine (n = 18), and no NNRTI (n = 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC(0-12)) was 110.1 (34%) microg x h/liter. For efavirenz, the geometric mean lopinavir AUC(0-12) (%CV) values were 91.8 microg x h/liter (58%), 65.7 microg x h/liter (39%), and 54.0 microg x h/liter (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P = 0.002) and 0.82 (90% CI, 0.68 to 0.99; P = 0.09), respectively, and the apparent oral clearance (CL/F) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC(0-12) (%CV) values were 112.9 microg x h/liter (30%), 68.1 microg x h/liter (53%), and 61.5 microg x h/liter (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88; P < 0.001) and 0.90 (90% CI, 0.77 to 1.06; P = 0.27), respectively, and the CL/F was reduced by 57% and 7%, respectively. Higher values for the lopinavir concentration at 12 h (C(12)) were observed with 3 tablets and efavirenz-nevirapine (P = 0.04 and P = 0.0005, respectively), and marginally lower C(12) values were observed with 2 tablets and efavirenz-nevirapine (P = 0.08 and P = 0.26, respectively). These data suggest that 2 tablets of lopinavir-ritonavir BD may be inadequate when dosed with NNRTIs in Ugandan adults, and the dosage should be increased by the addition of an additional adult tablet or a half-dose tablet (100/25 mg), where available.

Topics: Adult; Aged; Alkynes; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Uganda

Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings.. In the Republic of South Africa, antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals >14 years old with a CD4 cell count <200 cells/μL or a prior AIDS diagnosis were randomized to receive efavirenz (EFV) or lopinavir/ritonavir (LPV/r) with either zidovudine (ZDV) plus didanosine (ddI) or stavudine (d4T) plus lamivudine (3TC) in an open-label, 2-by-2 factorial study and followed up for the primary outcome of AIDS or death and prespecified secondary outcomes, including CD4 cell count and viral load changes, treatment discontinuation, and grade 4 events.. In total, 1771 persons were randomized and followed up for a median of 24.7 months. AIDS or death occurred in (1) 163 participants assigned EFV and 157 assigned LPV/r (hazard ratio [HR], 1.04 [95% confidence interval {CI}, 0.84-1.30]) and in (2) 170 participants assigned ZDV+ddI and 150 assigned d4T+3TC (HR, 1.15 [95% CI, 0.93-1.44]). HIV RNA levels were lower (P < .001) and CD4 cell counts were greater (P < .01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T because of toxicity (12.6%) than other treatments (<5%).. EFV and LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest that these treatments be used cautiously as initial therapy.. ClinicalTrials.gov identifier: NCT00342355.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; South Africa; Stavudine; Treatment Outcome; Zidovudine

The pharmacokinetics of lopinavir/ritonavir (LPV/RTV) 300 mg/m twice daily and efavirenz (EFV) 350 mg/m once daily were evaluated in HIV-infected children. The minimum concentrations for LPV contained values above the target range, and the estimated minimum concentrations for EFV contained values below the range. Our data support the current LPV/RTV dose, but EFV 350 mg/m may not be sufficient.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

Rifampin is a key drug in antituberculosis chemotherapy because it rapidly kills the majority of bacilli in tuberculosis lesions, prevents relapse and thus enables 6-month short-course chemotherapy. Little is known about the pharmacokinetics of rifampin in children. The objective of this study was to evaluate the pharmacokinetics of rifampin in children with tuberculosis, both human immunodeficiency virus type-1-infected and human immunodeficiency virus-uninfected.. Fifty-four children, 21 human immunodeficiency virus-infected and 33 human immunodeficiency virus-uninfected, mean ages 3.73 and 4.05 years (P = 0.68), respectively, admitted to a tuberculosis hospital in Cape Town, South Africa with severe forms of tuberculosis were studied approximately 1 month and 4 months after commencing antituberculosis treatment. Blood specimens for analysis were drawn in the morning, 45 minutes, 1.5, 3.0, 4.0 and 6.0 hours after dosing. Rifampin concentrations were determined by liquid chromatography tandem mass spectrometry. For two sample comparisons of means, the Welch version of the t-test was used; associations between variables were examined by Pearson correlation and by multiple linear regression.. The children received a mean rifampin dosage of 9.61 mg/kg (6.47 to 15.58) body weight at 1 month and 9.63 mg/kg (4.63 to 17.8) at 4 months after commencing treatment administered as part of a fixed-dose formulation designed for paediatric use. The mean rifampin area under the curve 0 to 6 hours after dosing was 14.9 and 18.1 microg/hour/ml (P = 0.25) 1 month after starting treatment in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children, respectively, and 16.52 and 17.94 microg/hour/ml (P = 0.59) after 4 months of treatment. The mean calculated 2-hour rifampin concentrations in these human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children were 3.9 and 4.8 microg/ml (P = 0.20) at 1 month after the start of treatment and 4.0 and 4.6 microg/ml (P = 0.33) after 4 months of treatment. These values are considerably less than the suggested lower limit for 2-hour rifampin concentrations in adults of 8.0 microg/ml and even 4 microg/ml. Both human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children with tuberculosis have very low rifampin serum concentrations after receiving standard rifampin dosages similar to those used in adults. Pharmacokinetic studies of higher dosages of rifampin are urgently needed in children to assist in placing the dosage of rifampin used in childhood on a more scientific foundation.

Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; C-Reactive Protein; Child; Child, Preschool; Cyclopropanes; Female; HIV Infections; Humans; Male; Metabolic Clearance Rate; Rifampin; Ritonavir; Tuberculosis

The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection.. Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids.. Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm.. Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.

Topics: Absorptiometry, Photon; Adult; Alkynes; Benzoxazines; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lipid Metabolism; Lopinavir; Male; Pyrimidinones; Ritonavir

Decreased bone mineral density (BMD) has been described in HIV-infected patients initiating antiretroviral therapy (ART), but the contributions of ART and immunologic and/or virologic factors remain unclear.. We compared total BMD changes over 96 weeks in 106 ART-naive HIV-infected subjects who were randomized to receive efavirenz (EFV) + zidovudine/lamivudine (n = 32) or lopinavir/ritonavir (LPV/r) + zidovudine/lamivudine induction (n = 74) for 24-48 weeks followed by LPV/r monotherapy. We also sought to identify factors associated with BMD loss, including markers of systemic inflammation [soluble tumor necrosis factor-alpha receptors (sTNFR I and II)].. After 96 weeks, the mean percent change from baseline in total BMD was -2.5% (LPV/r) and -2.3% (EFV) (P < 0.01 for within-group changes in either arm; P = 0.86 for between-group differences). No alteration in the rate of BMD change was observed upon simplification to LPV/r monotherapy. Although soluble tumor necrosis factor-alpha receptor II concentrations at baseline and 24 weeks were at least marginally associated with subsequent changes in BMD (P = 0.06 and P = 0.028, respectively), these associations were no longer significant after adjustment for CD4 T cell count. Subjects with lower baseline CD4 T cell count, non-black race, and higher baseline glucose demonstrated a higher risk for >5% decrease in BMD.. Similar decreases in BMD over 96 weeks occurred in ART-naive subjects receiving either EFV-based regimen or LPV/r-based regimen, which was not altered by simplification to LPV/r monotherapy and was unrelated to markers of tumor necrosis factor-alpha activity.

Topics: Absorptiometry, Photon; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Bone Density; Cyclopropanes; Female; HIV Infections; Humans; Inflammation Mediators; Lamivudine; Lopinavir; Male; Middle Aged; Osteoporosis; Prospective Studies; Pyrimidinones; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Risk Factors; Ritonavir; Zidovudine

Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated.. A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers.. Posaconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ATV by 2.6-fold and 3.7-fold, respectively. Posaconazole increased ATV Cmax and AUC when administered with ritonavir by 1.5-fold and 2.5-fold, respectively. Most subjects who received ATV (with and without ritonavir) and posaconazole experienced clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant decreases of posaconazole Cmax and AUC of approximately 45% and 50%, respectively.. Frequent monitoring of adverse events and toxicity related to antiviral exposure is recommended in the event of coadministration of posaconazole and ATV with or without ritonavir. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to patients outweighs the risk.

Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Atazanavir Sulfate; Benzoxazines; Cross-Over Studies; Cyclopropanes; Drug Interactions; Female; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Triazoles

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Diarrhea; Drug Therapy, Combination; Glucose Tolerance Test; HIV Protease Inhibitors; Humans; Lopinavir; Nausea; Pyrimidinones; Ritonavir; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

This study evaluated the effects of 3 class-sparing antiretroviral therapy (ART) regimens on endothelial function in human immunodeficiency virus (HIV)-infected subjects participating in a randomized trial.. Endothelial dysfunction has been observed in patients receiving ART for HIV infection.. This was a prospective, multicenter study of treatment-naive subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks.. There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV ribonucleic acid (RNA) values were 245 cells/mm(3) and 4.8 log(10) copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range [IQR] 1.98% to 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log(10) copies/ml, respectively. FMD increased by 0.74% (IQR -0.62% to +2.74%, p = 0.003) and 1.48% (IQR -0.20% to +4.30%, p < 0.001), respectively, with similar changes in each arm (Kruskal-Wallis p value >0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (r(s) = -0.30, p = 0.017).. Among treatment-naive individuals with HIV, 3 different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Brachial Artery; CD4 Lymphocyte Count; Cyclopropanes; Endothelium, Vascular; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Organophosphonates; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir; Time Factors; Zidovudine

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C(12 h)) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC(0-infinity)) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C(max)) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C(12 h) GMR (90% CI) was 0.79 (0.49, 1.28); AUC(0-infinity) was 0.64 (0.52, 0.80); and C(max) was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Young Adult

Induction-maintenance strategies were associated with a low response rate. We compared the virological response with two different induction regimens with trizivir plus efavirenz or lopinavir/ritonavir.. A randomized, multicentre, open-label clinical trial with 209 antiretroviral-naive HIV-infected patients assigned to trizivir plus either efavirenz or lopinavir/ritonavir during 24-36 weeks. Patients reaching undetectable plasma viral loads during induction entered a 48-week maintenance on trizivir alone. The primary endpoint was the proportion of patients without treatment failure at 72 weeks using an intent to treat (ITT) analysis (switching equals failure).. Patients were randomly assigned (efavirenz 104; lopinavir/ritonavir 105), and 114 (55%) entered the maintenance phase (efavirenz 54; lopinavir/ritonavir 60). Baseline characteristics were balanced between groups. The response rate at 72 weeks was 31 and 43% (ITT analysis, P = 0.076) and 63 and 75% (on-treatment analysis, P = 0.172) in the efavirenz and lopinavir/ritonavir arms, respectively. Virological failure occurred in 27 patients: six during induction (efavirenz, three; lopinavir/ritonavir, three; P = 1.0) and 21 during maintenance (efavirenz, 14; lopinavir/ritonavir, seven; P = 0.057). Thirty-four patients in the efavirenz arm switched treatment because of adverse events compared with 25 in the lopinavir/ritonavir arm (P = 0.17).. Trizivir plus either efavirenz or lopinavir/ritonavir followed by maintenance with trizivir achieved a low but similar response at 72 weeks, with a high incidence of adverse events leading to drug discontinuation during the induction phase in both arms. The study showed a trend towards an increased virological failure rate in the efavirenz arm during the maintenance phase.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Treatment Outcome; Zidovudine

Efavirenz and lopinavir/ritonavir are both recommended antiretroviral agents for combination first-line therapy, although information on direct comparisons between them is scarce. A retrospective longitudinal study from the VACH cohort comparing both regimens was performed.. Efficacy was examined comparing time to virological failure, CD4 recovery and clinical progression. Tolerability was examined comparing time to treatment discontinuation for any reason and for toxicity. Survival analysis was conducted using the Kaplan-Meier method, and standard and weighted Cox regression models.. A total of 1550 antiretroviral-naive patients starting a two-nucleoside reverse transcriptase inhibitor regimen plus either efavirenz (n = 1159) or lopinavir/ritonavir (n = 391) were included in the study. At baseline, patients starting lopinavir/ritonavir had higher HIV-1 RNA and lower CD4+ cell counts. There was no difference in the adjusted hazards of virological failure [efavirenz versus lopinavir/ritonavir hazard ratio (HR) = 0.93, 95% confidence interval (CI): 0.77-1.12, P = 0.43], CD4 recovery (HR = 1.11, 95% CI: 0.95-1.30, P = 0.19) and clinical progression (HR = 0.71, 95% CI: 0.39-1.31, P = 0.27). There was an increased risk of discontinuation for any reason or for toxicity for lopinavir/ritonavir (HR = 2.10, 95% CI: 1.40-3.15, P = 0.0003). CD4 recovery with both drugs was also similar in the lowest CD4 strata. A higher risk of early hypertriglyceridaemia was associated with lopinavir/ritonavir-based regimens.. Our study suggests similar virological efficacy for efavirenz- or lopinavir/ritonavir-based first-line antiretroviral regimens, but an increased risk of discontinuation because of toxicity in case of lopinavir/ritonavir-based therapy. Immunological outcome appeared similar with both regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Hypertriglyceridemia; Kaplan-Meier Estimate; Longitudinal Studies; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Withholding Treatment

A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4beta-hydroxycholesterol. We studied plasma 4beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A.. In patients treated with efavirenz, the median plasma 4beta-hydroxycholesterol level increased by 46 ng/mL (p = 0.004; n = 11). In contrast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4beta-hydroxycholesterol of -9.4 ng/mL (p = 0.0003; n = 22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p = 0.38; n = 19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4beta-hydroxycholesterol levels (p < 0.0001).. Changes in plasma 4beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Enzyme Induction; Enzyme Inhibitors; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxycholesterols; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Young Adult

The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs.. In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups.. At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups.. Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895 [ClinicalTrials.gov].).

Topics: Adolescent; Adult; Alkynes; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Kaplan-Meier Estimate; Lopinavir; Male; Middle Aged; Mutation; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Failure

Complex antiretroviral regimens can be associated with increased toxicity and poor adherence. Our aim was to compare the efficacy and safety of switching to two simplified, class-sparing antiretroviral regimens.. We conducted a randomized, open-label study in 236 patients with virologic suppression who were taking a three- or four-drug protease inhibitor or non-nucleoside reverse transcriptase inhibitor regimen for > or = 18 months. Patients received lopinavir/ritonavir (LPV/r) 533 mg/133 mg twice daily + efavirenz (EFV) 600 mg once daily or EFV + two nucleoside reverse transcriptase inhibitors (NRTI). Primary study endpoint was time to first virologic failure (VF, confirmed HIV-1 RNA > 200 copies/ml) or discontinuation because of study drug-related toxicity.. After 2.1 years of follow up, patients receiving LPV/r + EFV discontinued treatment at a greater rate than patients receiving EFV + NRTI (P < 0.001). Twenty-one patients developed VF (14 receiving LPV/r + EFV and seven receiving EFV + NRTI) and 26 discontinued because of a study drug-related toxicity (20 receiving LPV/r + EFV and six receiving EFV + NRTI). Time to VF or study drug related-toxicity discontinuation was significantly shorter for LPV/r + EFV than EFV + NRTIs (P = 0.0015). A significantly higher risk of drug-related toxicity occurred with LPV/r + EFV, mainly for increased triglycerides (P = 0021). A trend toward a higher VF rate occurred with LPV/r + EFV in an intent-to-treat and as-treated analyses (P = 0.088 and P = 0.063 respectively).. Switching to EFV + NRTI resulted in better outcomes, fewer drug-related toxicity discontinuations and a trend to fewer virologic failures compared to switching to LPV/r + EFV.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Resistance, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

Subcutaneous limb fat loss continues to be one the most troubling side effects of long-term antiretroviral regimens. Nucleoside analogues and protease inhibitors (PIs) have been linked to the development of this complication.. We evaluated the effects of nucleoside-sparing and PI-sparing regimens on fat distribution, bone mineral density, and metabolic parameters in 62 subjects, who were not selected for lipoatrophy, with advanced HIV (nadir CD4 count or=80,000 copies/mL) and an undetectable HIV viral load. Participants were randomized to switch their initial successful antiretroviral regimen to open-label lopinavir/ritonavir (LPV/r) at a dose of 533/133 mg twice a day and efavirenz (EFV) at a dose of 600 mg/d (the nucleoside-sparing arm) versus EFV and 2 nucleoside analogues (the PI-sparing arm).. At week 48, the median change in limb fat in the nucleoside-sparing arm was 562 g (6%, interquartile range [IQR]: -218-1186 g) versus a loss of -242 g (-4%, IQR: -539-452 g) in the nucleoside-containing PI-sparing arm (P = 0.086). At the time of last observation (median = 102 weeks, IQR: 73-152 weeks), a median gain of 782 g (10%, IQR: -380-1168 g) of limb fat was noted in the nonnucleoside arm (n = 22) versus a loss of 850 g (-15%, IQR: -1270 to -526 g) in the nucleoside-containing arm (n = 25; P = 0.002).. The switch to a nucleoside-sparing combination antiretroviral regimen (LPV/r + EFV) was associated with significant improvement in limb fat. These results provide additional evidence that nucleoside analogues are important in the progressive limb fat loss that characterizes antiretroviral treatment and that switching medications can significantly improve this complication. This option has to be carefully balanced with the potential to increase serum lipid levels and the trend to increase virologic failure.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Body Fat Distribution; Cyclopropanes; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Time Factors

To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant.. An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods.. Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced.. When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required.. The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

Topics: Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Area Under Curve; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dose-Response Relationship, Drug; Female; Graft Rejection; Half-Life; Hepatitis C; HIV; HIV Infections; Humans; Liver Transplantation; Lopinavir; Male; Middle Aged; Nelfinavir; Pyrimidinones; Ritonavir; Tacrolimus; Viral Load

Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions.. Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV (n=7) or without EFV (n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV (n=10) (Study 2).. In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (Cmin; 1.10 versus 1.06 microg/ml, P = 0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34 microg x h/ml, P = 0.22) or maximum concentration (Cmax; 2.61 versus 4.33 microg/ml, P = 0.08); for LPV there was no difference in Cmin, (median: 3.66 versus 6.18 microg/ml, P = 0.20), AUC (81.84 versus 93.75 microg x h/ml, P = 0.37) or Cmax (10.36 versus 10.93 microg/ml, P = 0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 microg/ml, P = 0.0001), AUC by 76% (19.41 versus 34.24 micorg x h/ml, P = 0.0001), and Cmax by 75% (3.50 versus 6.14, P = 0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up).. EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Ritonavir; Sulfonamides

To assess if enfuvirtide (ENF) increases antiviral activity of a highly active four-drug antiretroviral (ARV) regimen containing lopinavir/ritonavir, efavirenz, lamivudine and tenofovir in ARV-naive, HIV-infected patients.. Pilot study in ARV-naive, HIV-infected patients with viral load (VL) >10,000 copies/ml and no documented resistance to any of the study drugs. Patients were randomized to receive ENF (ENF Group) or not (Control Group) in combination with lopinavir/ritonavir, efavirenz, lamivudine and tenofovir as a backbone. The primary endpoint was to assess differences in the HIV-1 RNA decay rate during the first phase of viral decay. VL and treatment adherence were measured at baseline, every 6 h during the first 3 days, and once daily from day 3 to 6. Individual HIV-1 RNA decay rates were obtained using a non-linear least squares regression model.. Eight subjects were included in each study group. Mean (SD) baseline VL was 4.98 (0.38) log10 copies/ml in the ENF Group and 5.10 (0.49) log10 copies/ml in the Control Group (P=0.607). Baseline CD4+ cell count was 463 (306) and 362 (225) cells/mm3 in the ENF and the Control Group, respectively (P=0.484). First phase HIV-1 RNA decay rate was 0.802 (0.127) d(-1) in the ENF Group and 0.624 (0.182) d(-1) in the Control Group (P=0.045). By day 6, VL was 3.55 (0.40) and 3.92 (0.36) log10 copies/ml in the ENF and the Control Group, respectively (P=0.079).. The addition of ENF increased the antiviral potency of a highly active four-drug ARV regimen by 28.5% in ARV-naive, HIV-infected patients. The clinical impact of this finding should be assessed.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Synergism; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; Humans; Lamivudine; Lopinavir; Organophosphonates; Oxazines; Patient Compliance; Peptide Fragments; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence.. To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily.. Twenty-six centers in the United States, Canada, and Puerto Rico.. A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study.. Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients.. In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/mL (P = .5392, 95% 1-sided confidence interval [CI] = -33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .5015, 95% 1-sided CI = -33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL), in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 68-1750 ng/mL).. Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Capsules; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Female; Gelatin; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Oxazines; Ritonavir; Saquinavir

To compare alternative class-sparing antiretroviral regimens in treatment-naive subjects.. Open-label, multicenter, randomized trial of up to 3 consecutive treatment regimens over 96 weeks.. Two hundred ninety-one subjects received abacavir (ABC) and lamivudine and efavirenz (nonnucleoside reverse transcriptase inhibitors [NNRTIs]), ritonavir-boosted amprenavir (protease inhibitor [PI]), or stavudine (nucleoside reverse transcriptase inhibitor [NRTI]) by random assignment. The primary end points were the percentages of subjects with plasma HIV-1 RNA levels <400 copies/mL and time to treatment failure over 96 weeks.. Ninety percent of subjects completed 96 weeks of follow-up, and 79% remained on study treatment. At week 96, there were no differences between arms in the percentages of subjects with plasma HIV-1 RNA levels <400 and <50 copies/mL, mean changes in plasma HIV-1 RNA levels, time to treatment failure, time to first or second virologic failure, or CD4 cell counts. The NNRTI arm had a greater percentages of subjects with RNA levels

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Resistance; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Oxazines; Ritonavir; Stavudine; Treatment Outcome

The availability of enfuvirtide enables assessment of whether human immunodeficiency virus (HIV) decay can be enhanced by targeting reverse transcriptase, protease, and fusion. We performed a 12-week study of 22 patients randomized to receive ritonavir-boosted saquinavir and efavirenz with (the 3-target arm) or without (the 2-target arm) enfuvirtide. We observed no difference in the mean+/-SD elimination-rate constant for overall decay (0.142+/-0.040 per day and 0.128 +/- 0.033 per day in the 2- and 3-target arms, respectively; P>.1) or for modeled first-phase decay rate (-0.62+/-0.34 per day and -0.51+/-0.16 per day; P>.1). Antiretroviral therapy that inhibits HIV reverse transcriptase and protease exerts potent antiviral effects that might not be augmented by the addition of an HIV fusion inhibitor.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Male; Oxazines; Peptide Fragments; Ritonavir; Saquinavir; Viral Load

Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied.. To investigate the pharmacokinetics of increased-dose (300/75 mg/m2 twice-daily) lopinavir/ritonavir with normal-dose (14 mg/kg once-daily) efavirenz in HIV-1-infected children.. Steady-state pharmacokinetics of lopinavir and efavirenz were determined and compared with historical data.. Fifteen children of median age 11.8 (range, 5.7-16.3) years were included. Area under the plasma concentration-time curve (AUC0-12), peak levels (Cmax), and trough levels (Cmin) of lopinavir were similar to historical data in adults and children. Medians (interquartile range) were 92.3 (43.5-138.5) mg/L.h, 12.5 (6.9-16.7) mg/L, and 5.7 (1.3-8.0) mg/L, respectively. Efavirenz pharmacokinetics approximated previous data in adults and children.. The increased dose of 300/75 mg/m2 twice-daily lopinavir/ritonavir compensates for the enzyme-inducing effect of efavirenz in HIV-infected children.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Ritonavir; Safety

The influence of efavirenz on lopinavir pharmacokinetics was investigated using a population approach.. Forty-five HIV patients treated with lopinavir/ritonavir plus efavirenz (A) and 24 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (B) were studied.. A relationship (P < 0.01) was established between the elimination rate constant of lopinavir (k(10)) and treatment with efavirenz. Mean k(10) was higher in group A than in group B (0.3838 vs 0.2810 h(-1)) (P < 0.001, 95% confidence interval for difference between means 0.1004, 0.1052).. These results suggest that lopinavir metabolism is induced by efavirenz.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Ritonavir

Recommended antiretroviral regimens include a nucleoside reverse transcriptase inhibitor (NRTI) component. Class cross-resistance and mitochondrial toxicity are recognized as problems with this class of antiretrovirals.. In a pilot open-label study, 65 antiretroviral-naive and 21 experienced but nonnucleoside reverse transcriptase inhibitor-naive HIV-1-infected adults were given a combination of lopinavir/ritonavir (533.3/133.3 mg twice daily) and efavirenz (600 mg once daily) for 48 weeks.. At baseline, the mean viral load was 4.84 log10 copies/mL and the mean CD4 count was 311 cells/mm. At week 24, the proportions of patients with a viral load <400 copies/mL were 78% and 93% using an intent-to-treat and on-treatment analysis, respectively. At week 48, proportions were 73% and 97%, respectively. Treatment discontinuation occurred in 21 patients during the 48-week period, with 33% of those attributable to drug-related adverse effects. A viral load >400 copies/mL at week 24 or 48 was associated with nonadherence in 3 patients and virologic failure in 1 patient. After an increase during the first 8 weeks, fasting lipid levels remained stable up to 48 weeks.. The lopinavir/ritonavir-efavirenz combination is associated with a high rate of virologic response and should be compared with more classic NRTI-containing regimens in randomized and controlled clinical trials.

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Resistance, Viral; Drug Tolerance; Female; France; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oxazines; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Safety

Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity.. Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat.. Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved.. IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.

Topics: Adult; Aged; Alkynes; Anthropometry; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Blood Glucose; CD4 Lymphocyte Count; Creatinine; Cyclopropanes; Disease Progression; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lipids; Male; Middle Aged; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Treatment Outcome; Viral Load

To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV).. In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days. Amprenavir (APV) pharmacokinetic sampling and safety assessments were performed on the last day of each period.. Plasma APV exposure was not significantly altered when EFV was coadministered with GW433908 700 mg twice daily (BID) + RTV 100 mg BID. Plasma APV exposure was decreased when EFV was coadministered with GW433908 1395 mg QD + RTV 200 mg QD. However, administration of EFV with GW433908 1395 mg QD + RTV 300 mg QD (i.e., adding an extra 100 mg of RTV) was able to negate this interaction. Adverse events were consistent with prior data for each of the separate agents.. When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.

Topics: Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Carbamates; Cholesterol; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Female; Furans; Humans; Linear Models; Male; Middle Aged; Organophosphates; Oxazines; Prodrugs; Ritonavir; Sulfonamides; Triglycerides

We studied a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the treatment of children infected with NRTI-resistant HIV-1. The combination of lopinavir/ritonavir and efavirenz suppressed HIV-1 levels for a prolonged period and resulted in a significant increase in CD4+ T cell numbers despite an extensive prior treatment with NRTI (>4 years). Observed side effects were transient with the exception of dyslipidaemia.

Topics: Adolescent; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lopinavir; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

To compare CC chemokine mRNA levels from native peripheral blood mononucleated cells (PBMCs) before and 6 months after the initiation of two different regimens of highly active antiretroviral therapy (HAART), we treated group 1 (n = 11) with two nucleoside analogues and the protease inhibitor (PI) indinavir boosted by ritonavir (800/100 mg b.i.d.); group 2 (n = 8) was treated with the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz instead of PI. CC chemokine mRNA levels (regulated upon T cell activation expressed secreted [RANTES], macrophage inhibitory protein [MIP]-1alpha, MIP-1beta, monocyte chemotactic protein [MCP]-1, MCP-2) were quantified from PBMCs before and 6 months after the initiation of HAART using a reverse transcription/real-time polymerase chain reaction (PCR) assay. The mRNA levels of MCP-1 and MCP-2 were significantly decreased in both groups (P < 0.05), while MIP-1alpha and MIP-1beta were decreased significantly only in the PI-treated group, but not in the NNRTI group. A moderate decrease of RANTES was observed in both treatment groups. The data suggest that HAART regimens containing either NNRTI or PI are not equivalent with regard to modification of CC chemokine mRNA profiles.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokine CCL8; Chemokines; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Leukocytes, Mononuclear; Macrophage Inflammatory Proteins; Male; Middle Aged; Monocyte Chemoattractant Proteins; Oxazines; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Messenger

We assessed the pharmacokinetics of three different doses of indinavir in five patients. All doses achieved trough concentrations above efficacy thresholds. Toxic trough concentrations were observed in all patients receiving 800 mg, in two patients receiving 600 mg, and in none receiving 400 mg. Indinavir at 400 mg may be efficacious and less toxic in patients taking ritonavir and efavirenz.

Topics: Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; China; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Interactions; HIV Infections; Humans; Indinavir; Male; Middle Aged; Oxazines; Ritonavir

A once-daily (q.d.) nucleoside-sparing regimen can prevent mitochondrial toxicity, overcome viral resistance and improve compliance. In the present study the effect of efavirenz on the pharmacokinetics and tolerability of once-daily nelfinavir/ritonavir was evaluated in healthy subjects.. This was a multiple-dose, open-label, single-group, two-period study in 24 healthy subjects. Each received from days 1-10 (period 1): 1875 mg nelfinavir plus 200 mg ritonavir q.d. with a 300-kcal snack. During days 11-20 (period 2) efavirenz 600 mg q.d. was added to the regimen. Blood samples were collected up to 24 h after dosing on days 10 (period 1) and 20 (period 2). High-performance liquid chromatography methods were used for the determination of the concentrations of all compounds. The main pharmacokinetic parameters were calculated using noncompartmental methods.. All subjects completed the study. After the first period mean nelfinavir AUC(0-24 h), C(max) and C(24) were 49.6 mg h(-1) l(-1), 5.0 mg l(-1) and 0.37 mg l(-1), and the sum of nelfinavir plus its active metabolite M8 C(24) was 0.83 mg l(-1). The relative bioavailability, expressed as a geometric mean ratio (90% confidence interval) for nelfinavir AUC(0-24 h), C(max) and C(24) of period 2 compared with period 1 was: 1.30 (1.21, 1.40), 1.29 (1.19, 1.40) and 1.48 (1.32, 1.66). The sum of nelfinavir and M8 C(24) in period 2 was 0.99 mg l(-1), an increase of 19%. No serious adverse events occurred.. The studied regimens were well tolerated. Nelfinavir/ritonavir given together with efavirenz resulted in a 48% higher mean C(24) concentration for nelfinavir, and the sum of nelfinavir and M8 C(24) concentrations was 0.99 mg l(-1). Efavirenz exposure in this study was similar to that reported previously, and therefore can be used effectively in combination with ritonavir and nelfinavir.

Topics: Alkynes; Benzoxazines; Cyclopropanes; Drug Combinations; Female; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nelfinavir; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir

The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C(min,ss)) was 1.92 microg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 microg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C(max,ss)) was 7.12 microg/ml, the area under the concentration-time curve from 0 to 10 h (AUC(0-10)) was 32.06 microg. h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUC(ss)) was 35.74 microg. h/ml. Decreases in the mean values of C(min,ss) (29%), C(max,ss) (42%), AUC(0-10) (42%), and AUC(ss) (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C(min,ss) markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C(min,ss) above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.

Topics: Adult; Alkynes; Area Under Curve; Benzoxazines; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Female; Furans; Half-Life; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Oxazines; Ritonavir; Sulfonamides

The steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularly C(min), than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC(12)), C(predose), and C(min) by 46, 70, and 141%, respectively. The increase in lopinavir C(max) (33%,) did not reach statistical significance. Ritonavir AUC(12), C(max), C(predose), and C(min) values were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.

Topics: Adult; Alkynes; Area Under Curve; Benzoxazines; Biological Availability; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Reverse Transcriptase; Humans; Logistic Models; Lopinavir; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Oxazines; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Viral Load

Despite the clinical benefits of combination antiviral therapy, whether maximal antiviral potency has been achieved with current drug combinations remains unclear. We studied the first phase of decay of human immunodeficiency virus type 1 (HIV-1) RNA in plasma, one early indicator of antiviral activity, after the administration of a novel combination of lopinavir/ritonavir, efavirenz, tenofovir disoproxil fumarate, and lamivudine and compared it with that observed in matched cohorts treated with alternative combination regimens. On the basis of these comparisons, we conclude that the relative potency of highly active antiretroviral therapy may be augmented by as much as 25%-30%. However, it is important to emphasize that further study is warranted to explore whether these early measurements of relative efficacy provide long-term virologic and clinical benefits. Nevertheless, we believe that optimal treatment regimens for HIV-1 have yet to be identified and that continued research to achieve this goal is warranted.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cohort Studies; Cyclopropanes; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Organophosphonates; Organophosphorus Compounds; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Enfuvirtide; Female; Furans; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Peptide Fragments; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

Topics: Alkynes; Benzoxazines; Blood Glucose; Cholesterol; Cyclopropanes; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Triglycerides

This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics of the combination of indinavir (800 mg) and low-dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations.. Eighteen healthy male volunteers participated in this multiple-dose, 1-arm, 2-period interaction study. They took a combination of 800 mg indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once-daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of indinavir and ritonavir on days 15 and 29 were compared.. Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P <.01) in indinavir area under the curve (AUC, -25%), trough concentration (C(min), -50%), and maximum concentration (C(max), -17%). All indinavir C(min) levels on day 29 remained equivalent to or above the mean C(min) value described for the regimen of 800 mg indinavir three times a day, without ritonavir (0.15 mg/L). Changes in ritonavir AUC, C(min), and C(max) were -36%, -39%, and -34%, respectively. Pharmacokinetics of efavirenz on day 29 were comparable with published data.. The addition of efavirenz to a combination of 800 mg indinavir and 100 mg ritonavir twice daily results in significant decreases in AUC, C(max), and especially C(min) of indinavir. The dose of indinavir or ritonavir should be increased to maintain similar indinavir drug levels after addition of efavirenz to the indinavir-ritonavir combination. Dose modifications may not be needed in antiretroviral-naive human immunodeficiency virus-infected patients if the reference C(min) of the regimen of 800 mg indinavir 3 times a day is considered to be adequate.

Topics: Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Half-Life; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Oxazines; Ritonavir; Spectrophotometry, Ultraviolet

to assess the safety and efficacy of a combination of ritonavir, efavirenz and two recycled nucleosides in patients who failed on a conventional triple-drug regimen including indinavir or ritonavir.. An open label study of ritonavir (100 mg twice daily), saquinavir (1000 mg twice daily), efavirenz (600 mg per day) and nucleoside analogues in 32 saquinavir- and efavirenz-naive protease inhibitor-experienced patients. Patients were included on the basis of plasma levels of HIV RNA above 5000 copies/ml while on conventional antiretroviral therapy. Phenotypic resistance and genotypic resistance mutations to saquinavir were assessed at baseline. Peak and trough plasma levels of saquinavir were monitored throughout the study.. Median CD4 cell counts and median plasma HIV RNA at baseline were 258 x 10(6)/l and 4.31 log10 copies/ml, respectively. The plasma viral load decreased by a median of 1.20 log10 copies/ml and the CD4 cell count increased by a median 60 x 10(6) cells/l at week 24 of therapy. Seventy-one per cent of the patients achieved a plasma viral load < 500 copies/ml and 45% achieved a viral load < 50 copies/ml. Patients exhibiting phenotypic resistance to saquinavir at baseline experienced a median decrease in HIV RNA of 0.91 log10 copies/ml at week 24 of therapy, as compared with a decrease of 1.52 log10 copies/ml in those exhibiting sensitive viral strains (P = 0.03). Genotypic resistance to saquinavir was not predictive of virologic failure.. Our results indicate that the combination of ritonavir, saquinavir and efavirenz is safe and effective at 24 weeks in over two-thirds of patients who previously failed on highly active antiretroviral therapy, and that the determination of phenotypic resistance may be of greater value than the detection of resistance mutations to predict the outcome of salvage therapy in this setting.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Treatment Outcome

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Fluorenes; HIV Infections; Humans; Lopinavir; Lumefantrine; Malaria; Malaria, Falciparum; Nevirapine; Ritonavir; Uganda

The present investigations aimed to compare the efficiency of PAMAM G4 (PG4) and PEGylated PAMAM G4 (PPG4) dendrimers as novel nanocarriers for the treatment of HIV-1. Synthesized PG4 and PPG4 dendrimers were confirmed by electrospray ionization and particle size with its morphology. The anti-human immunodeficiency virus (HIV) drug efavirenz (EFV) with a booster dose of ritonavir (RTV) was encapsulated into PG4 and PPG4 formerly noted as PG4ER and PPG4ER, respectively. Further, evaluated for dendrimers mediated solubilization, drug release, cytotoxicity, drug uptake, plasma, and tissue pharmacokinetics, and histopathology. PG4ER and PPG4ER both promoted a prolonged release of EFV in weakly acidic pH 4 up to 84 h and 132 h, respectively. The results of the cytotoxicity assay and drug uptake study showed that PPG4ER was safe and biocompatible up to 12.5 µg/ml. The plasma pharmacokinetic profile of EFV and RTV was significantly increased by PPG4ER with prolonged

Topics: Benzoxazines; Dendrimers; Ritonavir; Tissue Distribution

The first nationally representative cross-sectional HIV drug resistance (HIVDR) survey was conducted in Uruguay in 2018-2019 among adults diagnosed with HIV and initiating or reinitiating antiretroviral therapy (ART).

Topics: Adult; Anti-Retroviral Agents; Cross-Sectional Studies; Female; HIV Infections; HIV-1; Humans; Male; Ritonavir; Uruguay

A highly sensitive LC-MS/MS methods were developed and validated to quantify nine antiretrovirals (atazanavir [ATV], tenofovir [TFV], emtricitabine [FTC], darunavir [DRV], dolutegravir [DTG], efavirenz [EFV], lamivudine [3TC], raltegravir [RAL], and ritonavir [RTV]) in human cerebral spinal fluid (CSF). The approach remedies adsorption issues caused by polypropylene based sample collection tubes. 1% ammonium hydroxide in methanol was added in an amount equal to the volume of each quality control (QC) or patient sample. Protein precipitation was utilized with a CSF sample volume of 100 μL and a 100 μL of methanol:ACN and vortexed. Chromatographic separation was achieved with a 3 × 100 ACE® C18 column for ATV, DRV, DTG, EFV, RTV and RAL, and a 2 × 100 Polar RP column for TFV/FTC/3TC. Mobile phase was methanol:water:formic acid (70:30:0.1, v/v/v) for ATV, DRV, DTG, EFV and RTV (10 uL injection, flow rate: 1.00 mL/min), ACN:water:formic acid (35:65:0.1, v/v/v) for RAL (50 uL injection, flow rate: 1.00 mL/min), ACN:water:formic acid (2:98:0.1, v/v/v) for TFV, FTC and 3TC (50 uL injection, flow rate: 0.35 mL/min). Column temperature was 40° C across all assays. The mass spectrometer was operated in positive, multiple-reaction-monitoring (MRM) mode with electrospray ionization (ESI) for all analytes with the exception of EFV, which was operated in negative, MRM mode with ESI. The assay was linear over the calibration range of 1 to 250 ng/mL for all analytes. The addition of 1% ammonium hydroxide in sample tubes overcame up to 44% negative bias in QC samples and allowed the methods to meet full validation criteria.

Topics: Adsorption; Ammonium Hydroxide; Anti-HIV Agents; Anti-Retroviral Agents; Benzoxazines; Chromatography, Liquid; Emtricitabine; HIV Infections; Humans; Lamivudine; Methanol; Ritonavir; Tandem Mass Spectrometry; Tenofovir; Water

We describe transition of HIV-positive children from efavirenz- or nevirapine-based antiretroviral therapy (ART) to optimal dolutegravir (DTG) or lopinavir/ritonavir (LPV/r) (solid formulation)-based ART in Lesotho.. We followed a cohort of children less than 15 years of age who were initiated on ART on or after January 1, 2018 from 21 selected health facilities in Lesotho. From March 2020 to May 2022, we collected data retrospectively through chart abstraction and prospectively through caregiver interviews to cover a period of 24 months following treatment initiation. We used a structured questionnaire to collect data on demographics, ART regimen, drug formulations and switches, viral suppression, retention, and drug administration challenges. Data were summarized as frequencies and percentages, using SAS ver.9.4.. Of 310 children enrolled in the study, 169 (54.5%) were female, and median age at ART initiation was 5.9 years (IQR 1.1-11.1). During follow-up, 19 (6.1%) children died, 41 (13.2%) were lost to follow-up and 74 (23.9%) transferred to non-study sites. At baseline, 144 (46.4%) children were receiving efavirenz-based ART regimen, 133 (42.9%) LPV/r, 27 (8.7%) DTG, 5 (1.6%) nevirapine; 1 child had incomplete records. By study end, 143 (46.1%) children were receiving LPV/r-based ART regimen, 109 (35.2%) DTG, and 58 (18.7%) were on efavirenz or nevirapine-based regimen. Of 116 children with viral load results after six months or more on a consistent regimen, viral suppression was seen in 35/53 (66.0%) children on LPV/r, 36/38 (94.7%) children on DTG and 19/24 (79.2%) children on efavirenz.. Following optimal ART introduction in Lesotho, most children in the cohort were transitioned and many attained or maintained viral suppression after transition; however, we recommend more robust viral load monitoring and patient tracking to reduce losses and improve outcomes after ART transition.

Topics: Anti-HIV Agents; Child; Child, Preschool; Female; HIV Infections; Humans; Infant; Lesotho; Lopinavir; Male; Nevirapine; Retrospective Studies; Ritonavir; Viral Load

The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.. We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.. Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.. ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Female; HIV; HIV Infections; Humans; Infant; Infant, Newborn; Isoniazid; Lopinavir; Male; Pyrazinamide; Rifampin; Ritonavir; Tuberculosis

We investigated prevalence and predictors of glucose metabolism disorders (GMDs) among People Living with HIV (PLWH) on efavirenz- and atazanavir/ritonavir-based combination antiretroviral therapy (cART).. This cross-sectional study involved adult PLWH on efavirenz- (n = 240) and atazanavir/ritonavir-based (n = 111) cART. The prevalence of GMDs was determined by fasting serum glucose, insulin, and homeostasis model assessment. A logistic regression model was used to determine predictors.. The overall prevalence of GMDs for all regimens was 27.6% (97/351) [95% CI 23.0-32.6%] s, with 31.1% (75/240) [95% CI 25.4-37.5%] for efavirenz-based and 19.8% (22/111) [95% CI 12.9-28.5%)] for atazanavir/ritonavir-based cART group. The prevalence of impaired fasting glycemia was significantly higher (p = 0.026) in the efavirenz- [(15.4%) (37/240); 95%CI (11.1-20.6%)] than atazanavir/ritonavir-based [(7.2%) (8/111), (95%CI (3.2-13.7%)] cART. However, no significant difference was observed in the prevalence of diabetes mellitus and insulin resistance between the two regimens. Age ≥46 years old and specific type of ARV contained in cART, such as TDF, were independent predictors of GMD in both groups. Whereas the male gender and BMI category were predictors of GMDs among EFV-based cART group, AZT- and ABC- containing regimens and triglyceride levels were predictors in the ATV/r-based group.. GMDs were highly prevalent among adults on EFV- than ATV/r-based cARTs. Age ≥46 years and TDF-containing cARTs are common predictors in both regimens. Close monitoring for impaired fasting glucose during long-term EFV-based cART is recommended for early diagnosis of type-2 diabetes and management.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Blood Glucose; Cross-Sectional Studies; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Ethiopia; Female; Glucose; Glucose Metabolism Disorders; HIV; HIV Infections; Humans; Insulin; Male; Prevalence; Ritonavir

Access to viral load measurements is constrained in resource-limited settings. A lateral flow urine tenofovir (TFV) rapid assay (UTRA) for patients whose regimens include TFV offers an affordable approach to frequent adherence monitoring.. We conducted a cross-sectional study of patients to assess the utility of UTRA to predict virologic failure, defined as a viral load greater than 400 copies/ml.. We assessed urine TFV among 113 participants at increased risk of viral failure (who had previous viral failure on this regimen or had previously been ≥30 days out of care), comparing low genetic-barrier efavirenz (EFV) regimens (n = 60) to dolutegravir (DTG)-boosted or ritonavir-boosted protease inhibitor (PI/r)-based high genetic-barrier regimens (n = 53). Dried blood spots (DBS) for TFV-diphosphate and plasma for TFV concentrations were collected, with drug resistance assessed if viral failure present.. Among 113 participants, 17 of 53 received DTG or PI/r had viral failure at the cross-sectional visit, with 11 (64.7%) demonstrating an undetectable urine TFV; the negative-predictive value (NPV) of undetectable UTRA for viral failure was 85% (34/40); none of the 16 sequenced had dual class drug resistance. In those treated with EFV regimens the sensitivity was lower, as only 1 (4.8%) of 21 with viral failure had an undetectable UTRA (P < 0.001).. Urine tenofovir-testing had a high negative-predictive value for viral failure in patients treated with DTG or ritonavir-boosted protease inhibitor regimens, where viral failure was largely explained by poor drug adherence. Frequent monitoring with inexpensive lateral flow urine TFV testing should be investigated prospectively in between viral load visits to improve viral load suppression on DTG-based first-line therapy in resource-limited settings.

Topics: Anti-HIV Agents; Cross-Sectional Studies; HIV Infections; Humans; Protease Inhibitors; Ritonavir; Tenofovir; Viral Load; Viremia

A liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been validated for quantification of three antiretroviral drugs (efavirenz [EFV], lopinavir [LPV], and ritonavir [RTV]) from human breast milk. The samples were extracted employing protein precipitation method using methanol as precipitating agent. The supernatant was evaporated and reconstituted before injecting into the chromatograph and separated on a biphenyl column. Calibration curves for the three tested antiretroviral drugs were linear (r ≥ 0.999) over the range examined. The inter- and intra-day coefficients of variation (CV) were ≤15% for efavirenz, lopinavir, and ritonavir. Mean recovery ranged from 96% to 105% and no major matrix effects were observed. This validated LC-MS/MS method was efficiently applied to determine EFV, LPV, and RTV concentrations in breast milk from Human Immunodeficiency Virus (HIV)-positive breastfeeding mothers. This assay requires a simple sample processing method with a short run time, making it well suited for high-throughput routine clinical or research purposes.

Topics: Anti-Retroviral Agents; Chromatography, Liquid; Female; HIV Infections; Humans; Lopinavir; Milk, Human; Ritonavir; Tandem Mass Spectrometry

While muscle fatigue, pain and weakness are common co-morbidities in HIV-1 infected people, their underlying cause remain poorly defined. To this end, we evaluated whether the common antiretroviral drugs efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) could be a contributing factor by pertubating sarcoplasmic reticulum (SR) Ca

Topics: Alkynes; Animals; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Calcium; Cell Line; Cyclopropanes; Homeostasis; Mice; Muscle, Skeletal; Myoblasts; Rabbits; Ritonavir; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Time-Lapse Imaging

Topics: Adult; Alkynes; Anthelmintics; Anti-HIV Agents; Benzoxazines; Cross-Over Studies; Cyclopropanes; Drug Interactions; Humans; Male; Praziquantel; Ritonavir; Stereoisomerism; Young Adult

Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug-drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate's appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.

Topics: Alkynes; Anti-Retroviral Agents; Antitubercular Agents; Benzoxazines; Contraceptive Agents, Hormonal; Contraceptive Effectiveness; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Delayed-Action Preparations; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Isoniazid; Lopinavir; Medroxyprogesterone Acetate; Nelfinavir; Rifampin; Ritonavir; Tuberculosis

Cryptococcal meningitis (CCM) is a common and deadly disease among HIV-infected patients. Notable about CCM is its association with the immune reconstitution inflammatory syndrome (IRIS). Though it has been posited a switch from first to second-line antiretroviral therapy (ART) can induce CCM IRIS, a case presentation of CCM IRIS has not been published.. A 10-year-old, HIV-infected girl who initially presented with severe headache and new-onset seizures, with cerebrospinal fluid that returned antigen, India Ink, and culture positive for Cryptococcus neoformans. Notably, 8 weeks prior to seizures, she had switched from first line to second-line ART (abacavir-lamivudine-efavirenz to zidovudine-lamivudine-lopinavir/ritonavir) due to virologic failure, with a viral load of 224,000 copies/milliliter. At time of seizures and 8 weeks on second-line ART, her viral load had reduced to 262 copies/milliliter. Her hospital course was prolonged, as she had ongoing headaches and developed bilateral cranial nerve VI palsies despite clearance of Cryptococcus from cerebrospinal fluid on antifungal therapy and therapeutic lumbar punctures. However, symptoms stabilized, and she was discharged with oral fluconazole. Cranial nerve palsies resolved 10 weeks post discharge and she has remained disease free.. We describe a case of CCM IRIS in a 10-year-old HIV infected child after changing to second-line ART. This case provides evidence that screening for cryptococcal antigenaemia prior to switch from first-line to second-line ART could be an important measure to prevent cryptococcal disease.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antifungal Agents; Antigens, Fungal; Benzoxazines; Child; Cryptococcus neoformans; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; Fluconazole; HIV; Humans; Immune Reconstitution Inflammatory Syndrome; Lamivudine; Lopinavir; Meningitis, Cryptococcal; Ritonavir; Treatment Outcome; Viral Load; Zidovudine

We previously found lower bone mass but similar bone turnover in pre-pubertal children living with HIV (CLWH) on a ritonavir-boosted lopinavir (LPV/r)-based vs. efavirenz-based antiretroviral therapy regimen 2 years after switch. Here, we evaluate if bone turnover differed between the groups close to the time of switch.. Samples from 108 children remaining on LPV/r and 104 children switched to efavirenz were available for analysis 8 weeks post-randomization. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx), procollagen type-I N-terminal propeptide (P1NP), and osteocalcin were measured. Markers of immune activation were also measured, including IL-6, TNF-alpha, soluble CD14 and high-sensitivity C-reactive protein (CRP).. Eight weeks post-randomization, we did not detect differences in CTx (1.42 vs. 1.44 ng/mL, p = 0.85) or P1NP concentrations (622 vs. 513 ng/mL, p = 0.68) between treatment groups. At 8 weeks, the treatment groups also had similar levels of IL-6, TNF-alpha, soluble CD14 and high-sensitivity CRP. Osteocalcin (ng/mL) was higher in the LPV/r than efavirenz group both at 8 weeks (88.6 vs. 67.3, p = 0.001) and 2 years (67.6 vs. 49.8, p = 0.001).. Overall, we failed to detect difference in bone turnover by P1NP and CTx in virologically-suppressed CLWH on different regimens at a time point close to the switch. We did observe higher levels of total osteocalcin in children remaining on LPV/r compared to children switched to efavirenz. Future studies should focus on uncovering the mechanism and determining whether perturbation in undercarboxylated osteocalcin could explain some of the bone side effects noted with protease inhibitors.

Topics: Alkynes; Benzoxazines; Bone Remodeling; Child; Cyclopropanes; HIV Infections; Humans; Lopinavir; Ritonavir

Patients living with HIV in malarial endemic regions may experience clinically significant drug interaction between antiretroviral and antimalarial drugs. Effects of nevirapine (NVP), efavirenz (EFV) and lopinavir/ritonavir (LPVr) on lumefantrine (LM) therapeutic concentrations and toxicity were evaluated. In a four-arm parallel study design, the blood samples of 40 participants, treated with artemether/lumefantrine (AL), were analysed. Lumefantrine Cmax was increased by 32% (p = 0.012) and 325% (p < 0.0001) in the NVP and LPVr arms respectively but decreased by 62% (p < 0.0001) in the EFV-arm. AUC of LM was, respectively, increased by 50% (p = 0.27) and 328% (p < 0.0001) in the NVP and LPVr arms but decreased in the EFV-arm by 30% (p = 0.019). Median day 7 LM concentration was less than 280 ng/mL in EFV-arm (239 ng/mL) but higher in control (290 ng/mL), NVP (369 ng/mL, p = 0.004) and LPVr (1331 ng/mL, p < 0.0001) arms. There were no clinically relevant toxicities nor adverse events in both control and test arms. Artemether/lumefantrine is safe and effective for treatment of malaria in PLWHA taking NVP and LPVr based ART regimen but not EFV-based regimen.

Topics: Adult; Alkynes; Anti-Retroviral Agents; Antimalarials; Artemether, Lumefantrine Drug Combination; Benzoxazines; Cyclopropanes; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Malaria; Male; Middle Aged; Nevirapine; Nigeria; Ritonavir; Treatment Outcome; Young Adult

Drug-drug interactions between orally administered antiretroviral therapy (ART) and hormones released from an intravaginal ring are not known. We hypothesised that ART containing either efavirenz or ritonavir-boosted atazanavir would alter plasma concentrations of vaginally administered etonogestrel and ethinylestradiol but that ART concentrations would be unchanged during use of an intravaginal ring.. We did a parallel, three-group, pharmacokinetic evaluation at HIV clinics in Asia (two sites), South America (five), sub-Saharan Africa (three), and the USA (11) between Dec 30, 2014, and Sept 12, 2016. We enrolled women with HIV who were either ART-naive (control group; n=25), receiving efavirenz-based ART (n=25), or receiving atazanavir-ritonavir-based ART (n=24). Women receiving ART were required to be on the same regimen for at least 30 days, with 400 copies or less per mL of plasma HIV-1 RNA; women not receiving ART had CD4 counts of 350 cells per μL or less. We excluded participants who had a bilateral oophorectomy or conditions that were contraindicated in the intravaginal ring product labelling. An intravaginal ring releasing etonogestrel and ethinylestradiol was inserted at entry (day 0). Single plasma samples for hormone concentrations were collected on days 7, 14, and 21 after intravaginal ring insertion. The primary outcome was the plasma concentration of etonogestrel and ethinylestradiol on day 21. Etonogestrel and ethinylestradiol concentrations were compared between each ART group and the control group by geometric mean ratio (GMR) with 90% CIs and Wilcoxon rank-sum test. As secondary outcomes, efavirenz or ritonavir-boosted atazanavir concentrations were assessed by 8-h intensive pharmacokinetic sampling at entry before intravaginal ring insertion and before intravaginal ring removal on day 21. Antiretroviral areas under the concentration-time curve (AUC. Between Dec 30, 2014, and Sept 12, 2016, we enrolled 84 participants in the study; ten participants were excluded from the primary hormone analysis. 74 participants met the primary endpoint: 25 in the control group, 25 in the efavirenz group, and 24 in the atazanavir group. On day 21 of intravaginal ring use, participants receiving efavirenz had 79% lower etonogestrel (GMR 0·21, 90% CI 0·16-0·28; p<0·0001) and 59% lower ethinylestradiol (0·41, 0·32-0·52; p<0·0001) concentrations compared with the control group. By contrast, participants receiving ritonavir-boosted atazanavir had 71% higher etonogestrel (1·71, 1·37-2·14; p<0·0001), yet 38% lower ethinylestradiol (0·62, 0·49-0·79; p=0·0037) compared with the control group. The AUC. Hormone exposure was significantly lower when an intravaginal ring contraceptive was combined with efavirenz-based ART. Further studies designed to examine pharmacodynamic endpoints, such as ovulation, when intravaginal ring hormones are combined with efavirenz are warranted.. National Institutes of Health, through the AIDS Clinical Trials Group and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Contraceptive Agents; Contraceptive Devices, Female; Cyclopropanes; Desogestrel; Drug Interactions; Female; HIV Infections; HIV-1; Humans; Lynestrenol; Middle Aged; Progesterone; Ritonavir; Viral Load; Young Adult

Antiretroviral therapy (ART) is associated with lipid abnormalities that contribute to increased risk of cardiovascular (CV) events among patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Although disorders of lipid metabolism associated with ART have been described before in developed countries, data on lipid profile disorders associated with ART use in China are limited. This study aimed to examine the changes in lipid profile among patients with HIV/AIDS who initiated lopinavir/ritonavir LPV/r or efavirenz (EFV)-based antiretroviral treatment regimens, which continue to be widely used China and other developing countries.. This is a retrospective, matched case-control study of HIV-positive patients initiating either LPV/r or EFV regimens at the Beijing You'an Hospital, Capital Medical University between July 2012 and January 2017. Generalized estimating equations were used to compare the differences in total cholesterol [TC], triglycerides [TG], low-density lipoprotein-cholesterol [LDL-C], and highdensity lipoprotein-cholesterol [HDL-C] at baseline and up to 24-months after ART initiation between the two treatment arms.. Baseline characteristics, including age, sex, CD4 cell count, viral load, and serum lipids, which were comparable between the two groups. The LPV/r-based regimen group had increased TC, TG, HDL-C, and LDL-C after 24-months of treatment. In the EFV-regimen group, TC, HDL-C, and LDL-C were increased compared to baseline, while the TC/HDL-C ratio decreased, and TG did not change significantly. After 24-months of treatment, the percentage of patients with dyslipidemia in the LPV/r group was much higher than in the EFV group (84.0% vs. 52.6%, P<0.001), and 17(10%) patients on LPV/r-based regimens had severe dyslipidemia. Patients on LPV/r-based regimens were at increased odds of hypercholesterolemia (odds ratio [OR]=1.709, P=0.038), hypertriglyceridemia (OR=4.315, P<0.001), and high TC/HDL-C ratio (OR=1.951, P=0.003). However, no significant difference was found in HDL-C (OR=1.246, P=0.186) or LDL-C (OR=1.253, P=0.410) between the treatment groups.. Both LPV/r or EFV treatment regimens impacted patients' lipid profiles. Compared to EFV-based regimens, patients on LPV/r-based regimens had increased odds of dyslipidemia, such as hypercholesterolemia, hypertriglyceridemia, or high TC/HDL-C ratio; however, there was no obvious effect on LDL-C, which is more relevant to the development of the cardiovascular disease.

Topics: Adult; Aged; Aged, 80 and over; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Asian People; Beijing; Benzoxazines; Case-Control Studies; Cyclopropanes; Drug-Related Side Effects and Adverse Reactions; Dyslipidemias; Female; HIV Infections; Hospitals, University; Humans; Lipids; Lopinavir; Male; Middle Aged; Retrospective Studies; Ritonavir; Treatment Outcome

Topics: Adolescent; Adult; Aged; Alkynes; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Humans; Ketoconazole; Male; Middle Aged; Pyridones; Ritonavir; Triazoles; Young Adult

Topics: Alkynes; Benzoxazines; Child; Cyclopropanes; HIV; Humans; Lopinavir; Nervous System; Nevirapine; Ritonavir

Topics: Alkynes; Benzoxazines; Child; Cyclopropanes; HIV; Humans; Lopinavir; Nevirapine; Ritonavir

Topics: Adipose Tissue; Alkynes; Anti-Retroviral Agents; Benzoxazines; Cyclopropanes; Diabetes Mellitus, Type 2; Drug Combinations; Endoplasmic Reticulum Stress; Fibroblast Growth Factors; Hep G2 Cells; HIV Infections; HIV Integrase Inhibitors; Humans; Klotho Proteins; Liver; Lopinavir; Maraviroc; Membrane Proteins; Muscle, Skeletal; Obesity; Oxidative Stress; Protease Inhibitors; Quinolones; Reverse Transcriptase Inhibitors; Ritonavir; Thapsigargin; Tunicamycin

Dyslipidemia represents a significant non-infectious comorbidity among people living with HIV. The aim of this study is to evaluate the impact on lipid profile of switches from an efavirenz (EFV) or protease inhibitor/ritonavir (PI/r)-based regimen to a rilpivirine (RPV) or a once-daily integrase inhibitor-based regimen.. We analyzed data from SCOLTA prospective database. All patients with HIV-RNA < 50 copies/ml in therapy with two NRTI + EFV or PI/r were included if they switched from EFV to dolutegravir (group EFV-DTG), elvitegravir (EFV-EVG), or RPV (EFV-RPV) and from PI/r to DTG (PI/r-DTG), PI/r to EVG (PI/r-EVG), or PI/r to RPV (PI/r-RPV). Total cholesterol (TC), TC/HDL ratio, LDL-cholesterol (LDL) and triglycerides (TG) were compared at baseline, six months and one year. Comparisons among groups were performed by a general linear model.. Four hundred and ninety patients were enrolled, 24.9% female, mean age 47.3 years (±10.1). According to ART switch, 11.4% were classified in group EFV-DTG, 3.9% in EFV-EVG, 23.9% in EFV-RPV, 17.6% in PI/r-DTG, 17.8% in PI/r-EVG, and 25.5% in PI/r-RPV. After adjusted analysis, TC significantly decreased in all groups but EFV-EVG, TC/HDL in all but EFV-DTG and EFV-EVG, while the reduction of TG was significant only in switches to RPV (EFV-RPV and PI/r-RPV). The one year decrease of TC, TC/HDL, LDL and TG was higher in patients with higher baseline levels of the same variable (p < .0001 for all).. In SCOLTA, all switches from PI/r regimens gave advantages on lipid profile, while stopping EFV had consistently favorable lipid effects only if replaced by RPV.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cohort Studies; Cyclopropanes; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Integrase Inhibitors; Lipid Metabolism; Lipids; Male; Middle Aged; Oxazines; Piperazines; Protease Inhibitors; Pyridones; Rilpivirine; Ritonavir; Treatment Outcome

There are limited data on viral suppression (VS) in children with HIV receiving antiretroviral therapy (ART) in routine care in low-resource settings. We examined VS in a cohort of children initiating ART in routine HIV care in Eastern Cape Province, South Africa.. The Pediatric Enhanced Surveillance Study enrolled HIV-infected ART eligibility children zero to twelve years at five health facilities from 2012 to 2014. All children received routine HIV care and treatment services and attended quarterly study visits for up to 24 months. Time to VS among those starting treatment was measured from ART start date to first viral load (VL) result <1000 and VL <50 copies/mL using competing risk estimators (death as competing risk). Multivariable sub-distributional hazards models examined characteristics associated with VS and VL rebound following suppression among those with a VL >30 days after the VS date.. Of 397 children enrolled, 349 (87.9%) started ART: 118 (33.8%) children age <12 months, 122 (35.0%) one to five years and 109 (31.2%) six to twelve years. At study enrolment, median weight-for-age z-score (WAZ) was -1.7 (interquartile range (IQR):-3.1 to -0.4) and median log VL was 5.6 (IQR: 5.0 to 6.2). Cumulative incidence of VS <1000 copies/mL at six, twelve and twenty-four months was 57.6% (95% CI 52.1 to 62.7), 78.7% (95% CI 73.7 to 82.9) and 84.0% (95% CI 78.9 to 87.9); for VS <50 copies/mL: 40.3% (95% CI 35.0 to 45.5), 63.9% (95% CI 58.2 to 69.0) and 72.9% (95% CI 66.9 to 78.0). At 12 months only 46.6% (95% CI 36.6 to 56.0) of children <12 months had achieved VS <50 copies/mL compared to 76.9% (95% CI 67.9 to 83.7) of children six to twelve years (p < 0.001). In multivariable models, children with VL >1 million copies/mL at ART initiation were half as likely to achieve VS <50 copies/mL (adjusted sub-distributional hazards 0.50; 95% CI 0.36 to 0.71). Among children achieving VS <50 copies/mL, 37 (19.7%) had VL 50 to 1000 copies/mL and 31 (16.5%) had a VL >1000 copies/mL. Children <12 months had twofold increased risk of VL rebound to VL >1000 copies/mL (adjusted relative risk 2.03, 95% CI: 1.10 to 3.74) compared with six to twelve year olds.. We found suboptimal VS among South African children initiating treatment and high proportions experiencing VL rebound, particularly among younger children. Greater efforts are needed to ensure that all children achieve optimal outcomes.

Topics: Adult; Alkynes; Ambulatory Care Facilities; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; Health Resources; HIV Infections; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Male; Medication Adherence; Ritonavir; South Africa; Viral Load

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Chromatography, Liquid; Cyclopropanes; Female; Hair; Humans; Limit of Detection; Linear Models; Lopinavir; Male; Medication Adherence; Middle Aged; Reproducibility of Results; Ritonavir; Tandem Mass Spectrometry; Young Adult; Zidovudine

PREVALEAT (PREmature VAscular LEsions and Antiretroviral Therapy) II is a multicenter, longitudinal cohort study aimed at the evaluation of cardiovascular risk among advanced HIV-positive, treatment-naïve patients starting their first therapy. We hypothesized that these patients, present a higher cardiovascular (CV) risk.. The study included all consecutive naïve patients with less than 200 CD4 cells/ml starting antiretroviral therapy. Our primary objective was to evaluate changes in carotid intima- media thickness (IMT). Secondary endpoints included changes in flow mediated vasodilation (FMD), inflammatory markers, triglycerides and cholesterol. Patients were evaluated at time 0, and after 3, 6 and 12 months.. We enrolled 119 patients, stratified into three different groups: patients receiving atazanavir/ritonavir boosted (ATV/r) based regimens, efavirenz (EFV) based regimens and darunavir/ritonavir boosted (DRV/r) based regimens. At baseline, advanced naïve patients showed a relevant deterioration of CV conditions in terms of traditional CV risk factors, endothelial dysfunction and serum biomarkers. During the 12-month follow up period, mean blood lipids significantly increased: total cholesterol from 159 to 190 mg/dL, HDL-C from 31 to 41 mg/dL, and LDL-C from 99 to 117 mg/dL. D-dimers steadily decreased (median level 624 at baseline and 214 at T3), whereas ICAM and VCAM consistently raised. DRV/r and ATV/r determined a more marked decrease of D-dimers as compared to EFV. Regarding the epi-aortic changes (IMT >1 mm or presence of atherosclerotic plaques), patients in the DRV/r group were at risk of developing pathological IMT during the study (OR 6.0, 95% CI 0.9-36.9), as compared to EFV ones.. CV risk was elevated in advanced naïve patients and tended to remain high in the first year of therapy.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Biomarkers; Brachial Artery; Cardiovascular Diseases; Carotid Intima-Media Thickness; CD4 Lymphocyte Count; Chi-Square Distribution; Cyclopropanes; Darunavir; Endothelium, Vascular; Female; HIV Infections; Humans; Inflammation Mediators; Italy; Lipids; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Predictive Value of Tests; Risk Factors; Ritonavir; Time Factors; Treatment Outcome; Vasodilation

Preventing virological failure following HIV treatment remains a difficult task that is further complicated by the emergence of drug resistance. We have developed a mathematical model able to explain and predict HIV virological outcomes for various compounds and patients' drug intake patterns. Compared to current approaches, this model considers, altogether, drug penetration into lymph nodes, a refined adherence representation accounting for the propensity for long drug holidays, population pharmacokinetic and pharmacodynamic variability, drug interaction, and crossresistance. In silico results are consistent with clinical observations for treatment with efavirenz, efavirenz in association with tenofovir DF and emtricitabine, or boosted darunavir. Our findings indicate that limited lymph node drug penetration can account for a large proportion of cases of virological failure and drug resistance. Since a limited amount of information is required by the model, it can be of use in the process of drug discovery and to guide clinical treatment strategies.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Lymph Nodes; Medication Adherence; Models, Biological; Mutation; Ritonavir; Tenofovir; Viral Load

Topics: Alkynes; Antimalarials; Benzoxazines; Cyclopropanes; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Malaria; Models, Biological; Population Groups; Pregnancy; Quinolines; Ritonavir; Serum Albumin, Human

Single nucleotide polymorphisms (SNPs) in the genes that encode the cytochrome P450 (CYP) drug metabolizing enzymes and drug transporters have been reported to influence antiretroviral drug pharmacokinetics. Although primarily metabolized by CYP2B6 and -3A, efavirenz (EFV) and lopinavir/ritonavir (LPV/r) are substrates of P-glycoprotein and the solute carrier organic (SLCO) anion transporter, respectively. We investigated the association between SNPs and efavirenz (EFV) or lopinavir/ritonavir (LPV/r) concentrations in Chinese children infected with the human immunodeficiency virus (HIV). Genotyping was performed on CYP2B6 516G→T, -1459C→T, and -983T→C, ABCB1 3435C→T, and SLCO1B1 521T→C in 229 HIV-infected Chinese pediatric patients (age range 4.0 to 17.5 yrs). Plasma concentrations of EFV and LPV/r were measured using validated high-performance liquid chromatography coupled with the mass spectrum method among 39 and 69 children who received EFV- and LPV/r-containing regimens, respectively. The frequencies of CYP2B6 516G→T in the study participants were 71%, 25%, and 4% for the G/G, G/T, and T/T genotypes, respectively. Among the children under therapeutic drug monitoring, 21% and 39% experienced EFV and LPV concentrations, respectively, above the upper threshold of the therapeutic window. CYP2B6 516G→T was significantly associated with EFV concentrations (p<0.001). Older children (older than 10 yrs) were more likely to have significantly higher EFV concentrations than the younger ones (p=0.0314). CYP2B6 genotyping and EFV concentration monitoring may help optimize antiretroviral therapy in pediatric patients who initiate an EFV-based regimen.

Topics: Adolescent; Alkynes; Asian People; Benzoxazines; Child; Cohort Studies; Cross-Sectional Studies; Cyclopropanes; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Polymorphism, Single Nucleotide; Retrospective Studies; Ritonavir

HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve.. An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs).. There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required.. The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV-1; Lamivudine; Lopinavir; Nelfinavir; Oxazines; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Ritonavir; Zidovudine

Drug therapy has been instrumental in prolonging the lives of patients infected by human immunodeficiency virus (HIV). In order to combat development of resistance, therapies involving three or more drugs in combination are recommended by the World Health Organization (WHO) to suppress HIV and prevent development of acquired immune deficiency syndrome (AIDS). It is desirable for multidrug combinations to be coformulated into single dosage forms where possible, to promote patient convenience and adherence to dosage regimens, for which amorphous solid dispersion (ASD) is particularly well-suited. We investigated multidrug ASDs of three model anti-HIV drugs, ritonavir (Rit), etravirine (Etra), and efavirenz (Efa), in cellulosic polymer matrices. We hypothesized that the presence of multiple drugs would reduce crystallization tendency, thereby providing stable, supersaturating formulations for bioavailability enhancement. We explored new ASD polymers including cellulose acetate suberate (DS

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cellulose; Crystallization; Cyclopropanes; Drug Stability; Humans; Hydrophobic and Hydrophilic Interactions; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Solubility

Data on long-term toxicity of antiretroviral therapy (ART) in HIV-infected children are sparse. PENPACT-1 was an open-label trial in which HIV-infected children were assigned randomly to receive protease inhibitor (PI)- or nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART.. We examined changes in clinical, immunologic, and inflammatory markers from baseline to year 4 in the subset of children in the PENPACT-1 study who experienced viral suppression between week 24 and year 4 of ART. Liver enzyme, creatinine, and cholesterol levels and hematologic parameters were assessed during the trial. Cystatin C, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), d-dimer, and soluble CD14 (sCD14) were assayed from cryopreserved specimens.. Ninety-nine children (52 on PI-based and 47 on NNRTI-based ART) met inclusion criteria. The median age at initiation of ART was 6.5 years (interquartile range [IQR], 3.7-13.4 years), and 22% were aged <3 years at ART initiation; 56% of the PI-treated children received lopinavir/ritonavir, and 70% of NNRTI-treated children received efavirenz initially. We found no evidence of significant clinical toxicity in either group; growth, liver, kidney, and hematologic parameters either remained unchanged or improved between baseline and year 4. Total cholesterol levels increased modestly, but no difference between the groups was found. IL-6 and hs-CRP levels decreased more after 4 years in the NNRTI-based ART group. The median change in IL-6 level was -0.35 pg/ml in the PI-based ART group and -1.0 in the NNRTI-based ART group (P = .05), and the median change in hs-CRP level was 0.25 µg/ml in the PI-based ART group and -0.95 µg/ml in the NNRTI-based ART group (P = .005).. These results support the safety of prolonged ART use in HIV-infected children and suggest that suppressive NNRTI-based regimens can be associated with lower levels of systemic inflammation.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Cholesterol; Creatinine; Cyclopropanes; Cystatin C; Drug Monitoring; Europe; Female; Fibrin Fibrinogen Degradation Products; HIV Infections; Humans; Inflammation; Interleukin-6; Kidney; Lipopolysaccharide Receptors; Liver; Lopinavir; Male; North America; Reverse Transcriptase Inhibitors; Ritonavir; Time Factors; Treatment Outcome

Angiogenic processes in the placenta are critical regulators of fetal growth and impact birth outcomes, but there are limited data documenting these processes in HIV-infected women or women from low-resource settings.. We sought to determine whether angiogenic factors are associated with adverse birth outcomes in HIV-infected pregnant women started on antiretroviral therapy.. This is a secondary analysis of samples collected as part of a clinical trial randomizing pregnant women and adolescents infected with HIV to lopinavir/ritonavir-based (n = 166) or efavirenz-based (n = 160) antiretroviral therapy in Tororo, Uganda. Pregnant women living with HIV were enrolled between 12-28 weeks of gestation. Plasma samples were evaluated for angiogenic biomarkers (angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin) by enzyme-linked immunosorbent assay between: 16-<20, 20-<24, 24-<28, 28-<32, 32-<36, 36-<37 weeks of gestation. The primary outcome was preterm birth.. In all, 1115 plasma samples from 326 pregnant women and adolescents were evaluated. There were no differences in angiogenic factors according to antiretroviral therapy group (P > .05 for all). The incidence of adverse birth outcomes was 16.9% for spontaneous preterm births, 25.6% for small-for-gestational-age births, and 2.8% for stillbirth. We used linear mixed effect modelling to evaluate longitudinal changes in angiogenic factor concentrations between birth outcome groups adjusting for gestational age at venipuncture, maternal age, body mass index, gravidity, and the interaction between treatment arm and gestational age. Two angiogenic factors-soluble endoglin and placental growth factor-were associated with adverse birth outcomes. Significantly higher concentrations of soluble endoglin throughout gestation were found in study participants destined to deliver preterm [likelihood ratio test, χ. An antiangiogenic state in the second or third trimester is associated with adverse birth outcomes, including stillbirth in women and adolescents living with HIV and receiving antiretroviral therapy.

Topics: Adult; Alkynes; Angiopoietin-1; Angiopoietin-2; Anti-HIV Agents; Benzoxazines; Biomarkers; Cyclopropanes; Drug Combinations; Endoglin; Female; HIV Infections; Humans; Infant, Newborn; Infant, Small for Gestational Age; Lopinavir; Neovascularization, Physiologic; Placenta Growth Factor; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Premature Birth; Ritonavir; Stillbirth; Uganda; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug-mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25-hydroxyvitamin D

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Calcifediol; Calcitriol; Cells, Cultured; Cholecalciferol; Cholestanetriol 26-Monooxygenase; Cyclopropanes; Cytochrome P450 Family 2; Dermis; Female; Gene Expression Regulation, Enzymologic; Humans; Male; Reproducibility of Results; Ritonavir; RNA, Messenger; Stavudine; Vitamin D3 24-Hydroxylase; Young Adult

There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010.. We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004-2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity.. We included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively.. While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Follow-Up Studies; HIV; HIV Infections; Humans; Infant; Kaplan-Meier Estimate; Lopinavir; Outcome Assessment, Health Care; Proportional Hazards Models; Ritonavir; South Africa; Stavudine; Withholding Treatment; Zidovudine

Simeprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, displays nonlinear pharmacokinetics (PK) at therapeutic doses. Using physiologically based PK modeling, various drug-drug interactions were simulated with simeprevir as victim drug to identify whether saturation of the predominant metabolic enzyme (CYP3A4) or the active hepatic transporters (organic anion-transporting polypeptide (OATP)1B1/3) could account for the nonlinear PK. Interactions with ritonavir, a strong CYP3A4 inhibitor that does not affect OATP (at 100 mg dose), erythromycin, a moderate CYP3A4 inhibitor, and efavirenz, a moderate CYP3A inducer that does not affect OATP, demonstrated the involvement of CYP3A4. Interaction studies with low-dose cyclosporine confirmed the role of OATP. The interplay between hepatic uptake and CYP3A4 metabolism was verified by simulations with rifampicin, a potent CYP3A4 inducer and OATP1B1/3 inhibitor, and maintenance doses of cyclosporine. Saturation of gut and liver metabolism by CYP3A4, and saturation of hepatic uptake by OATP1B1/3, seem to account for the observed nonlinear PK of simeprevir.

Topics: Alkynes; Antiviral Agents; Benzoxazines; Cyclopropanes; Cyclosporine; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Erythromycin; Hepatitis C; Humans; Liver; Liver-Specific Organic Anion Transporter 1; Nonlinear Dynamics; Organic Anion Transporters; Rifampin; Ritonavir; Simeprevir; Viral Nonstructural Proteins

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cognitive Dysfunction; Coinfection; Cyclopropanes; Drug Therapy, Combination; Executive Function; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Lopinavir; Male; Memory; Middle Aged; Neuropsychological Tests; Ritonavir; Verbal Learning

HIV may amplify immunological, physiological and functional changes of ageing. We determined associations of frailty phenotype, a T-cell senescence marker (p16(INK4a) expression), age and demographics with exposures of the intracellular metabolites (IM) and endogenous nucleotides (EN) of tenofovir/emtricitabine (TFV/FTC), efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV).. Plasma and peripheral blood mononuclear cell samples for drug, IM and EN concentrations were collected at four time points in HIV+ adults receiving TFV/FTC with EFV or ATV/RTV. Subjects underwent frailty phenotyping and p16(INK4a) expression analysis. Non-compartmental analysis generated an area under the curve (AUC) for each analyte. Spearman rank correlation and Kruskal-Wallis tests were used to assess associations between AUC, demographics and ageing markers, adjusting for multiple comparisons with the Holm procedure.. Subjects (n=79) ranged in age from 22-73 years (median 48 years); 48 were African-American, 24 were female, 54 received EFV. Three subjects (range 51-60 years) demonstrated frailty, with 17 subjects (range 26-60 years) demonstrating pre-frailty. Negative associations were observed between p16(INK4a) expression and each of FTC-triphosphate (r=-0.45), deoxyadenosine triphosphate (dATP; r=-0.47) and deoxycytidine triphosphate (dCTP; r=-0.57) AUCs (P-values <0.02). TFV and FTC AUCs were larger among subjects with lower renal function or higher chronological age (P-values ≤0.05). No associations were observed for EFV, ATV or RTV AUCs.. Associations of IM/EN exposure and p16(INK4a) expression observed here suggest that senescence may alter drug phosphorylation, metabolism or transport. This finding warrants further mechanistic study to ensure optimal treatment in the ageing HIV+ population. Clinicaltrials.gov NCT01180075.

Topics: Adult; Aged; Aging; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclin-Dependent Kinase Inhibitor p16; Cyclopropanes; Drug Therapy, Combination; Emtricitabine; Female; Gene Expression; HIV Infections; Humans; Male; Middle Aged; Nucleotides; Ritonavir; Tenofovir; Young Adult

There have been several important developments in antiretroviral treatment in the past two years. Randomized clinical trials have been conducted to evaluate a lower dose of efavirenz (400 mg once daily). Integrase inhibitors such as dolutegravir have been approved for first-line treatment. A new formulation of tenofovir (alafenamide) has been developed and has shown equivalent efficacy to tenofovir in randomized trials. Two-drug combination treatments have been evaluated in treatment-naïve and -experienced patients. The novel pharmacokinetic booster cobicistat has been compared to ritonavir in terms of pharmacokinetics, efficacy and safety. The objective of this commentary is to assess recent developments in antiretroviral drug treatment to determine whether new treatments should be included in new international guidelines.. The use of first-line treatment with tenofovir and efavirenz at the standard 600 mg once-daily dose should remain the first-choice standard of care treatment. Evidence supporting a switch to efavirenz 400 mg once daily or integrase inhibitors is sufficient to consider these drugs as alternative first-line options, but more data are needed on their use in pregnant women and people with TB co-infection. The use of new formulations of tenofovir is currently too preliminary to justify immediate adoption and scale-up across HIV programmes in low- and middle-income countries. The evidence supporting use of two-drug combinations is not considered strong enough to justify changed recommendations from use of standard triple drug combinations. Cobicistat does not offer significant safety advantages over ritonavir as a pharmacokinetic booster.. For continued scale-up of antiretroviral treatment in low- and middle-income countries, use of first-line triple combinations including efavirenz 600 mg once daily is supported by the largest evidence base. Additional studies are underway to evaluate new treatments in key populations, and these results may justify changes to these recommendations.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Oxazines; Phosphorous Acids; Piperazines; Public Health; Pyridones; Ritonavir

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

HIV patients on highly-active antiretroviral therapy (HAART) have shown elevated incidence of dyslipidemia, lipodystrophy, and markers of cardiovascular disease. Evidence is beginning to emerge that implicates efavirenz (EFV) as a potential mediator of early on-set cardiovascular disease.. Pediatric and adult HIV-infected HAART-naïve, EFV-treated, nevirapine (NVP)-treated, and ritonavir-boosted lopinavir (LPV/r)-treated subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Pulse wave velocity (PWV), carotid intima-media thickness (cIMT), carotid arterial stiffness, brachial artery flow-mediated dilation (FMD), body mass index, waist-to-hip circumference ratio, and skinfold thickness were measured. CD4+ cell count, fasting glucose, lipoprotein profiles and triglycerides were also determined. Results were segmented into pediatric (6-17 years of age), young adults (25-39 years old) and older adults (40-60 years old).. PWV was generally elevated in EFV- and LPV/r-treated subjects compared to NVP-treated subjects across age groups. cIMT was elevated in EFV- and LPV/r-treated compared to NVP-treated older adults and in EFV-treated compared to HAART-naïve older adults. FMD was impaired in EFV- and LPV/r-treated compared to HAART-naïve younger adults, in EFV-treated compared to NVP-treated young and older adults, and in LPV/r-treated compared to NVP-treated older adults. Differences in lipoprotein profiles and skinfold thickness with HAART regimen were observed in pediatric and young adults, but less so in older adults.. Whereas LPV/r and other protease inhibitors have long been recognized as mediators of HIV/HAART-associated atherosclerosis, this report supports the emerging evidence that EFV may also mediate cardiovascular disease in people living with HIV on HAART.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atherosclerosis; Benzoxazines; Biomarkers; Carotid Intima-Media Thickness; Child; Cyclopropanes; Ethiopia; Female; HIV Infections; Humans; Lipids; Lopinavir; Male; Middle Aged; Pulse Wave Analysis; Ritonavir; Young Adult

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Darunavir; Emtricitabine; HIV; Humans; Lamivudine; Ritonavir; Tenofovir; United Kingdom

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

Persistent low-level viraemia (LLV) during the treatment of antiretroviral therapy (ART) is associated with emergent drug resistance mutation (DRM); however, insight into its driver is limited. The objectives were to study HIV-1 pol sequence evolution in subjects with persistent LLV and evaluate factors associated with sequence changes.. HIV-1 pol sequences from 54 treatment-naive subjects undergoing first-line lopinavir/ritonavir- or efavirenz-containing ART were obtained at pre-ART and end of LLV. HIV-1 sequence evolution was evaluated using phylogenetic analysis and Hamming distance calculation. DRMs were interpreted based on the International AIDS Society-USA 2011 update.. Subjects with new DRM during LLV had greater HIV-1 evolution across pol from the pre-ART to end of LLV compared with subjects without DRM. Evolution over non-DRM sites was similar between groups. Higher degree of genetic evolution was positively associated with higher HIV-1 RNA levels during LLV, both at DRM and non-DRM sites.. The magnitude of LLV was the primary driver of evolution rate at DRM as well as non-DRM sites. Higher viral load was associated with DRM emergence in these subjects. These findings provide insights that may be applicable to the management of patients with persistent LLV during ART.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Evolution, Molecular; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation; Phylogeny; pol Gene Products, Human Immunodeficiency Virus; Retrospective Studies; Ritonavir; RNA, Viral; Viral Load; Viremia

Randomized trials and observational cohorts reported higher rates of virological suppression after highly active antiretroviral therapy (HAART) including efavirenz (EFV), compared with boosted protease inhibitors (PIs). Correlations with immunological and clinical outcomes are unclear. Patients of the Italian MASTER cohort who started HAART from 2000 to 2010 were selected. Outstanding outcome (composite outcome for success (COS)) was introduced. We evaluated predictors of COS (no AIDS plus CD4+ count >500/mm(3)plus HIV-RNA <500 copies/mL) and of eight single outcomes either at month 6 or at year 3. Multivariable logistic regression was conducted. There were 6259 patients selected. Patients on EFV (43%) were younger, had greater CD4+ count, presented with AIDS less frequently, and more were Italians. At year 3, 90% of patients had HIV RNA <500 copies/mL, but only 41.4% were prescribed EFV, vs. 34.1% prescribed boosted PIs achieved COS (p <0.0001). At multivariable analysis, patients on lopinavir/ritonavir had an odds ratio of 0.70 for COS at year 3 (p <0.0001). Foreign origin and positive hepatitis C virus-Ab were independently associated with worse outcome (OR 0.54, p <0.0001 and OR 0.70, p 0.01, respectively). Patients on boosted PIs developed AIDS more frequently either at month 6 (13.8% vs. 7.6%, p <0.0001) or at year 3 (17.1% vs. 13.8%, p <0.0001). At year 3, deaths of patients starting EFV were 3%, vs. 5% on boosted PIs (p 0.008). In this study, naïve patients on EFV performed better than those on boosted PIs after adjustment for imbalances at baseline. Even when virological control is achieved, COS is relatively rare. Hepatitis C virus-positive patients and those of foreign origin are at risk of not obtaining COS.

Topics: Adult; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Female; HIV Infections; Humans; Italy; Male; Middle Aged; Ritonavir; RNA, Viral; Treatment Outcome; 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

HIV patients on antiretroviral therapy have shown elevated incidence of dyslipidemia, lipodystrophy, and cardiovascular disease (CVD). Most studies, however, focus on cohorts from developed countries, with less data available for these co-morbidities in Ethiopia and sub-Saharan Africa.. Adult HIV-negative (n = 36), treatment naïve (n = 51), efavirenz (EFV)-treated (n = 91), nevirapine (NVP)-treated (n = 95), or ritonavir-boosted lopinavir (LPV/r)-treated (n=44) subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Aortic pressure, augmentation pressure, and pulse wave velocity (PWV) were measured via applanation tonometry and carotid intima-media thickness (cIMT) and carotid arterial stiffness, and brachial artery flow-mediated dilation (FMD) were measured via non-invasive ultrasound. Body mass index, waist-to-hip circumference ratio (WHR), skinfold thickness, and self-reported fat redistribution were used to quantify lipodystrophy. CD4+ cell count, plasma HIV RNA levels, fasting glucose, total-, HDL-, and LDL-cholesterol, triglycerides, hsCRP, sVCAM-1, sICAM-1, leptin and complete blood count were measured.. PWV and normalized cIMT were elevate and FMD impaired in EFV- and LPV/r-treated subjects compared to NVP-treated subjects; normalized cIMT was also elevated and FMD impaired in the EFV- and LPV/r-treated subjects compared to treatment-naïve subjects. cIMT was not statistically different across groups. Treated subjects exhibited elevated markers of dyslipidemia, inflammation, and lipodystrophy. PWV was associated with age, current EFV and LPV/r used, heart rate, blood pressure, triglycerides, LDL, and hsCRP, FMD with age, HIV duration, WHR, and glucose, and cIMT with age, current EFV use, skinfold thickness, and blood pressure.. Current EFV- or LPV/r-treatment, but not NVP-treatment, correlated with elevated markers of atherosclerosis, which may involve mechanisms distinct from traditional risk factors.

Topics: Adult; Alkynes; Anti-HIV Agents; Atherosclerosis; Benzoxazines; Biomarkers; Blood Pressure; C-Reactive Protein; Carotid Intima-Media Thickness; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Cyclopropanes; Ethiopia; Female; Heart Rate; HIV Infections; HIV-1; Humans; Lipodystrophy; Lopinavir; Male; Middle Aged; Nevirapine; Pulse Wave Analysis; Ritonavir; Triglycerides

Inducers and inhibitors of CYP3A, such as ritonavir and efavirenz, may be used as part of the highly active antiretroviral therapy (HAART) to treat HIV patients. HIV patients with chronic myeloid leukemia or gastrointestinal stromal tumour may need imatinib, a CYP3A4 substrate with known exposure response-relationships. Administration of imatinib to patients on ritonavir or efavirenz may result in altered imatinib exposure leading to increased toxicity or failure of therapy, respectively. We used primary human hepatocyte cultures to evaluate the magnitude of interaction between imatinib and ritonavir/efavirenz.. Hepatocytes were pre-treated with vehicle, ritonavir, ketoconazole, efavirenz or rifampicin, and the metabolism of imatinib was characterized over time. Concentrations of imatinib and metabolite were quantitated in combined lysate and medium, using LC-MS.. The predicted changes in imatinib CLoral (95% CI) with ketoconazole, ritonavir, rifampicin and efavirenz were 4.0-fold (0, 9.2) lower, 2.8-fold (0.04, 5.5) lower, 2.9-fold (2.2, 3.5) higher and 2.0-fold (0.42, 3.5) higher, respectively. These predictions were in good agreement with clinical single dose drug-drug interaction studies, but not with reports of imatinib interactions at steady-state. Alterations in metabolism were similar after acute or chronic imatinib exposure.. In vitro human hepatocytes predicted increased clearance of imatinib with inducers and decreased clearance with inhibitors of CYP enzymes. The impact of HAART on imatinib may depend on whether it is being initiated or has already been dosed chronically in patients. Therapeutic drug monitoring may have a role in optimizing imatinib therapy in this patient population.

Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Hepatocytes; Humans; Imatinib Mesylate; Ketoconazole; Male; Middle Aged; Primary Cell Culture; Rifampin; Ritonavir; Young Adult

Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib.. Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC).. Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure.. CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.

Topics: Administration, Oral; Alkynes; Animals; Anti-Retroviral Agents; Antineoplastic Agents; Benzoxazines; Biological Availability; Biotransformation; Cyclopropanes; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Dexamethasone; Drug Evaluation, Preclinical; Drug Interactions; Erlotinib Hydrochloride; Half-Life; Ketoconazole; Male; Metabolic Clearance Rate; Mice, Inbred Strains; Protein Kinase Inhibitors; Quinazolines; Ritonavir

Comparing the results of HIV trials using different endpoints and scale is a difficult task. The two main primary endpoints are the proportion of patients with HIV-1 RNA less than 50 copies/ml at week 48 and the time to virologic failure. In the A5202 study, the use of the risk difference scale instead of the risk ratio scale would have led to equivalence in the comparisons between efavirenz and atazanavir/ritonavir. We discuss these results and their impact on the design of the A5257, as well as alternative approaches.

Topics: Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Endpoint Determination; HIV Infections; HIV-1; Humans; Randomized Controlled Trials as Topic; Ritonavir; RNA, Viral; Time; Treatment Outcome; Viral Load

HIV causes neural dysfunction in infected individuals. This dysfunction often manifests as cognitive symptoms and can be detected using neuroimaging. Highly active anti-retroviral therapy (HAART), in addition to providing virologic control, has reduced the number of profoundly impaired individuals but more mild forms of neurocognitive disorders remains prevalent. A potential confound in previous studies of HIV-associated cognitive dysfunction is that HAART may be neurotoxic. Thus, observed effects, attributed to HIV, may be in part due to HAART. It is unclear whether and to what extent current medications contribute to observed brain dysfunction. We studied changes in functional connectivity and cerebral blood flow in HIV uninfected (HIV-) individuals before and after being given two common antiretroviral medications: efavirenz and ritonavir. Neither drug was associated with significant changes in functional connectivity or cerebral blood flow. Our results suggests that previous changes in functional connectivity and cerebral blood flow in HIV infected individuals receiving HAART may largely due to the virus and remaining reservoirs and less due to toxic action of these anti-retroviral medications.

Topics: Adult; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Brain; Cerebrovascular Circulation; Connectome; Cyclopropanes; Female; Healthy Volunteers; HIV Infections; Humans; Magnetic Resonance Imaging; Male; Ritonavir

Lipodystrophy is a common complication in HIV-infected patients taking highly active antiretroviral therapy. Its early diagnosis is crucial for timely modification of antiretroviral therapy. We hypothesize that mitochondrial DNA in plasma may be a potential marker of LD in HIV-infected individuals. In this study, we compared plasma mitochondrial DNA levels in HIV-infected individuals and non-HIV-infected individuals to investigate its potential diagnostic value. Total plasma DNA was extracted from 67 HIV-infected patients at baseline and 12, 24 and 30 months after initiating antiretroviral therapy. Real-time quantitative PCR was used to determine the mitochondrial DNA levels in plasma. Lipodystrophy was defined by the physician-assessed presence of lipoatrophy or lipohypertrophy in one or more body regions. The mitochondrial DNA levels in plasma were significantly higher at baseline in HIV-infected individuals than in non-HIV-infected individuals (p<0.05). At month 30, 33 out of 67 patients (49.2%) showed at least one sign of lipodystrophy. The mean plasma mitochondrial DNA levels in lipodystrophy patients were significantly higher compared to those without lipodystrophy at month 24 (p<0.001). The receiver operating curve analysis demonstrated that using plasma mitochondrial DNA level (with cut-off value <5.09 log10 copies/ml) as a molecular marker allowed identification of patients with lipodystrophy with a sensitivity of 64.2% and a specificity of 73.0%. Our data suggest that mitochondrial DNA levels may help to guide therapy selection with regards to HIV lipodystrophy risk.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Biomarkers; Case-Control Studies; Cyclopropanes; DNA, Mitochondrial; Drug Combinations; Female; HIV; HIV Infections; Humans; Lamivudine; Lipodystrophy; Lopinavir; Male; Middle Aged; Mitochondria; Nelfinavir; Predictive Value of Tests; Ritonavir; ROC Curve; Stavudine; Zidovudine

An analysis of 570 HIV-infected women in Swaziland using the Jadelle implant showed that age, condom use, the provider who placed the implant, and CD4 cell count had no effect on unintentional pregnancy rates. Antiretroviral regimen at the time of pregnancy, however, correlated with pregnancy outcomes (P < 0.001). None of the women on nevirapine or lopinavir/ritonavir-based regimens (n = 208 and 13, respectively) became pregnant, whereas 15 women on efavirenz (n = 121; 12.4%) became pregnant.

Topics: Adolescent; Adult; Alkynes; Anti-Retroviral Agents; Benzoxazines; Contraceptive Agents, Female; Cyclopropanes; Drug Interactions; Eswatini; Female; HIV Infections; Humans; Lopinavir; Middle Aged; Nevirapine; Pregnancy; Pregnancy, Unplanned; Ritonavir; Young Adult

There are no clinical trials in which the main objective is to compare the efficacy of efavirenz versus ritonavir-boosted protease inhibitor (PI/r)-based initial antiretroviral therapy (ART) in patients with high plasma HIV-1 RNA levels. This study aims to compare these regimens in this patient population in the setting of routine clinical practice.. This was a multicentre, observational cohort study, including 596 consecutive treatment-naive patients with plasma HIV-1 RNA>100,000 copies/ml initiating efavirenz or PI/r-based ART between 2000 and 2010. The primary effectiveness end point was the percentage of patients with HIV-1 RNA<50 copies/ml at week 48 by intent-to-treat analysis.. Among a total of 596 patients, 57% initiated efavirenz and 43% PI/r-regimens (73% lopinavir and fosamprenavir [62% lopinavir, 11% fosamprenavir]). HIV-1 RNA suppression to <50 copies/ml at week 48 was higher in the efavirenz group (84% versus 74% [difference 10%, 95% CI 3.4%, 16.7%; P=0.002]). The percentage of virological failures was similar (efavirenz 4% versus PI/r 4%; P=0.686), but voluntary discontinuations and toxicity-related treatment changes were higher with PI/r (4% versus 1%; P=0.006 and 11% versus 6%; P=0.069, respectively). However, resistance selection at failure was higher in patients receiving efavirenz (89% versus 50%; P=0.203). Efavirenz was significantly more effective than lopinavir/r or fosamprenavir/r, whereas no significant differences were observed between efavirenz and darunavir/r or atazanavir/r. The high viral suppression in the efavirenz group was also evident in patients with very high viral loads (>500,000 copies/ml) and in those with low CD4(+) T-cell counts.. In routine clinical practice, the effectiveness of initial efavirenz-based regimens was at least similar to or even higher than various PI/r-based regimens in HIV-1-infected patients with plasma HIV-1 RNA>100,000 copies/ml.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Time Factors; Treatment Failure; Treatment Outcome; Viral Load

Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug-drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations.. Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. ×4d), efavirenz (25 mg/kg p.o. ×4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression.. Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure.. Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered.

Topics: Alkynes; Animals; Antineoplastic Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dexamethasone; Docetaxel; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; HIV Protease Inhibitors; Ketoconazole; Liver; Male; Mice; Reverse Transcriptase Inhibitors; Ritonavir; Taxoids

Few studies have compared the impact of different antiretroviral regimens on residual immune activation and inflammation with discordant results. Aim of the study was to investigate the impact of various antiretroviral regimens on markers of immune activation and inflammation during the first two years of effective therapy.. We studied HIV-infected antiretroviral-naïve patients who began cART with either abacavir/lamivudine or tenofovir/emtricitabine, combined with ritonavir-boosted lopinavir (LPV/r), atazanavir (ATV/r) or efavirenz (EFV). All the patients had a virological response within 6 months, which was maintained for 2 years with no change in their ART regimen. C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble CD14 (sCD14), monokine induced by interferon-γ (MIG) and interferon-γ-inducible protein-10 (IP-10) were measured in stored plasma obtained at cART initiation and 24 months later. Mean changes from baseline were analyzed on loge-transformed values and multivariable linear regression models were used to study the effect of the treatment components, after adjusting for factors that might have influenced the choice of ART regimen or biomarker levels. Differences were expressed as the mean fold change percentage difference (Δ).. Seventy-eight patients (91% males) with a median age of 43 years met the inclusion criteria. Their median baseline CD4 cell count was 315/mm3 and HIV-1 RNA level 4.6 log10 copies/ml. During the 2-years study period, IL-6, IP-10 and MIG levels fell significantly, while hs-CRP and sCD14 levels remained stable. IP-10 and MIG levels declined significantly less strongly with ATV/r than with EFV (IP-10Δ -57%, p = 0.011; MIGΔ -136%, p = 0.007), while no difference was noted between LPV/r and EFV. The decline in IL-6 did not differ significantly across the different treatment components.. After the first 2 years of successful cART, IL-6, IP-10 and MIG fell markedly while hs-CRP and sCD14 levels remained stable. The only impact of ART regimen was a smaller fall in markers of immune activation with ATV/r than with EFV. Our results suggest that these markers could be worthwhile when evaluating new antiretroviral drugs.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; C-Reactive Protein; CD4 Lymphocyte Count; Chemokine CXCL10; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Immune System; Inflammation; Interferon-gamma; Interleukin-6; Lipopolysaccharide Receptors; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome

An ultrasensitive assay utilizing high-pressure liquid chromatography and mass spectrometry detection was developed and validated for the quantification of the antiretrovirals atazanavir (ATV), darunavir (DRV), lopinavir (LPV), ritonavir (RTV), and efavirenz (EFV) in human mononuclear cell (MNC) extracts. The assay utilizes 20 μl of cellular extract that contains as few as 50,000 MNCs. The analytical range of the assay is 0.0200 to 10.0 fmol/μl for ATV, 0.0500 to 25.0 fmol/μl for DRV, LPV, and RTV, and 0.200 to 100 fmol/μl for EFV. The assay has proven to be a clinically useful tool for investigating antiretroviral drug concentrations in virologic sanctuaries where harvested cell numbers are extremely low. The assay provides a tool for investigators to explore the clinical pharmacology of strategies for prevention, treatment, and cure in pathophysiologically relevant sites.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Cell Extracts; Chromatography, Liquid; Cyclopropanes; Darunavir; Humans; Leukocytes, Mononuclear; Lopinavir; Mass Spectrometry; Oligopeptides; Pyridines; Ritonavir; Sulfonamides

We compared reasons for the choice of regimen, time to and reasons for third drug modification, virological response and change in CD4 T-cell counts in patients started on atazanavir/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line regimens.. We included patients from the Cohort of the Spanish HIV Research Network (CoRIS), a multicentre cohort of HIV-positive treatment-naïve subjects, in the study. We used logistic regression to assess factors associated with choosing ATV/r vs. EFV, proportional hazards models on the subdistribution hazard to estimate subdistribution hazard ratios (sHRs) for third drug modification, logistic regression to estimate odds ratios (ORs) for virological response and linear regression to assess mean differences in CD4 T-cell count increase from baseline.. Of 2167 patients, 10.7% started on ATV/r. ATV/r was more likely than EFV to be prescribed in injecting drug users [adjusted OR 1.85; 95% confidence interval (CI) 1.03-3.33], in 2009-2010 (adjusted OR 1.63; 95% CI 1.08-2.47) and combined with abacavir plus lamivudine (adjusted OR 1.53; 95% CI 0.98-2.43). Multivariate analyses showed no differences, comparing ATV/r vs. EFV, in the risk of third drug modification (sHR 1.04; 95% CI 0.74-1.46) or in virological response (OR 0.81; 95% CI 0.46-1.41); differences in mean CD4 T-cell count increase from baseline were at the limit of statistical significance (mean difference 29.8 cells/μL; 95% CI -4.1 to 63.6 cells/μL). In patients changing from EFV, 48% of changes were attributable to toxicity/adverse events, 16% to treatment failure/resistance, 3% to simplification, and 8 and 12%, respectively, to patients' and physicians' decisions; these percentages were 24, 6, 12, 14 and 24%, respectively, in those changing from ATV/r.. ATV/r- and EFV-based regimens meet the requirements of both efficacy and safety for initial combination antiretroviral regimen, which relate to better durability.

Topics: Adult; Age Factors; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Prospective Studies; Ritonavir; RNA, Viral; Spain; Treatment Outcome; Viral Load

Nilotinib is used to treat chronic myeloid leukemia (CML), and is metabolized by CYP3A. With a black-box warning for QT prolongation, which is exposure dependent, controlling for drug interactions is clinically relevant. Treatments of HIV patients with CML are with HAART drugs, ritonavir and efavirenz, may cause complex drug interactions through CYP3A inhibition or induction. We evaluated the interactions of ritonavir or efavirenz on nilotinib using human hepatocytes and compared these interactions with those of ketoconazole or rifampin, classical CYP3A inhibitor and inducer, respectively. Hepatocytes were treated with vehicle, ritonavir (10 μM), ketoconazole (10 μM), efavirenz (10 μM), or rifampin (10 μM) for 5 days. On day 5, nilotinib (3 μM) was coincubated for an additional 24-48 hours. The concentrations of nilotinib were quantitated in collected samples (combined lysate and medium) by LC-MS. Apparent intrinsic clearance (CL(int,app)) of nilotinib was lowered 5.8- and 3.1-fold, respectively, by ritonavir and ketoconazole. Efavirenz and rifampin increased the CL(int,app) of nilotinib by 2.1- and 4.1-fold, respectively. The clinically recommended dose (300 mg twice daily) of nilotinib may have to be reduced substantially (150 mg once daily) or increased (400 mg thrice daily), respectively, to achieve desired drug exposure, when ritonavir or efavirenz is co-administered.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antifungal Agents; Antineoplastic Agents; Area Under Curve; Benzoxazines; Cells, Cultured; Cyclopropanes; Drug Interactions; Female; Half-Life; Hepatocytes; Humans; Ketoconazole; Male; Middle Aged; Pyrimidines; Rifampin; Ritonavir; Young Adult

Regimens sparing RATE (ritonavir, abacavir, tenofovir, efavirienz) agents might have better long-term safety. We conducted a feasibility exercise to assess the potential for a randomised trial evaluating RATE-sparing regimens.. Observational.. We first calculated RATE-sparing options available to an average patient receiving RATE agents. We reviewed treatment history and all resistance assays from patients attending the St. Vincent's Hospital (Sydney) clinic and receiving ≥2 RATE agents (n = 120). A viable RATE-sparing regimen with 2 or 3 fully-active agents was constructed from the following six 'safer' agents: rilpivirine or etravirine; atazanavir; raltegravir; maraviroc; and lamivudine. Activity for each drug was predicted as 1 (full-activity), 0.5 or 0 (no activity) using the Stanford mutation database. The utility of maraviroc was calculated assuming both maraviroc activity and inactivity where unknown. The analysis was restricted to regimens for which supporting evidence was identified in the literature or conference proceedings. Finally, we calculated the proportion of patients in the nationally representative Australian HIV Observational Database (AHOD) cohort receiving ≥2 RATE agents (n = 1473) to measure the potential population-level uptake of RATE-sparing agents.. Assuming full maraviroc activity, 117(97.5%) and 107(89.2%) individuals had at least one option with 2 or 3 active RATE-sparing agents, respectively. Assuming no maraviroc activity this decreased to 113(94.2%) and 104(86.7%), respectively. In AHOD, 837(56.8%) patients were receiving ≥2 RATE agents.. Feasible treatment switch options sparing RATE agents exist for the majority of patients. Understanding the pros and cons of switching stable patients onto new RATE-sparing regimens requires evidence derived from randomised controlled trials.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Clinical Trials as Topic; Cyclohexanes; Cyclopropanes; Dideoxynucleosides; Feasibility Studies; Female; Humans; Male; Maraviroc; Middle Aged; Organophosphonates; Ritonavir; Tenofovir; Triazoles

We report three cases of tricuspid valve infective endocarditis associated with intravenous nyoape use. Nyoape is a variable drug combination of an antiretroviral (efavirenz or ritonavir), heroin, metamphetamines and cannabis. Its use is becoming increasingly common among poor communities in South Africa. All our patients were young HIV-positive men from disadvantaged backgrounds. They all presented with tricuspid regurgitation and septic pulmonary emboli. They were treated with prolonged intravenous antibiotic courses, and one required referral for surgery.

Topics: Adult; Alkynes; Anti-Bacterial Agents; Benzoxazines; Cannabis; Cyclopropanes; Endocarditis; Heroin; HIV Infections; Humans; Illicit Drugs; Male; Methamphetamine; Pulmonary Embolism; Ritonavir; South Africa; Substance-Related Disorders; Tricuspid Valve; Tricuspid Valve Insufficiency; Young Adult

The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented.. HIV-infected subjects ≥ 55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h (AUC0-24h ) and maximal concentration (Cmax )]. These parameters were compared with historical values from the general HIV-infected population.. Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax , and 19-78% increased FTC and RTV AUC0-24h and Cmax . Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax . Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects.. This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.

Topics: Adenine; Aged; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Black or African American; Cyclopropanes; Data Interpretation, Statistical; Deoxycytidine; Emtricitabine; Female; Frail Elderly; HIV; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Organophosphonates; Pilot Projects; Pyridines; Ritonavir; Tenofovir; White People

The rate of depression in patients with HIV is higher than in the general population. The use of antidepressants can have a beneficial effect, improving antiretroviral therapy adherence and consequently their efficacy and safety. Efavirenz and protease inhibitor boosted with ritonavir are major components of the antiretroviral therapy and are inducers and/or inhibitors of several cytochrome P450 (CYP) isoforms. Although antidepressants are prescribed to a significant proportion of patients treated with antiretrovirals, there are limited clinical data on drug-drug interactions. The aim of this study was to predict the magnitude of drug-drug interactions among efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants using an in vitro-in vivo extrapolation (IVIVE) model simulating virtual clinical trials.. In vitro data describing the chemical characteristics, and absorption, distribution, metabolism and elimination (ADME) properties of efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants were obtained from published literature or generated by standard methods. Pharmacokinetics and drug-drug interaction were simulated using the full physiologically based pharmacokinetic model implemented in the Simcyp™ ADME simulator. The robustness of our modeling approach was assessed by comparing the magnitude of simulated drug-drug interactions using probe drugs to that observed in clinical studies.. Simulated pharmacokinetics and drug-drug interactions were in concordance with available clinical data. Although the simulated drug-drug interactions with antidepressants were overall weak to moderate according to the classification of the US FDA, fluoxetine and venlafaxine represent better candidates from a pharmacokinetic standpoint for patients on efavirenz and venlafaxine or citalopram for patients on boosted protease inhibitors.. The modest magnitude of interaction could be explained by the fact that antidepressants are substrates of multiple isoforms and thus metabolism can still occur through CYPs that are weakly impacted by efavirenz or boosted protease inhibitors. These findings indicate that IVIVE is a useful tool for predicting drug-drug interactions and designing prospective clinical trials, giving insight into the variability of exposure, sample size and time-dependent induction or inhibition.

Topics: Alkynes; Anti-Retroviral Agents; Antidepressive Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Darunavir; Drug Interactions; Humans; Models, Biological; Oligopeptides; Pyridines; Ritonavir; Sulfonamides

Our laboratory developed long-acting nanoformulations of antiretroviral therapy (nanoART) to improve drug compliance, reduce toxicities, and facilitate access of drug to viral reservoirs. These all function to inevitably improve treatment of human immunodeficiency virus (HIV) infection. Formulations are designed to harness the carrying capacities of mononuclear phagocytes (MP; monocytes and macrophages) and to use these cells as Trojan horses for drug delivery. Such a drug distribution system limits ART metabolism and excretion while facilitating access to viral reservoirs. Our prior works demonstrated a high degree of nanoART sequestration in macrophage recycling endosomes with broad and sustained drug tissue biodistribution and depots with limited untoward systemic toxicities. Despite such benefits, the effects of particle carriage on the cells' functional capacities remained poorly understood. Thus, we employed pulsed stable isotope labeling of amino acids in cell culture to elucidate the macrophage proteome and assess any alterations in cellular functions that would affect cell-drug carriage and release kinetics. NanoART-MP interactions resulted in the induction of a broad range of activation-related proteins that can enhance phagocytosis, secretory functions, and cell migration. Notably, we now demonstrate that particle-cell interactions serve to enhance drug loading while facilitating drug tissue depots and transportation.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cell Movement; Cells, Cultured; Chemokines; Cyclopropanes; Cytoskeletal Proteins; Drug Carriers; Drug Compounding; Humans; Macrophages; Membrane Potentials; Nanoparticles; Oligopeptides; Particle Size; Phagocytosis; Potassium Channels; Proteome; Pyridines; Ritonavir

The presence of an effective crystal growth inhibitor in solution is desirable to prolong supersaturation since residual crystalline material in an amorphous formulation resulting from the manufacturing process or formed during storage or dissolution can potentially have a significant impact on the extent and duration of supersaturation. In this study, the effectiveness of a group of chemically diverse polymers, including several recently synthesized cellulose derivatives, on solution crystal growth of three structurally diverse compounds (celecoxib, efavirenz, and ritonavir) was quantified at different extents of supersaturation and compared. Despite the different chemical properties and structures of the model compounds, nonspecific hydrophobic drug-polymer interactions appeared to be important in determining the impact of a given polymer on crystal growth for of all these drug compounds. Specific intermolecular interactions were also found to be important for crystal growth inhibition of celecoxib and efavirenz by the hydrophilic polymer, PVPVA. These interactive forces-hydrophobicity and specific intermolecular interactions-are likely to promote adsorption of the polymer onto the surface of the crystalline drugs, thus influencing crystal growth. The effectiveness of the polymers also depended on the rate of crystallization of the drug molecules. At a similar supersaturation ratio of ∼1.2, ritonavir and celecoxib had slower normalized crystal growth rates (0.20 and 0.91 mg min(-1) m(-2), respectively), while the normalized crystal growth rate of efavirenz was significantly higher (2.97 mg min(-1) m(-2)), resulting in lower levels of crystal growth inhibition by the polymers for efavirenz.

Topics: Alkynes; Benzoxazines; Celecoxib; Crystallization; Cyclopropanes; Hydrophobic and Hydrophilic Interactions; Polymers; Pyrazoles; Ritonavir; Solubility; Spectroscopy, Fourier Transform Infrared; Sulfonamides

Left ventricular hypertrophy (LVH) is a predictor of overall mortality in the general population. The most sensitive diagnostic method is transthoracic echocardiography (TTE). In this study, we describe the prevalence of LVH, and the factors associated with it, in a group of patients with HIV infection.. TTE was offered to all patients attending the outpatient clinic of the Hospital Costa del Sol (Marbella, Spain) between 1 December 2009 and 28 February 2011. The corresponding demographic and clinical data were obtained. The left ventricular mass (LVM) was calculated and indexed by height(2.7). LVH was defined as LVM >48g/m(2.7) in men or >44g/m(2.7) in women.. We examined 388 individuals (75.5% male, mean age 45.38years). Of these, 76.1% were receiving HAART; 11.9% had hypertension, 6.2% had diabetes mellitus, 23.2% had dyslipidaemia and 53.6% were tobacco users. The risk of cardiovascular disease at 10years (RV10) was 12.15% (95%CI: 10.99-13.31%). 19.1% of these patients had a high RV10. A total of 69 patients (19.8%) presented high LVM. Age, hypertension, dyslipidaemia, RV10 and the use of nevirapine were associated with a greater presence of LVH in the univariate analysis. In the logistic regression analysis performed, the factors retained in the model were the presence of high RV10 (OR: 2.92, 95%CI: 1.39-6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18-4.14).. In this group of patients, the use of nevirapine and the presence of high RV10 were associated with LVH. The use of nevirapine might be related to its prescription for patients with higher RV10.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Comorbidity; Cross-Sectional Studies; Cyclopropanes; Diabetes Mellitus; Drug Combinations; Dyslipidemias; Echocardiography; Female; Furans; HIV Infections; Humans; Hypertension; Hypertrophy, Left Ventricular; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Organophosphates; Organophosphonates; Risk Factors; Ritonavir; Smoking; Spain; Sulfonamides; Tenofovir; Zidovudine

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

Erlotinib is approved for the treatment of non-small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 μM)], ketoconazole (10 μM), efavirenz (10 μM), or rifampin (10 μM) for 4 days. On day 5, erlotinib (5 μM) was incubated with the above agents for another 24-48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t(½)) of erlotinib increased from 10.6 ± 2.6 to 153 ± 80 and 23.9 ± 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (C(Lint, app)) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t1/2 of erlotinib from 10.3 ± 1.1 to 5.0 ± 1.5 and 3.4 ± 0.2 hours, respectively. Efavirenz and rifampin increased the C(Lint, app) of erlotinib by 2.2- and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.

Topics: 14-alpha Demethylase Inhibitors; Adult; Aged; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Interactions; Erlotinib Hydrochloride; Female; Half-Life; Hepatocytes; HIV Infections; HIV Protease Inhibitors; Humans; Ketoconazole; Male; Middle Aged; Neoplasms; Nucleic Acid Synthesis Inhibitors; Quinazolines; Rifampin; Ritonavir

To explore the durability of three first-line tenofovir/emtricitabine-based regimens in combination with atazanavir/ritonavir, efavirenz or lopinavir/ritonavir in HIV-1-infected patients.. A retrospective, longitudinal, multicentre analysis of adult patients enrolled in the Antiretroviral Resistance Cohort Analysis (ARCA), a national prospective observational cohort of HIV-1-infected patients followed up at more than 100 clinical and laboratory units in Italy. Patients eligible were those starting first-line antiretroviral therapy between 1 June 2004 and 15 April 2011 and who were followed up for at least 6 months. The primary endpoint was durability, defined as the time from antiretroviral therapy initiation to first treatment modification. Time-dependent events were analysed by the Kaplan-Meier approach and the Cox proportional hazard model.. There are 26,000 HIV-infected patients in the ARCA database, of whom 1654 met study inclusion criteria. Six hundred and thirty-nine (38.6%) received efavirenz, 321 (19.4%) received atazanavir/ritonavir and 694 (41.9%) received lopinavir/ritonavir as a first-line regimen. Over a total observation period of 88 months, equivalent to more than 2805 person-years of follow-up, 618 patients underwent treatment modification. Lopinavir/ritonavir, given twice daily, was associated with a higher discontinuation rate than efavirenz- and atazanavir-based regimens [hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.56-2.15, P = 0.001]. Comparing the once-daily regimens, the rate of discontinuation of efavirenz was higher than that of atazanavir/ritonavir (HR 1.39, 95% CI 1.06-1.83, P = 0.016).. Significant differences in treatment duration were observed among the three studied regimens. Once-daily regimens exhibited greater durability than the twice-daily regimen. Among the specific regimens examined, tenofovir/emtricitabine plus atazanavir/ritonavir showed the greatest durability.

Topics: Adenine; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Cohort Studies; Cyclopropanes; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Italy; Longitudinal Studies; Lopinavir; Oligopeptides; Organophosphonates; Prospective Studies; Pyridines; Retrospective Studies; Ritonavir; Tenofovir; Time Factors

We performed a retrospective cohort study of HIV-infected antiretroviral-naïve patients starting a first antiretroviral therapy with tenofovir/emtricitabine plus efavirenz (EFV), atazanavir/ritonavir (ATV/r), or lopinavir/ritonavir (LPV/r).. The incidence of renal impairment or proximal tubular dysfunction was evaluated during a 12-month follow-up. Renal impairment was diagnosed by a reduced estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) formula, and tubular dysfunction was diagnosed when ≥ 2 among proteinuria, glucosuria, hypouricaemia, hypophosphataemia, and hypokalaemia, were identified.. A total of 235 patients were enrolled: 82 taking EFV, 78 ATV/r, and 75 LPV/r. The mean decline in eGFR after the 12-month follow-up was significantly greater in subjects treated with ATV/r (-10.4 ml/min/1.73 m(2)) than in those receiving EFV (- 5.1; p = 0.002) or LPV/r (-4.8; p = 0.003). Similarly, a significantly higher incidence of proximal tubulopathy was observed among ATV/r-treated patients (14.1%) compared with patients receiving EFV (4.9%) or LPV/r (5.3%).. In our retrospective study, naïve patients receiving tenofovir/emtricitabine and ATV/r for 12 months showed a significantly higher decline in eGFR and a significantly higher incidence of proximal tubulopathy than those receiving tenofovir/emtricitabine plus EFV or LPV/r, even though clinically evident renal toxicity associated with tenofovir-based treatment is a very uncommon event.

Topics: Adenine; Adult; Alkynes; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Emtricitabine; Female; Glomerular Filtration Rate; Glycosuria; HIV Infections; HIV Protease Inhibitors; Humans; Kidney Diseases; Lopinavir; Male; Middle Aged; Oligopeptides; Organophosphonates; Proteinuria; Pyridines; Retrospective Studies; Ritonavir; Tenofovir

Quantification of the effect of antiretroviral drugs on the insulin aggregation process is an important area of research due to the serious metabolic diseases observed in AIDS patients after prolonged treatment with these drugs. In this work, multivariate curve resolution alternating least squares (MCR-ALS) was applied to infrared monitoring of the insulin aggregation process in the presence of three antiretroviral drugs to quantify their effect. To evidence concentration dependence in this process, mixtures at two different insulin:drug molar ratios were used. The interaction between insulin and each drug was analysed by (1)H NMR spectroscopy. In all cases, the aggregation process was monitored during 45 min by infrared spectroscopy. The aggregates were further characterised by scanning electron microscopy (SEM). MCR-ALS provided the spectral and concentration profiles of the different insulin-drug conformations that are involved in the process. Their feasible band boundaries were calculated using the MCR-BANDS methodology. The kinetic profiles describe the aggregation pathway and the spectral profiles characterise the conformations involved. The retrieved results show that each of the three drugs modifies insulin conformation in a different way, promoting the formation of aggregates. Ritonavir shows the strongest promotion of aggregation, followed by efavirenz and zidovudine. In the studied concentration range, concentration dependence was only observed for zidovudine, with shorter aggregation time obtained as the amount of zidovudine increased. This factor also affected the aggregation pathway.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Humans; Insulin; Kinetics; Least-Squares Analysis; Magnetic Resonance Spectroscopy; Microscopy, Electron, Scanning; Ritonavir; Spectrophotometry, Infrared; Zidovudine

A study was conducted in healthy adults (n = 19) to evaluate the pharmacokinetics of lopinavir/ritonavir when coadministered with efavirenz. Participants were administered lopinavir/ritonavir 400/100 mg alone twice daily (bid) from the morning of day 1 through the morning of day 10, and then lopinavir/ritonavir 500/125 mg bid was coadministered with efavirenz 600 mg every evening (qhs) from the evening of day 10 through day 20. Lopinavir and ritonavir exposures when administered alone versus with efavirenz were determined on days 10 and 20 and compared using point estimates and 90% confidence intervals. The point estimates for the ratios of lopinavir maximum observed plasma concentration (C(max)), plasma concentration prior to morning dosing (C(trough)), and area under the plasma concentration-time curve over a dosing interval (AUC(12)) were 1.121, 0.954, and 1.060, respectively. The lopinavir/ritonavir dose of 500/125 mg bid administered with efavirenz most closely approximates the pharmacokinetic exposure of lopinavir/ritonavir 400/100 mg bid administered alone.

Topics: Adolescent; Adult; Alkynes; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Humans; Lopinavir; Male; Middle Aged; Ritonavir; Tablets; Young Adult

Tenofovir is associated with reduced renal function, but it is not clear whether there is a greater decline in renal function when tenofovir is co-administered with a boosted protease inhibitor rather than with a nonnucleoside reverse transcriptase inhibitor (NNRTI).. We calculated the estimated glomerular filtration rate (eGFR) for patients in the Swiss HIV Cohort Study. We estimated the difference in eGFR over time between first therapies containing tenofovir and either the NNRTI efavirenz or the protease inhibitors lopinavir (LPV/r) or atazanavir (ATV/r), both boosted with ritonavir.. Patients on a first therapy of tenofovir co-administered with efavirenz (n  = 484), LPV/r (n = 269) and ATV/r (n =  187) were followed for a median of 1.7, 1.2 and 1.3 years, respectively. Relative to tenofovir and efavirenz, the estimated difference in eGFR for tenofovir and LPV/r was -2.6 ml/min per 1.73 m [95% confidence interval (CI) -7.3 to 2.2) during the first 6 months of therapy, then followed by a difference of 0.0 ml/min per 1.73 m (95% CI -1.1 to 1.1) for each additional 6 months of therapy. Relative to tenofovir and efavirenz, the estimated difference in eGFR for tenofovir and ATV/r was -7.6 ml/min per 1.73 m (95% CI -11.8 to -3.4) during the first 6 months of therapy, then followed by a difference of -0.5 ml/min per 1.73 m (95% CI -1.6 to 0.7) for each additional 6 months of therapy.. Tenofovir with either boosted protease inhibitor leads to a greater initial decline in eGFR than tenofovir with efavirenz; this decline may be worse with ATV/r than with LPV/r.

Topics: Adenine; Adult; Alkynes; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; Glomerular Filtration Rate; HIV Infections; HIV Protease Inhibitors; Humans; Kidney; Lopinavir; Male; Middle Aged; Oligopeptides; Organophosphonates; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome

To determine the indications for, rates of therapeutic anticoagulation during, and complications of warfarin therapy in HIV-infected individuals, in whom long-term anticoagulation is frequently indicated. To identify risk factors for nonoptimal anticoagulation and to determine if warfarin dosing is differentially affected by specific antiretroviral agents. Retrospective study of a dedicated anticoagulation program at one of the largest clinics for HIV-infected individuals in the United States. Seventy-three HIV-infected individuals on warfarin were followed for a total of 911 visits. The rate of therapeutic internation normalized ratio (INR) levels was 34.5% when including only visits at which patients were assessed to be adherent with warfarin. In multivariable analysis, injection drug use at baseline was an independent risk factor for subtherapeutic INR (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3-4.7, p=0.01). Additionally, warfarin adherence was protective of both subtherapeutic (OR 0.4, 95% CI 0.2-0.6, p<0.0001) and supratherapeutic (OR 0.5, 95% CI 0.3-0.9, p=0.02) INR status. Efavirenz-based antiretroviral regimens were associated with lower weekly warfarin doses (46 mg) to maintain therapeutic INR compared to lopinavir/ritonavir-based regimens (68 mg; p=0.01) and atazanavir/ritonavir-based regimens (71 mg; p=0.007). Consistently therapeutic warfarin therapy is difficult to achieve in HIV-infected individuals, even with a dedicated anticoagulation program. Adherence to warfarin therapy is important but rates of therapeutic INR levels are nonetheless low. Lower warfarin dosing was required for efavirenz compared to two commonly used protease inhibitor-based regimens. Because of these factors, the emergence of new oral anticoagulants is an important development for HIV-infected individuals who require long term anticoagulation therapy.

Topics: Adult; Alkynes; Anti-HIV Agents; Anticoagulants; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Female; HIV Seropositivity; Humans; International Normalized Ratio; Lopinavir; Male; Medication Adherence; Patient-Centered Care; Retrospective Studies; Ritonavir; Thromboembolism; Treatment Outcome; United States; Venous Thrombosis; Warfarin

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Clinical Trials, Phase III as Topic; Cobicistat; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Combinations; Drug Resistance, Viral; Emtricitabine; Glomerular Filtration Rate; HIV Infections; Humans; Oligopeptides; Organophosphonates; Pyridines; Quinolones; Randomized Controlled Trials as Topic; Ritonavir; Tenofovir; Thiazoles; Viral Load

Topics: Adenine; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cote d'Ivoire; Cyclopropanes; Drug Therapy, Combination; Enterobacter aerogenes; Enterobacteriaceae Infections; Fanconi Syndrome; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Malaria; Male; Middle Aged; Organophosphonates; Pyelonephritis; Pyrimidinones; Ritonavir; Tenofovir

Long-term antiretroviral therapy (ART) for human immunodeficiency virus type one (HIV-1) infection shows limitations in pharmacokinetics and biodistribution while inducing metabolic and cytotoxic aberrations. In turn, ART commonly requires complex dosing schedules and leads to the emergence of viral resistance and treatment failures. We posit that the development of nanoformulated ART could preclude such limitations and affect improved clinical outcomes. To this end, we wet-milled 20 nanoparticle formulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz, collectively referred to as "nanoART," then assessed their performance using a range of physicochemical and biological tests. These tests were based on cell-nanoparticle interactions using monocyte-derived macrophages and their abilities to uptake and release nanoformulated drugs and affect viral replication. We demonstrate that physical characteristics such as particle size, surfactant coating, surface charge, and most importantly shape are predictors of cell uptake and antiretroviral efficacy. These studies bring this line of research a step closer to developing nanoART that can be used in the clinic to affect the course of HIV-1 infection.

Topics: Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; HIV-1; Humans; Indinavir; Macrophages; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nanoparticles; Oligopeptides; Particle Size; Pyridines; Ritonavir; Static Electricity; Surface-Active Agents; Virus Replication

To evaluate the effect of antiretroviral treatment on aminotransferase serum levels in treatment-naïve patients infected with human immunodeficiency virus (HIV).. We conducted a longitudinal study in treatment-nanaïve patients infected with HIV. Patients were excluded if they had consumed alcohol during the last three months or had an opportunistic disease or co-infection. All 54 enrolled patients were evaluated and those having a CD4+ cell count <350 cells/ml (41/54) were allocated to the treatment group (TG), while those with CD4+ counts >350 cells/ml (13/54) did not receive any anti-retroviral treatment (ART). TG patients received either efavirenz (EFV) (21/41) or lopinavir/ritonavir (LPV/RTV) (20/41), each with zidovudine/lamivudine (ZDV/LMV).. During the trial, 2 subjects in the EFV group were excluded due to rash and 1 subject in the LPV/RTV group due to gastric intolerance. The remaining 51 subjects (13 (25.5%) in the NTG and 38 (74.5%) in the TG) were included in the data analysis. Overall, 43 (84%) of analyzed patients were male and 8 (16%) female with an overall mean age of 33 ± 9 years. Of the 38 treated patients, 19 received LPV/RTV and 19 received EFV. Patients in the TG showed an increase in their CD4+ cell count, a decrease in aspartate aminotransferase (AST) from 39.3 ± 28 IU/ml to 22.7 ± 6 IU/ml (p = 0.02), and a decrease in alanine aminotransferase (ALT) from 52.0 ± 25 IU/ml to 23.8 ± 13 IU/ml (p < 0.01). Patients in the NTG showed no statistically significant differences in these measurements. Positive correlation was found between HIV viral load, AST (r = 0.31, p = 0.001) and ALT (r = 0.40, p = 0.04).. There is a significant decrease in aminotransferase serum levels following the initiation of antiretroviral treatment in HIV infected patients.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Female; HIV Infections; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Pyrimidinones; Ritonavir; Serum; Transaminases; Zidovudine

To evaluate the effect of a previous single dose of nevirapine given to prevent mother-to-child transmission of human immunodeficiency virus (HIV) on virologic and immunologic measures after months of an antiretroviral regimen containing either efavirenz or lopinavir-ritonavir.. Retrospective subgroup analysis of data from the Phidisa II trial.. Six South African research clinics. Patients. A total of 394 women with HIV who completed 6 months of combination antiretroviral regimen containing either efavirenz or lopinavirritonavir as part of the Phidisa II trial.. During the screening process for the Phidisa II study, 478 women were asked about previous nevirapine use: 392 women (82%) were nevirapine naïve, and 86 (18%) had received nevirapine. During the study, patients received either an efavirenz-based or lopinavir-ritonavir- based antiretroviral regimen. After 6 months of treatment, virologic (HIV RNA levels) and immunologic (CD4(+) cell count) responses were measured. These data were compared between women with or without previous nevirapine exposure, and between women who received efavirenz versus lopinavirritonavir. After 6 months of treatment, 394 women (324 nevirapine naïve, 70 exposed to nevirapine) had follow-up HIV RNA results. Two hundred twenty-seven (70.1%) of the nevirapine-naïve patients and 48 (68.6%) of the nevirapine-exposed patients achieved HIV RNA levels lower than 400 copies/ml (p=0.89), with CD4(+) cell count increases of 115.5 and 120.4 cells/mm(3), respectively (p=0. 7). Among the nevirapine-exposed women, 27 (75%) of 36 efavirenz-treated and 21 (61.8%) of 34 lopinavir-ritonavir-treated patients had HIV RNA levels lower than 400 copies/ml at months (p=0.31).. In this retrospective analysis of a small cohort, previous exposure to a single dose of nevirapine did not affect virologic outcomes after 6 months of either an efavirenz-based or lopinavir-ritonavir-based antiretroviral regimen. As efavirenz is one of the first-line combination antiretroviral therapies administered in Africa, it remains an option for women who received single-dose nevirapine.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Clinical Trials, Phase II as Topic; Cyclopropanes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Nevirapine; Pyrimidinones; Randomized Controlled Trials as Topic; Retrospective Studies; Ritonavir; RNA, Viral; South Africa; Young Adult

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

There have been no data presented on the relative rates of the development of renal stones in those receiving ritonavir-boosted atazanavir (ATZ/r) when compared with other commonly used antiretrovirals (ARVs). We compared the rate of development of renal stones in a cohort of HIV-infected individuals attending the Chelsea and Westminster Hospital Foundation Trust exposed to ATZ/r with those exposed to efavirenz (EFV)/ritonavir-boosted lopinavir (LPV/r) and ritonavir-boosted darunavir (DRV/r) over a 45-month study period. The rate of development of renal stones in the ATZ/r group (n = 1206) compared with the EFV/LPV/r/DRV/r combined group (n = 4449) was 7.3 [95% confidence interval (CI) 4.7-10.8] per 1000 patient-years and 1.9 (95% CI 1.2-2.8) per 1000 patient-years (P < 0.001), respectively. The renal stones rate remained significantly higher in the ATZ/r group after adjusting for prior ATZ/r/indinavir (IND) exposure. When choosing a boosted protease inhibitor, ATZ/r renal stones should be considered as a potential comorbidity.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cohort Studies; Cyclopropanes; Darunavir; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nephrolithiasis; Oligopeptides; Pyridines; Pyrimidinones; Retrospective Studies; Ritonavir; Sulfonamides

Antiretroviral therapy (ART) access with successful outcomes for children is expanding in resource-limited countries. The aim of this study was to determine treatment responses of children in a routine setting where first-line therapy with lopinavir/ritonavir is routinely included for young children.. Outpatient records of children who initiated ART between April 2004 and March 2008 at a government clinic in Soweto were reviewed. Children <3 years initiated ART with lopinavir/ritonavir and those ≥ 3 years initiated with efavirenz-containing regimens.. ART was initiated at a median age of 4.3 years, 28.6% also received tuberculosis treatment. During 3155 child-years of follow-up (median follow-up 17 months), 132 children (6%) died giving a mortality rate of 4.2 (95% confidence interval: 3.5, 5.0) deaths per 100 child-years. By 12 and 24 months, 84% and 96% of children achieved virologic suppression. The proportion of children with viral rebound increased from 5.4% to 16.3% at 24 and 36 months from start of ART. Younger children (receiving lopinavir/ritonavir-based first-line therapy) with higher viral loads suppressed more slowly and were more likely to die. Children who were started on treatment for tuberculosis at the time of viral suppression were more likely to have virologic rebound.. Despite good treatment outcomes overall, children with advanced disease at ART initiation had poorer outcomes, particularly those <3 years of age, most of whom were treated with lopinavir/ritonavir-containing therapy. The increasing risk of viral rebound over time for the whole cohort is concerning, given currently limited available treatment options for children.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Coinfection; Cyclopropanes; Female; Follow-Up Studies; HIV; HIV Infections; Hospitals, Public; Humans; Infant; Lopinavir; Male; Mycobacterium tuberculosis; Recurrence; Ritonavir; South Africa; Survival Analysis; Tuberculosis, Pulmonary; Viral Load

Animal pharmacokinetic and tissue distribution assays of antiretroviral therapeutic drugs require accurate drug quantification in biological fluids and tissues. Here we report a simple, rapid, and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of commonly used antiretroviral drugs ritonavir (RTV), indinavir (IDV), atazanavir (ATV), and efavirenz (EFV) in mouse serum and tissues (liver, kidney, lung, and spleen). These antiretroviral drugs are currently the cornerstones of common therapeutic regimens for human immunodeficiency virus (HIV) infection. Chromatographic separation was achieved using a gradient mobile phase (5% acetonitrile in methanol and 7.5mM ammonium acetate (pH 4.0)) on an ACQUITY UPLC(®)BEH Shield RP 18 column. All compounds eluted within a 7 min run time. Lopinavir was used as an internal standard. Detection was achieved by dual positive and negative ionization modes on a quadrupole linear ion trap hybrid mass spectrometer with an electrospray ionization (ESI) source. The dynamic range was 0.2-1000 ng/mL for RTV, IDV, and ATV, and 0.5-1000 for EFV. The method was validated and showed high and consistent intra-day and inter-day accuracy and precision for all analytes. This method is used to support the preclinical development studies of targeted- and sustained-release combination ART (nanoART). The current data demonstrate a 1.5-4 fold increase in serum and tissue AUC of nanoformulated ATV, RTV, and EFV administered to mice when compared to native drug. In addition, the tested formulation enhanced exposure of the same anti-HIV drugs in mouse tissues.

Topics: Alkynes; Animal Structures; Animals; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; HIV Infections; Humans; Indinavir; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Pyridines; Ritonavir; Tandem Mass Spectrometry

Malaria and HIV infection are both very common in many developing countries. With the increasing availability of therapy for HIV infection, it was of interest to determine whether antiretroviral drugs exert antimalarial effects. We therefore tested the in vitro activity of 19 antiretroviral drugs against the W2 and 3D7 strains of Plasmodium falciparum at concentrations up to 50 μM. None of 5 tested nucleoside reverse transcriptase inhibitors demonstrated activity. Two nonnucleoside reverse transcriptase inhibitors, efavirenz (mean 50% inhibitory concentration [IC(50)] of 22 to 30 μM against the two strains) and etravirine (3.1 to 3.4 μM), were active; nevirapine was not active. Also active were the fusion inhibitor enfuvirtide (6.2 to 7.9 μM) and the entry inhibitor maraviroc (15 to 21 μM). Raltegravir was not active. However, for all active drugs mentioned above, the IC(50)s were considerably greater than the concentrations achieved with standard dosing. The effects most likely to be clinically relevant were with HIV protease inhibitors. Of the tested compounds, activity was seen with lopinavir (2.7 to 2.9 μM), atazanavir (3.3 to 13.0 μM), saquinavir (5.0 to 12.1 μM), nelfinavir (6.5 to 12.1 μM), ritonavir (9.5 to 10.9 μM), tipranavir (15.5 to 22.3 μM), and amprenavir (28.1 to 40.8) but not darunavir. Lopinavir was active at levels well below those achieved with standard dosing of coformulated lopinavir-ritonavir. Lopinavir also demonstrated modest synergy with the antimalarial lumefantrine (mean fractional inhibitory concentration index of 0.66 for W2 and 0.53 for 3D7). Prior data showed that lopinavir-ritonavir also extends the pharmacokinetic exposure of lumefantrine. Thus, when used to treat HIV infection, lopinavir-ritonavir may have clinically relevant antimalarial activity and also enhance the activity of antimalarials.

Topics: Alkynes; Animals; Anti-Retroviral Agents; Antimalarials; Benzoxazines; Carbamates; Cyclopropanes; Darunavir; Furans; Lopinavir; Nelfinavir; Nevirapine; Plasmodium falciparum; Pyridines; Pyrones; Ritonavir; Saquinavir; Sulfonamides

To compare the frequency of grade 3 or 4 transaminase elevations (TEs) in HIV/hepatitis C virus (HCV) co-infected patients who started a three-antiretroviral drug regimen including efavirenz or a ritonavir-boosted protease inhibitor (PI/r) and the influence of pre-existing significant hepatic fibrosis or cirrhosis.. All pre-treated or treatment-naive HIV/HCV co-infected patients who started an antiretroviral regimen including two nucleos(t)ide reverse transcriptase inhibitors along with efavirenz or a PI/r in seven Spanish centres from January 2007 to December 2009 were included in this prospective study.. Of 262 patients included in this study, 76 (29%) individuals began antiretroviral therapy (ART) including efavirenz and 186 (71%) a PI/r-based combination. The median (interquartile) follow-up was 14.0 (6.2-23.7) months. A total of 20 (7.6%) patients presented grade 3-4 TEs. Four (1.5%) subjects discontinued ART due to this adverse event. Grade 3-4 TEs were observed in 5 (6.6%) subjects receiving efavirenz and 15 (8.1%) treated with PI/r (P = 0.681). Three (6.5%) patients in the efavirenz group with significant fibrosis developed grade 3-4 TEs versus 2 (8.7%) without pre-existing significant fibrosis (P = 0.743). In the PI/r group, the corresponding figures were 10 (8.8%) and 5 (9.3%), respectively (P = 0.931).. The frequency of grade 3-4 TEs associated with efavirenz-based ART combinations under clinical practice conditions is low and similar to that found in patients receiving PI/r currently used in HIV/HCV co-infected patients. The baseline fibrosis stage does not have an impact on the development of TEs caused by these antiretroviral drugs in this population.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver; Liver Cirrhosis; Male; Middle Aged; Ritonavir; Transaminases

The optimal therapeutic strategies for patients presenting with advanced disease at HIV-1 diagnosis are as yet incompletely defined.. All patients presenting at two outpatient clinics in 2000-2009 with an AIDS-defining clinical condition or a CD4+ T cell count < 200/μL at HIV-1 diagnosis were analyzed for the presence of combined immunovirological response, defined by the concomitant presence of an absolute number of CD4+ T cells > 200 cells/μL and a plasma HIV-1 RNA copy number < 50/mL after 12 months of HAART.. Among 102 evaluable patients, first-line regimens were protease inhibitors [PI]-based in 78 cases (77%) and efavirenz-based in 24 cases (23%). The overall response rate was 65% (95% CI: 55-74), with no differences by gender, age, nationality, route of transmission, hepatitis virus coinfections, presence of AIDS-defining clinical events, baseline HIV-1 viral load, or type of regimen (response rates with PI-based and efavirenz-based therapy: 63% and 71%, respectively, p = 0.474). Response rate was significantly better with higher baseline CD4+ T cell counts (78% with CD4+ ≥ 100/μL, compared to 50% with CD4+ < 100/μL; odds ratio: 3.5; 95% CI: 1.49-8.23, p = 0.003). Median time on first-line antiretroviral therapy was 24 months (interquartile range: 12-48). Switch to a second line treatment occurred in 57% of patients, mainly for simplification (57%), and was significantly more common with PI-based regimens [adjusted hazard ratios (AHR) with respect to efavirenz-based regimens: 3.88 for unboosted PIs (95% CI: 1.40-10.7, p = 0.009) and 4.21 for ritonavir-boosted PI (95% CI 1.7-10.4, p = 0.002)] and in older subjects (≥ 50 years) (AHR: 1.83; 95% CI: 1.02-3.31, p = 0.044). Overall mortality was low (3% after a median follow up of 48 months).. Our data indicate that a favorable immunovirological response is possible in the majority of naive patients presenting at HIV-1 diagnosis with AIDS or low CD4+ T cell counts, and confirm that starting HAART with a more compromised immune system may be associated with a delayed and sometimes partial immune recovery. Simpler regimens may be preferable in this particular population.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Viral Load

Nanoformulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz were manufactured by wet milling, homogenization or sonication with a variety of excipients. The chemical, biological, immune, virological, and toxicological properties of these formulations were compared using an established monocyte-derived macrophage scoring indicator system. Measurements of drug uptake, retention, release, and antiretroviral activity demonstrated differences amongst preparation methods. Interestingly, for drug cell targeting and antiretroviral responses the most significant difference among the particles was the drug itself. We posit that the choice of drug and formulation composition may ultimately affect clinical utility.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cell Survival; Chemistry, Pharmaceutical; Cyclopropanes; Histocytochemistry; Humans; Indinavir; Macrophages; Nanomedicine; Nanoparticles; Nanotechnology; Oligopeptides; Pyridines; Ritonavir; Sonication

The relation between treatment outcome and trough plasma concentrations of efavirenz (EFV), atazanavir (ATV) and lopinavir (LPV) was studied in a pharmacokinetic/pharmacodynamic substudy of the NORTHIV trial-a randomised phase IV efficacy trial comparing antiretroviral-naïve human immunodeficiency virus-1-infected patients treated with (1) EFV + 2 nucleoside reverse transcriptase inhibitors (2NRTI) once daily, (2) ritonavir-boosted ATV + 2NRTI once daily or (3) ritonavir-boosted LPV + 2NRTI twice daily. The findings were related to the generally cited minimum effective concentration levels for the respective drugs (EFV 1,000 ng/ml, ATV 150 ng/ml, LPV 1,000 ng/ml). The relation between atazanavir-induced hyperbilirubinemia and virological efficacy was also studied.. Drug concentrations were sampled at weeks 4 and 48 and optionally at week 12 and analysed by high-performance liquid chromatography with UV detector. When necessary, trough values were imputed by assuming the reported average half-lives for the respective drugs. Outcomes up to week 48 are reported.. No relation between plasma concentrations of EFV, ATV or LPV and virological failure, treatment withdrawal due to adverse effects or antiviral potency (viral load decline from baseline to week 4) was demonstrated. Very few samples were below the suggested minimum efficacy cut-offs, and their predictive value for treatment failure could not be validated. There was a trend toward an increased risk of virological failure in patients on ATV who had an average increase of serum bilirubin from baseline of <25 micromol/l.. The great majority of treatment-naïve and adherent patients on standard doses of EFV, ritonavir-boosted ATV and ritonavir-boosted LPV have drug concentrations above that considered to deliver the maximum effect for the respective drug. The results do not support the use of routine therapeutic drug monitoring (TDM) for efficacy optimisation in treatment-naïve patients on these drugs, although TDM may still be of value in some cases of altered pharmacokinetics, adverse events or drug interactions. Serum bilirubin may be a useful marker of adherence to ATV therapy.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Bilirubin; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Cyclopropanes; Drug Interactions; HIV-1; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Treatment Outcome; Viral Load

Currently used combinations of anti-HIV drugs, known as Highly Active Antiretroviral Therapy (HAART), have considerably reduced the mortality in patients with AIDS. However, HAART medications such as efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) often cause adverse drug-drug interactions (DDIs) that result from changes in the expression and activity of drug metabolizing enzymes. Since EFV is most commonly used with ATV and RTV, the known CYP inhibitors, we evaluated the effects of combinations of these agents on the CYP3A4 induction by EFV. We determined the induction of CYP3A4 by EFV, RTV, ATV, EFV+RTV, EFV+ATV, EFV+RTV+ATV and rifampicin (RIF) employing primary human hepatocytes from 3 donors. Also, concentration dependent activation of human Pregnane X-receptor (hPXR) which is key transcriptional regulator of CYP3A4 by EFV, RIF and RTV was estimated in transiently transfected LS180 cells. CYP3A4 activity (testosterone-6beta-hydroxylation) was induced by EFV (3 fold) and RIF (4 fold), but was significantly suppressed in the presence of RTV and ATV. All treatments significantly induced the CYP3A4 transcripts (3-25 fold) as quantitated by RT-PCR. hPXR activation data in LS180 cells were consistent with the induction of transcripts and the estimated EC(50) values were 0.87 microM, 0.44 microM and 3.7 microM for RIF, RTV and EFV, respectively. However, in primary hepatocytes the net effect was suppression of EFV mediated CYP3A4 induction by RTV and ATV. This observation corresponds to the clinical observations of attenuated CYP3A4 induction by EFV induction in the presence of RTV and other protease inhibitors (PIs). Our results underscore the limitation of transcriptional activation assays in predicting the net outcome for compounds that exhibit complex interactions resulting from induction and inhibition of CYP enzymes.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cell Line, Tumor; Cyclopropanes; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Hepatocytes; Humans; Oligopeptides; Pregnane X Receptor; Pyridines; Receptors, Steroid; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Transfection

We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus type one-infected people can be achieved through nanoformulationed drug delivery systems. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies to assess antiretroviral responses. This resulted in improved drug uptake, release, and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated individual drug release from 15 to >20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cells, Cultured; Cyclopropanes; Delayed-Action Preparations; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Immunohistochemistry; Macrophages; Microscopy, Confocal; Microscopy, Electron, Transmission; Nanoconjugates; Nanotechnology; Oligopeptides; Pyridines; Ritonavir

HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0-->t for atovaquone relative to the healthy volunteers was 0.25 (0.16-0.38), 0.26 (0.17-0.41) and 0.54 (0.35-0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38-43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.

Topics: Adolescent; Adult; Aged; Alkynes; Atazanavir Sulfate; Atovaquone; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Proguanil; Pyridines; Pyrimidinones; Ritonavir; Young Adult

Free ritonavir, lopinavir and efavirenz injected intraperitoneally were compared with antiretroviral (AR) nanoparticles (NPs).. This is a prospective study in BALB/c mice comparing the pharmacokinetics of free drugs with AR NPs. All animals received free drugs or AR NPs (20 mg/kg) in PBS. In vitro replication assays were used for determination of the anti-HIV efficacy of NP formulations. At specific times (free drugs 0.08, 0.125, 0.25, 0.33, 1, 2 and 3 days; AR NPs 0.125, 0.33, 1, 2, 4, 7, 14, 21, 28, 35 and 42 days) mice were euthanized and serum and organs were harvested for determination of AR concentrations by HPLC. Single treatment of monocyte-derived macrophages (MDMs) infected with HIV-1(ada) compared AR NPs (0.005-0.05 mg/mL) with free efavirenz or lopinavir/ritonavir (0.01-0.1 mg/mL), blank NPs and controls. Results are presented as means ± SEM.. Serum free AR drug concentrations peaked 4 h post-injection (ritonavir 3.9 ± 3.05, lopinavir 3.4 ± 2.5 and efavirenz 1.8 ± 0.63 µg/mL) and were eliminated by 72 h. Poly(dl-lactide-co-glycolide) NP animals had detectable ritonavir, lopinavir and efavirenz concentrations in all tissues for 28 days. Treatment of MDMs with AR NPs resulted in sustained inhibition of HIV-1(ada) replication.. AR drug concentrations from NPs are sustained for 28 days in vivo and anti-HIV inhibition was comparable to that of free drugs in vitro and could be a sustained treatment for delivery of AR drugs.

Topics: Alkynes; Animal Structures; Animals; Anti-HIV Agents; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Delivery Systems; Injections, Intraperitoneal; Lopinavir; Mice; Mice, Inbred BALB C; Monocytes; Nanoparticles; Polyesters; Pyrimidinones; Ritonavir; Serum; Time Factors

In the present study, a comparative assessment of the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r; 4:1) on human adipocytes in culture has been performed. Human pre-adipocytes were treated with EFV or LPV/r during or after adipogenic differentiation. Acquisition of adipocyte morphology, expression of gene markers of mitochondrial toxicity, adipogenesis and inflammation, and release of adipokines and cytokines to the medium were measured. Results indicated that EFV and LPV/r impaired adipocyte differentiation in association with a reduction in transcript levels for adipogenic differentiation genes (adiponectin, lipoprotein lipase, leptin) and master regulators of adipogenesis (PPAR, C/EBP). The effects were greater with EFV than LPV/r. Both LPV/r and EFV induced increases in monocytechemoattactant protein-1 (MCP-1) mRNA levels, but the effect was greater with EFV. Similarly, the release of proinflammatory cytokines and other inflammation-related molecules (interleukins 6 and 8, MCP-1, PAI-1) was enhanced to a much higher degree by EFV than by LPV/r. Adiponectin and leptin release by adipocytes was reduced by both drugs, although to a higher extent by EFV. Neither drug affected mitochondrial DNA levels, transcripts encoding mitochondrial proteins or lactate release by adipocytes. In previously differentiated adipocytes, EFV caused a significant reduction in PPARγ and adiponectin expression, whereas LPV/r did not. We conclude that both EFV and LPV/r impair human adipogenesis, reduce adipokine release and increase the expression and release of inflammation-related cytokines, but the overall effects are greater with EFV. These findings may have implications for the pathogenesis of HIV-1-associated lipodystrophy and the development of HIV-1 therapies.

Topics: Adipocytes; Adipogenesis; Adipokines; Adiponectin; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cells, Cultured; Cyclopropanes; Cytokines; Female; Gene Expression; Humans; Lopinavir; Mitochondria; PPAR gamma; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Messenger

Most HPLC-UV methods for therapeutic drug monitoring of anti-HIV drugs have long run times, which reduce their applicability for high-throughput analysis. We developed an ultra-performance liquid chromatography (UPLC)-diode array detection method for the simultaneous quantification of the HIV-protease inhibitors (PIs) amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir (TPV), and the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine.. Solid-phase extraction of 1 mL plasma was performed with Waters HLB cartridges. After 3 wash steps, we eluted the drugs with methanol, evaporated the alcohol, and reconstituted the residue with 50 microL methanol. We injected a 4-microL volume into the UPLC system (Waters ACQUITY UPLC BEH C8 column maintained at 60 degrees C) and used a linear gradient of 50 mmol/L ammonium acetate and 50 mmol/L formic acid in water versus acetonitrile to achieve chromatographic separation of the drugs and internal standard (A-86093). Three wavelengths (215, 240, and 260 nm) were monitored.. All drugs were eluted within 15 min. Calibration curves with concentrations of 0.025-10 mg/L (1.875-75 mg/L for TPV) showed coefficients of determination (r(2)) between 0.993 and 0.999. The lower limits of quantification were well below the trough concentrations reported in the literature. Inter- and intraassay CVs and the deviations between the nominal and measured concentrations were <15%. The method was validated by successful participation in an international interlaboratory QC program.. This method allows fast and simultaneous quantification of all commercially available PIs and NNRTIs for therapeutic drug monitoring.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sensitivity and Specificity; Solid Phase Extraction; Sulfonamides

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load; Viremia

Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C(max)s, and C(min)s comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C(min), which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Interactions; Female; Humans; Male; Middle Aged; Pyridines; Pyrones; Ritonavir; Sulfonamides

Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery.. NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography.. Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited.. These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cell Survival; Cells, Cultured; Cyclopropanes; HIV Core Protein p24; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Macrophages; Microscopy, Atomic Force; Monocytes; Nanoparticles; Ritonavir

Combination antiretroviral (AR) therapy continues to be the mainstay for HIV treatment. However, antiretroviral drug nonadherence can lead to the development of resistance and treatment failure. We have designed nanoparticles (NP) that contain three AR drugs and characterized the size, shape, and surface charge. Additionally, we investigated the in vitro release of the AR drugs from the NP using peripheral blood mononuclear cells (PBMCs).. Poly-(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing ritonavir (RTV), lopinavir (LPV), and efavirenz (EFV) were fabricated using multiple emulsion-solvent evaporation procedure. The nanoparticles were characterized by electron microscopy and zeta potential for size, shape, and charge. The intracellular concentration of AR drugs was determined over 28 days from NPs incubated with PBMCs. Macrophages were imaged by fluorescent microscopy and flow cytometry after incubation with fluorescent NPs. Finally, macrophage cytotoxicity was determined by MTT assay.. Nanoparticle size averaged 262 +/- 83.9 nm and zeta potential -11.4 +/- 2.4. AR loading averaged 4% (w/v). Antiretroviral drug levels were determined in PBMCs after 100 microg of NP in 75 microL PBS was added to media. Intracellular peak AR levels from NPs (day 4) were RTV 2.5 +/- 1.1; LPV 4.1 +/- 2.0; and EFV 10.6 +/- 2.7 microg and continued until day 28 (all AR >or= 0.9 microg). Free drugs (25 microg of each drug in 25 microL ethanol) added to PBMCs served as control were eliminated by 2 days. Fluorescence microscopy and flow cytometry demonstrated phagocytosis of NP into monocytes-derived macrophages (MDMs). Cellular MTT assay performed on MDMs demonstrated that NPs are not significantly cytotoxic.. These results demonstrated AR NPs could be fabricated containing three antiretroviral drugs (RTV, LPV, EFV). Sustained release of AR from PLGA NP show high drug levels in PBMCs until day 28 without cytotoxicity.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Carriers; Drug Combinations; Drug Compounding; HIV Infections; Humans; Lactic Acid; Lopinavir; Macrophages; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrimidinones; Ritonavir

Oral lesions (OL) have an important prognostic value for HIV/AIDS patients. However, the behavior of OL in HIV/AIDS patients undergoing highly active antiretroviral therapy including efavirenz (HAART/EFV) has not been documented. Our objective was to establish the prevalence of OL in HIV/AIDS patients undergoing HAART/EFV and to compare it with the prevalence of OL in patients undergoing antiretroviral therapy including a protease inhibitor (HAART/PI). Seventy-three HIV/AIDS patients undergoing antiretroviral treatment for at least for 6 months at "La Raza" Medical Center's Internal Medicine Unit (IMSS, Mexico City) were included. To detect OL, a detailed examination of oral soft tissues was performed in each patient. Patient records recorded gender, seropositivity time, route of contagion, antiretroviral therapy type and duration, CD4 lymphocyte count/ml, and viral load. Two groups were formed: 38 patients receiving HAART/EFV [two nucleoside analogue reverse transcriptase inhibitors (NARTI) plus efavirenz] and 35 patients receiving HAART/PI (two NARTIs plus one PI). OL prevalence was established in each study group. The Chi-square test was applied (p < 0.05(IC95%)). OL prevalence in the HAART/EFV group (32%) was lower (p < 0.007) than in the HAART/PI group (63%). Candidosis was the most prevalent OL in both groups. Herpes labialis, HIV-associated necrotizing periodontitis, xerostomia, hairy leukoplakia, and nonspecific oral sores were identified. The highest prevalence for all OL was found in the HAART/PI group. These findings suggest that HIV/AIDS patients undergoing HAART/EFV show a lower prevalence of oral lesions than patients undergoing HAART/PI.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Female; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Mouth Diseases; Prevalence; Ritonavir; Saquinavir; Viral Load

Corticosteroids are cytochrome P450 3A4 substrates, which have been associated with toxicities in patients receiving cytochrome P450 3A4 inhibitors such as human immunodeficiency virus protease inhibitors. In a study in healthy volunteers, ritonavir significantly increased prednisolone exposure.. We investigated the influence of antiretroviral (ARV) medications on prednisolone pharmacokinetics in 3 groups of 10 human immunodeficiency virus-infected subjects. One group received lopinavir/ritonavir, and another efavirenz, as part of their ARV regimen; a third group did not receive ARV medications. Each subject received a single 20-mg prednisone dose followed by serial blood sampling for prednisolone. Prednisolone pharmacokinetics were compared among the groups.. Area under the concentration-time curve was significantly lower in efavirenz recipients versus subjects receiving lopinavir/ritonavir (geometric mean ratio = 0.60, P = 0.01). Average prednisolone area under the concentration-time curve was higher in subjects taking lopinavir/ritonavir versus subjects not on ARVs; however, this difference was not significant (P > 0.05).. These data indicate that prednisolone concentrations may fluctuate widely when human immunodeficiency virus-positive individuals established on efavirenz therapy change to lopinavir/ritonavir or vice versa.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Prednisolone; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Alkynes; Benzoxazines; Cause of Death; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Alkynes; Anti-Retroviral Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Failure

To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.. Prospective, observational study of HIV-infected hemodialysis patients receiving one 600 mg tablet daily of EFV (N = 13) or three 133.3/33.3 mg capsules twice daily of LPV/RTV (N = 13).. Twenty-four-hour EFV and 12-h LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored.. The geometric mean [95% confidence interval (CI); percentage of coefficient of variation (% CV)] Cmin, Cmax, and area under the curve (AUC) for the EFV group were 1.81 microg/ml (0.93, 3.53; 103%), 5.04 microg/ml (3.48, 7.29; 72%), and 71.5 microg h/ml (43.2, 118.3; 93%), respectively. These parameters were 2.76 microg/ml (1.86, 4.11; 53%), 8.45 microg/ml (6.41, 11.15; 52%), and 69.6 microg h/ml (55.6, 87.2; 37%) for LPV and 0.08 microg/ml (0.05, 0.14; 63%), 0.58 microg/ml (0.44, 0.76; 41%), and 3.74 microg h/ml (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism.. The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggests that no dosing adjustments are necessary in treatment-naive patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease-inhibitor-experienced patients.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Kidney Failure, Chronic; Lopinavir; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Pyrimidinones; Renal Dialysis; Reverse Transcriptase Inhibitors; Ritonavir

A highly sensitive and selective method using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) was developed and validated for the measurement of three antiretroviral agents, efavirenz, lopinavir and ritonavir, in human hair. Hair samples from adherent HIV-infected patients on antiretroviral therapies were cut into about 1 mm length segments and drugs were extracted by first shaking the samples with methanol in a 37 degrees C water bath overnight (>14 h), followed by methyl tert-butyl ether/ethyl acetate (1:1) extraction under weak alkaline conditions. The extracted lopinavir and ritonavir were separated by reversed-phase chromatography and detected by tandem mass spectrometry in electrospray positive ionization mode with multiple reaction monitoring (MRM), while efavirenz was monitored in negative ionization MRM mode. This method was validated from 0.01 to 4.0 ng/mg hair for ritonavir and 0.05-20 ng/mg hair for lopinavir and efavirenz by using 2 mg of a human hair sample. The interday and intraday assay precision (coefficients of variation, CV) for spiked quality control (QC) samples at low, medium and high concentrations were within 15% and accuracy ranged from 89% to 110%. Assay reproducibility was also demonstrated by analysis of incurred hair QC samples (CV <14%). No significant matrix ionization suppression was observed. This developed method allowed for the monitoring of these target medications in the hair samples of HIV-infected women on antiretroviral therapy in an observational study using small amounts of hair.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Case-Control Studies; Chromatography, Liquid; Cyclopropanes; Dose-Response Relationship, Drug; Hair; Humans; Lopinavir; Pyrimidinones; Quality Control; Reference Standards; Reproducibility of Results; Ritonavir; Sensitivity and Specificity; Solutions; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Monitoring; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; Humans; Organophosphonates; Peptide Fragments; Pyridines; Pyrones; Retrospective Studies; Ritonavir; Sulfonamides; Tenofovir

Topics: Adult; Aged; Alkynes; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2C9; Drug Interactions; Female; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Warfarin

The influence of nevirapine or efavirenz co-administration on ritonavir-boosted amprenavir pharmacokinetics was investigated in HIV-infected patients with a population pharmacokinetic approach. The analysis was performed with a population of 61 patients treated with fosamprenavir/ritonavir (700 mg/100 mg twice daily) combined with nucleoside/nucleotide reverse transcriptase inhibitors +/- enfuvirtide and no other antiretroviral drugs (group A, n = 46) or nevirapine (group B, n = 10) or efavirenz (group C, n = 5). No significant increase in amprenavir clearance [mean +/- standard deviation: 22.49 +/- 10.32 (group A) vs. 21.57 +/- 9.62 (group B) vs. 20.15 +/- 5.18 (group C) L/h] and no significant decrease in trough amprenavir plasma concentrations [1.75 +/- 0.95 (group A) vs. 1.82 +/- 0.72 (group B) vs. 1.55 +/- 0.66 (group C) mg/L] were found in groups B and C in comparison with group A, although nevirapine and efavirenz are inductors of protease inhibitors metabolism. These results suggest that fosamprenavir/ritonavir should be used at standard doses of 700 mg/100 mg twice daily when combined with efavirenz or nevirapine.

Topics: Adult; Alkynes; Anti-HIV Agents; Bayes Theorem; Benzoxazines; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; France; Furans; HIV Infections; Humans; Male; Models, Biological; Nevirapine; Organophosphates; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

The authors describe a patient with known human immunodeficiency virus (HIV)-1 infection who presented with two generalized seizures and was found to have extensive white matter disease and a left/bilateral temporo-occipital focal slowing on electroencephalography (EEG). There were no magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) indications for opportunistic infection. Plasma viremia was controlled, whereas viral replication was uncontrolled in CSF. CSF-specific genotype-guided adaptation of the antiretroviral therapy in order to optimize central nervous system (CNS) penetration resulted in clinical improvement and normalization of MRI and EEG. Our case report illustrates the importance of individualized antiretroviral therapy in HIV infected patients with neurological complications.

Topics: Adenine; Adult; AIDS Dementia Complex; Alkynes; Anti-HIV Agents; Anticonvulsants; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cerebrospinal Fluid; Cyclopropanes; Didanosine; HIV-1; Humans; Indinavir; Lamivudine; Male; Nelfinavir; Nevirapine; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Seizures; Stavudine; Tenofovir; Viral Load; Virus Replication; Zidovudine

HIV infection is associated with an increased risk of coronary artery disease, but the contribution of inflammation versus antiretroviral drugs is not well understood. Fibrinogen is an inflammatory factor associated with atherosclerosis.. A total of 1131 HIV-infected patients and 281 controls [from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based study of cardiovascular risk assessment] in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) had plasma fibrinogen levels measured. Multivariable linear regression identified factors associated with fibrinogen.. HIV-infected patients had higher levels of fibrinogen compared with controls (males: 25 mg/dl higher, P = 0.006; females: 21 mg/dl higher, P = 0.39). Among HIV-infected persons, median levels of fibrinogen were 11% higher in patients currently using any protease inhibitor (PI) compared with those not using a PI (P < 0.0001). The strongest univariate associations were with the individual PIs, ritonavir and indinavir. Patients taking indinavir boosted with ritonavir had median fibrinogen levels 8% higher than those on indinavir alone (P = 0.049). Lower levels of fibrinogen were seen in those HIV-infected patients currently using any nonnucleoside reverse transcriptase inhibitor (NNRTI) compared to those not using an NNRTI (nevirapine -14.4%, P < 0.0001; efavirenz -7%, P = 0.0002). The associations of ritonavir, indinavir, efavirenz and nevirapine with fibrinogen levels persisted after multivariable analysis and were independent of other antiretroviral use.. Protease inhibitor use is associated with elevated fibrinogen levels which may contribute to increased risk of atherosclerosis in HIV-infected patients. Conversely, NNRTI use is associated with lower fibrinogen levels which may decrease risk of atherosclerosis.

Topics: Adult; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Case-Control Studies; Cyclopropanes; Female; Fibrinogen; HIV Infections; Humans; Indinavir; Linear Models; Male; Nevirapine; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Alkynes; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

An efficient, isocratic high performance liquid chromatography (HPLC) method for determining human immunodeficiency virus (HIV) non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in plasma is advantageous for laboratories participating in clinical trials and therapeutic drug monitoring (TDM) programs, or conducting small animal research. The combination of isocratic reversed phase chromatography using an S-3, 3.0 mm x 150 mm column along with low plasma volume (200 microl), rapid liquid-liquid extraction, and detection at a single wavelength (212 nm) over a short run time makes this method valuable. Within and between assay variability ranges from 0.8 to 3.5% and 1.2-6.2%, respectively. Accuracy ranges from 91.0 to 112.8% for four quality controls (50, 100, 1000, and 10,000 ng/ml) for all drugs measured (efavirenz, nevirapine, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir).

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Pyridines; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Spectrophotometry, Ultraviolet; Sulfonamides

An accurate, sensitive and simple reverse-phase (RP) high-performance liquid chromatography (HPLC) assay has been developed and validated for the simultaneous quantitative determination of tipranavir with nine other antiretroviral drugs in plasma. A liquid-liquid extraction of the drugs in tert-butylmethylether (TBME) from 200 microL of plasma is followed by a reversed phase gradient HPLC assay with UV detection at 210 nm. The standard curve for the drug was linear in the range of 80-80,000 ng/mL for tipranavir; 10-10,000 ng/mL for nevirapine, indinavir, efavirenz, and saquinavir; and 25-10,000 ng/mL for amprenavir, atazanavir, ritonavir, lopinavir, and nelfinavir. The regression coefficient (r(2)) was greater than 0.998 for all analytes. This method has been fully validated and shown to be specific, accurate and precise. Due to an excellent extraction procedure giving good recovery and a clean baseline, this method is simple, rapid, accurate and provides excellent resolution and peak shape for all analytes. Thus this method is very suitable for therapeutic drug monitoring.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Stability; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Molecular Structure; Nelfinavir; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Pyrones; Reproducibility of Results; Ritonavir; Saquinavir; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Sulfonamides; Time Factors

Most antiretrovirals are metabolized in the liver, and lower dosing could be advisable in patients with severe liver insufficiency.. Plasma drug levels were measured in hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected patients receiving nevirapine (NVP), efavirenz (EFV), lopinavir/ritonavir (LPV/r), or atazanavir (ATV) with or without ritonavir. Liver fibrosis was measured using elastometry.. A total of 268 coinfected patients with compensated liver disease were analyzed. Mean plasma levels were 6.1 micro g/mL for NVP (35 patients), 2.8 micro g/mL for EFV (46 patients), 5.8 micro g/mL for LPV (56 patients), 0.4 micro g/mL for ATV (58 patients), and 0.7 micro g/mL for ATV/r (73 patients). Overall, drug levels were higher in patients with cirrhosis than in those without cirrhosis for EFV (median, 3.4 vs. 1.9 micro g/mL; P<.01) and NVP (median, 6.6 vs. 5.8 micro g/mL; P=.33). EFV plasma levels above the toxic threshold (>4 micro g/mL) were more frequent in patients with cirrhosis than in those without (31% vs. 3%; P<.001). The same trend was seen for NVP levels >8 micro g/mL (50% vs. 27%; P=.27). By contrast, plasma levels of protease inhibitors (PIs) did not differ significantly between patients with and those without cirrhosis.. Liver clearance of nonnucleoside reverse-transcriptase inhibitors, particularly EFV, is impaired in patients with cirrhosis. No similar effect is seen for PIs. Assessment of liver fibrosis by noninvasive tools may identify HCV/HIV-coinfected patients who might benefit from therapeutic drug monitoring to avoid drug overexposure.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Monitoring; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Lopinavir; Male; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Ritonavir; Severity of Illness Index

The effects of HIV infection, highly active antiretroviral therapy (HAART), and specific antiretroviral agents on lipoproteins in women are not well described.. In a cross-sectional substudy of the Women's Interagency HIV Study with 623 HIV-negative and 1556 HIV-positive women (636 untreated, 419 on non-protease inhibitor [PI] HAART, and 501 on PI-containing HAART), we performed multivariate analyses of associations among fasting lipoprotein levels, HIV infection, and HAART.. Untreated HIV-positive women had lower high-density lipoprotein cholesterol (HDL-C) and higher triglycerides (TGs) but not lower low-density lipoprotein cholesterol (LDL-C) than HIV-negative women and were the most likely to have unfavorable HDL-C by National Cholesterol Education Program (NCEP) guidelines. PI HAART users had higher LDL-C than untreated HIV-infected women (107 vs. 100 mg/dL, P = 0.0006) and were the most likely to have unfavorable LDL-C and TGs by NCEP guidelines. HIV-negative women and non-PI HAART users had similar HDL-C levels (55 and 53 mg/dL, respectively), which were higher than those in untreated HIV-infected women and PI HAART users (42 and 49 mg/dL, respectively; P < 0.001 for all). Lamivudine, didanosine, nevirapine, and efavirenz were independently associated with higher HDL-C (P < 0.001 for all). Ritonavir, indinavir/ritonavir, and nelfinavir were associated with higher LDL-C (P < 0.01 for all). Stavudine, abacavir, and all ritonavir-containing regimens were associated with higher TGs (P < 0.05 for all), and tenofovir was associated with lower TGs (P = 0.009).. A dyslipidemic pattern was associated with HIV infection itself, was more severe in users of PI-containing HAART, but was not present in women taking non-PI HAART.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Black People; Cholesterol; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Fasting; Female; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; HIV Seropositivity; HIV-1; Humans; Indinavir; Lamivudine; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Multivariate Analysis; Nelfinavir; Nevirapine; Organophosphonates; Ritonavir; Stavudine; Tenofovir; Triglycerides; United States; White People

A 38-year-old Caucasian woman with uncontrolled human immunodeficiency virus (HIV) infection was treated with highly active antiretroviral therapy (HAART) consisting of zidovudine, lamivudine, and nevirapine. Because her therapeutic response was inadequate, the HAART regimen was changed to abacavir, lamivudine, and lopinavir-ritonavir. Three months after this therapy was started, the patient developed progressive and notable hair loss. Her hair became fair and thin, and her appearance deteriorated considerably. Hair loss due to HAART was diagnosed. Lopinavir-ritonavir was stopped, and efavirenz was substituted; abacavir and lamivudine were continued. After 4 weeks, her hair growth substantially improved, as evidenced by rapid growth of new hair. Her general condition also improved. No relapse was observed with the new HAART regimen, and the patient's hair loss completely reversed in 8 weeks. Alopecia is a possible adverse event in HIV-infected patients treated with protease inhibitors, particularly indinavir. Our patient's severe and generalized alopecia was temporally related to the initiation and discontinuation of lopinavir-ritonavir. On the basis of the Naranjo adverse drug reaction probability scale, the adverse reaction was considered probable. Although generalized hair loss due to lopinavir-ritonavir is rare, clinicians should be aware of this potential adverse reaction of this widely used drug. If alopecia is severe or particularly distressing to the patient, the offending drug should be discontinued, and therapy with another HIV drug should be started.

Topics: Adult; Alkynes; Alopecia; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Probability; Pyrimidinones; Ritonavir

This open-label, crossover study investigated the pharmacokinetic interaction between TMC114 (darunavir [Prezista]), administered with low-dose ritonavir (TMC114/r) and efavirenz (EFV) in HIV-negative, healthy volunteers.. Volunteers received TMC114/r 300/100 mg twice daily for 6 days, and once daily on day 7 (session 1). After a 7-day washout period volunteers received EFV 600 mg once daily for 18 days (session 2), with coadministration of TMC114/r 300/100 mg twice daily from day 11-day 16 and TMC114/r once daily on day 17.. When coadministered with TMC114/r, plasma concentrations of EFV were slightly increased. In the presence of TMC114/r, EFV minimum (Cmin) and maximum (Cmax) plasma concentrations increased by 15-17%, and by 21% for EFV area under the curve (AUC24h). TMC114/r and EFV coadministration resulted in TMC114 Cmin, Cmax and AUC12h decreases of 31%, 15% and 13%, respectively. No serious adverse events (AEs) or AEs leading to withdrawal were reported in this trial. Overall, TMC114/r and EFV coadministration was well tolerated.. The clinical significance of the changes in AUC and Cmin seen with TMC114/r and EFV coadministration has not been established; this combination should be used with caution. Similar findings are expected with the approved TMC114/r 600/100 mg twice daily dose.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Darunavir; Drug Interactions; Drug Therapy, Combination; HIV Seronegativity; Humans; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Volunteers

To assess the presence of insulin resistance in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy.. Cross-sectional study in consecutive HIV-infected patients treated with regimens containing efavirenz, lopinavir/ritonavir or atazanavir. Insulin resistance was assessed by HOMA (Homeostasis Model Assessment).. We analyzed 47 patients, 18 on treatment with efavirenz, 17 with lopinavir/ritonavir and 12 with atazanavir. Patients treated with lopinavir/ritonavir had higher insulinemia than those treated with efavirenz (p = 0.007) or atazanavir (p = 0.020). The HOMA index was also higher in subjects treated with lopinavir/ritonavir than in those receiving efavirenz (p = 0.07) or atazanavir (p = 0.028). Insulin resistance was found in 5 (10.6%) patients, 4 among those receiving lopinavir/ritonavir, one among those treated with efavirenz and none among subjects receiving atazanavir (p = 0.065). In the logistic regression analysis, the antiretroviral regimen was associated with risk of insulin resistance.. A substantial number of patients on antiretroviral therapy may have insulin resistance according to the HOMA index. Alterations of the hydrocarbonated metabolism appear to be more likely to occur in patients receiving regimens with lopinavir/ritonavir.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cross-Sectional Studies; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Metabolic Syndrome; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Time Factors

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Urolithiasis

The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood.. Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively.. Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks).. Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each--to varying degrees--associated with various metabolic disturbances.

Topics: Adipose Tissue; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Body Composition; Body Fat Distribution; Body Mass Index; Cholesterol; Cholesterol, HDL; Cyclopropanes; Extremities; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Intra-Abdominal Fat; Male; Reverse Transcriptase Inhibitors; Ritonavir; Thailand; Triglycerides

We report on a Subsaharian patient with HIV infection and disseminated tuberculosis who developed acute, severe hypersensitivity reaction to efavirenz including acute renal failure in addition to liver and lung involvement, in the absence of skin changes or blood eosinophilia.

Topics: Acute Kidney Injury; Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Hypersensitivity; Ghana; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Mycobacterium tuberculosis; Organophosphonates; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Tuberculosis

To examine the effect of antiretroviral agents and clinical factors on the development of elevated blood pressure (BP).. Observational cohort study of patients initiating their first HAART regimen. We evaluated mean BP prior to HAART and while receiving HAART in relation to antiretroviral classes and individual agents, and demographic and clinical characteristics including change in body mass index (BMI) while on HAART. We used logistic regression analysis to examine factors associated with elevated BP [> or = 10 mmHg increase in systolic BP (SBP), diastolic BP (DBP) or new diagnosis of hypertension].. Among 444 patients who had 4592 BP readings, 95 patients developed elevated SBP (n = 83), elevated DBP (n = 33), or a new diagnosis of hypertension (n = 11) after initiating HAART. In multivariate analysis, patients on lopinavir/ritonavir had the highest risk of developing elevated BP [odds ratio (OR), 2.5; P = 0.03] compared with efavirenz-based regimens. When change in BMI was added to the model, increased BMI was significantly associated with elevated BP (OR, 1.3; P = 0.02), and the association between lopinavir/ritonavir and elevated BP was no longer present. Compared with lopinavir/ritonavir-based regimens, patients receiving atazanavir (OR, 0.2; P = 0.03), efavirenz (OR, 0.4; P = 0.02), nelfinavir (OR, 0.3; P = 0.02), or indinavir (OR, 0.3; P = 0.01) had significantly lower odds of developing elevated BP.. Treatment with lopinavir/ritonavir is significantly associated with elevated BP, an effect that appears to be mediated through an increase in BMI. Patients receiving atazanavir were least likely to develop elevated BP. The impact of antiretroviral medications on cardiovascular disease risk factors will increasingly influence treatment decisions.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Blood Pressure; Body Mass Index; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Protease Inhibitors; Humans; Hypertension; Indinavir; Longitudinal Studies; Lopinavir; Male; Middle Aged; Nelfinavir; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir

Topics: Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Oxazines; Ritonavir; Treatment Outcome; Tuberculosis, Pulmonary

The efficacy and safety of a combination regimen including either efavirenz or lopinavir-ritonavir was examined in a cohort of 65 patients positive for human immunodeficiency virus-1 (HIV-1). Both the efavirenz (n = 33, 18 anti-retroviral naive) and lopinavir-ritonavir (n = 32, 15 naive) regimens achieved significant changes from baseline CD4 cell counts and HIV RNA levels after 108 weeks (p < 0.01). Despite diminished immunological and virological parameters at study entry, the lopinavir-ritonavir group showed greater virological effects than the efavirenz group after 108 weeks (median change 3.3 log(10), interquartile range (IQR) 2.2-3.8 log(10) vs. 2.4 log(10), IQR 0.9-3.3 log(10), respectively, p 0.004). Use of lopinavir-ritonavir, in contrast to use of efavirenz, was associated with significant hypertriglyceridaemia.

Topics: Adult; Aged; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Male; Middle Aged; Oxazines; Pyrimidinones; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Triglycerides; Viral Load

Human immunodeficiency virus-infected patients on antiretroviral drug therapy frequently experience hepatotoxicity, the underlying mechanism of which is poorly understood. Hepatotoxicity from other compounds such as bosentan and troglitazone has been attributed, in part, to inhibition of hepatocyte bile acid excretion. This work tested the hypothesis that antiretroviral drugs modulate hepatic bile acid transport. Ritonavir (28 microM), saquinavir (15 microM), and efavirenz (32 microM) inhibited [(3)H]taurocholate transport in bile salt export pump expressing Sf9-derived membrane vesicles by 90, 71, and 33%, respectively. In sandwich-cultured human hepatocytes, the biliary excretion index (BEI) of [(3)H]taurocholate was maximally decreased 59% by ritonavir, 39% by saquinavir, and 20% by efavirenz. Likewise, in sandwich-cultured rat hepatocytes, the BEI of [(3)H]taurocholate was decreased 100% by ritonavir and 94% by saquinavir. Sodium-dependent and -independent initial uptake rates of [(3)H]taurocholate in suspended rat hepatocytes were significantly decreased by ritonavir, saquinavir, and efavirenz. [(3)H]Taurocholate transport by recombinant NTCP and Ntcp was inhibited by ritonavir (IC(50) = 2.1 and 6.4 microM in human and rat, respectively), saquinavir (IC(50) = 6.7 and 20 microM, respectively), and efavirenz (IC(50) = 43 and 97 microM, respectively). Nevirapine (75 microM) had no effect on bile acid transport in any model system. In conclusion, ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibited both the hepatic uptake and biliary excretion of taurocholate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkynes; Animals; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Benzoxazines; Biological Transport; Cells, Cultured; Child; Cyclopropanes; Hepatocytes; Humans; Male; Middle Aged; Nevirapine; Organic Anion Transporters; Organic Anion Transporters, Sodium-Dependent; Oxazines; Rats; Ritonavir; Saquinavir; Symporters; Taurocholic Acid

The influence of nevirapine, efavirenz and tenofovir co-administration on ritonavir-boosted atazanavir pharmacokinetics was investigated in HIV (human immunodeficiency virus)-infected patients.. A population pharmacokinetic analysis was performed in the context of therapeutic drug monitoring (87 patients, 121 samples).. A significant increase of atazanavir clearance (Cl/F) was found when either tenofovir (group B), efavirenz (group C), or nevirapine (group D) were co administered with atazanavir/ritonavir in comparison with patients treated with atazanavir/ritonavir and nucleoside reverse transcriptase inhibitors (group A): 6.24+/-0.36 l h(-1) (group A) versus 7.42+/-0.25 l h(-1) (group B) versus 9.60+/-0.27 l h(-1) (group C) versus 17.53+/-0.57 l h(-1) (group D) (P<0.001). However, the decrease of the mean trough plasma concentration of atazanavir was significant only in group D: 1.02+/-0.86 mg/l (group A) versus 0.21+/-013 mg/l (group D) (P<0.001).. The increase in atazanavir clearance when it is used in combination with nevirapine, efavirenz and/or tenofovir suggests that therapeutic drug monitoring of atazanavir should be performed in such circumstances.

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Interactions; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Male; Nevirapine; Oligopeptides; Organophosphonates; Oxazines; Pyridines; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir

Although efavirenz (EFV) and lopinavir/ ritonavir (LPV/r) are both recommended antiretroviral agents for combination therapy in drug-naive HIV-infected patients, no randomized comparison of their efficacy and tolerability is available yet. A multi-cohort prospective observational comparative study was performed.. Efficacy was examined comparing time to virological failure, CD4 recovery and clinical progression. Tolerability was examined comparing time to treatment discontinuation for any reason and for toxicity and time to liver enzymes or lipid alterations. Survival analysis was conducted by an intent-to-treat principle using the Kaplan-Meier method, and standard and weighted Cox regression models.. A total of 674 antiretroviral-naive patients starting a two nucleoside reverse transcriptase inhibitor regimen plus either EFV (n = 481) or LPV/r (n = 193) were examined. At baseline, patients starting LPV/r had higher HIV RNA and lower CD4+ T-cell counts. There was no difference in the adjusted hazards of virological failure (LPV/r versus EFV relative hazard [RH] 1.16, 95% confidence intervals [CI]: 0.58-2.32, P = 0.67), CD4 recovery (RH = 0.93, 95% CI: 0.66-1.30, P = 0.66), clinical progression (RH = 1.64, 95% CI: 0.70-3.84, P = 0.25), drug discontinuation for toxicity (RH = 0.92, 95% CI: 0.51-1.64, P = 0.76) and for any reason, and rates of liver enzyme and total/low density lipoprotein (LDL) cholesterol elevation. In contrast, the rate of triglycerides elevations (> 1 NCEP Adult Treatment Panel III category increase) was higher in the LPV/r group (RH = 1.69, 95% CI: 1.14-2.50; P = 0.01). Models weighted for the inverse of conditional probability of receiving either drug applied to the efficacy endpoints yielded similar results. CD4 recovery with both drugs was also similar in the lowest CD4 strata.. Our analysis suggests similar efficacy and tolerability for EFV- or LPV/r-based first-line antiretroviral regimens. LPV/r was associated with higher rates of hypertriglyceridaemia.

Topics: Adult; Aged; Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Disease Progression; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypertriglyceridemia; Italy; Lopinavir; Male; Middle Aged; Nucleosides; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Viral Load

Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.. Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.. Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.. ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Topics: Adult; Alkynes; Benzoxazines; Cohort Studies; Cyclopropanes; Female; Genetic Variation; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Male; Middle Aged; Nelfinavir; Orosomucoid; Oxazines; Phenotype; Pyrimidinones; Ritonavir; Switzerland

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

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Hepatitis; HIV Infections; Humans; Indinavir; Liver Function Tests; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Zidovudine

Several studies suggest that therapeutic drug monitoring of protease inhibitors and nonnucleoside reverse transcriptase inhibitors may contribute to the clinical outcome of HIV-infected patients. Because of the growing number of antiretroviral drugs and of drug combinations than can be administered to these patients, an accurate high-performance liquid chromatographic (HPLC) method allowing the simultaneous determination of these drugs may be useful. To date, the authors present the first simultaneous HPLC determination of the new protease inhibitor atazanavir with all the others currently in use (M8 nelfinavir metabolite included) and the 2 widely used nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. This simple HPLC method allows the analysis all these drugs at a single ultraviolet wavelength following a 1-step liquid-liquid extraction procedure. A 500-muL plasma sample was spiked with internal standard and subjected to liquid-liquid extraction using by diethyl ether at pH 10. HPLC was performed using a Symmetry Shield RP18 and gradient elution. All the drugs of interest and internal standard were detected with ultraviolet detection at 210 nm. Calibration curves were linear in the range 50-10,000 ng/mL. The observed concentrations of the quality controls at plasma concentrations ranging from 50 to 5000 ng/mL for these drugs showed that the overall accuracy varied from 92% to 104% and 92% to 106% for intraday and day-to-day analysis, respectively. No metabolites of the assayed compounds or other drugs commonly coadministered to HIV-positive patients were found to coelute with the drugs of interest or with the internal standard. This assay was developed for the purpose of therapeutic monitoring (TDM) in HIV-infected patients.

Topics: Alkynes; Atazanavir Sulfate; Benzoxazines; Calibration; Carbamates; Chromatography, Liquid; Cyclopropanes; Drug Stability; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oligopeptides; Oxazines; Pyridines; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Specimen Handling; Spectrophotometry, Ultraviolet; Sulfonamides

This retrospective longitudinal cohort study compared the virological and immunological responses to highly active antiretroviral therapy containing either efavirenz or lopinavir/ritonavir in previously antiretroviral-naive HIV-infected patients.. A total of 472 patients were selected (348 efavirenz and 124 lopinavir/ritonavir). The primary endpoint of this study was virological success (HIV RNA <50 copies/mL). The immunological response was assessed on the basis of either CD4+ T cell count variations (absolute and percentage) with respect to baseline values or categorical endpoints (defined as either a CD4+ T cell increase of > or =1;50 cells/mm(3) at week 24 or of > or =1;75 cells/mm(3) at week 48).. At intention-to-treat (ITT) analysis, the adjusted odds ratio of virological success for patients who started lopinavir/ritonavir, compared with those who started efavirenz, was 0.54 (95% CI: 0.33-0.89, P = 0.016) at week 24 and 0.40 (95% CI: 0.33-0.89, P = 0.002) at week 48. However, patients receiving lopinavir/ritonavir had a more pronounced CD4+ T cell recovery, demonstrating both a mean absolute and percentage increase up to week 48 (MANOVA P < 0.0001).. Although comparisons of drug efficacy in non-randomized studies should be viewed with caution, from a virological point of view efavirenz-containing regimens performed as well (on-treatment analysis) or better (ITT analysis) than those containing lopinavir/ritonavir. In contrast, immunological outcome appeared to favour lopinavir/ritonavir.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Seropositivity; Humans; Longitudinal Studies; Lopinavir; Male; Middle Aged; Oxazines; Pyrimidinones; Retrospective Studies; Ritonavir

We report a case of small cell lung cancer in a patient with human immunodeficiency virus (HIV) infection. The patient was a 51-year-old man diagnosed 8 years previously as seropositive for HIV, who was admitted to our hospital for re-evaluation of antiretroviral medications due to multidrug resistance. Chest radiograph revealed an abnormal hilar shadow subsequently confirmed to be small cell lung cancer. He received chemotherapy concurrently with highly active antiretroviral therapy (HAART), and lived for 14 months after the diagnosis. The prognosis of lung cancer in HIV-seropositive patients is very poor, and adverse effects of chemotherapy occur more frequently than in other patients. However, the simultaneous antiretroviral agents and combination chemotherapy was successful. Such treatment may be effective despite an otherwise poor prognosis, including HIV infection.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Benzoxazines; Camptothecin; Carbamates; Carboplatin; Carcinoma, Small Cell; Cisplatin; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Administration Schedule; Furans; HIV Infections; HIV Long-Term Survivors; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Oxazines; Ritonavir; Sulfonamides; Tomography, X-Ray Computed

Researchers reported on the benefits of once-daily tenofovir + FTC + efavirenz as initial therapy, described a needle-free injection system for T-20, and announced the impending availability of lopinavir/ritonavir in tablet formulation.

Topics: Alkynes; Anti-HIV Agents; Atenolol; Benzoxazines; Brazil; Congresses as Topic; Cyclopropanes; Deoxycytidine; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Oxazines; Pyrimidinones; Ritonavir

Topics: Adolescent; Alkynes; Anti-Retroviral Agents; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclopropanes; HIV Infections; Humans; Infant; Lamivudine; Lopinavir; Nevirapine; Oxazines; Pyrimidinones; Ritonavir; South Africa; Stavudine; Viral Load

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Drug Synergism; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Long-Term Care; Lopinavir; Organophosphonates; Oxazines; Pyrimidinones; Ritonavir; Tenofovir; Viral Load

Ninety-seven consecutive patients started anti-HIV therapy based on efavirenz (46) or lopinavir-ritonavir (51) in an observational study. Despite the significantly more compromised immunological-clinical baseline conditions of patients starting lopinavir-ritonavir, a mean clinical-laboratory follow-up of 17 months showed a comparable laboratory response and therapy interruption or change rate, although the toxicity profile of the two compounds proved significantly different. Randomized studies comparing these two recommended first-line treatments are warranted, particularly from a pharmacoeconomic viewpoint.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Antidepressive Agents, Second-Generation; Benzoxazines; Bupropion; Cyclopropanes; Drug Therapy, Combination; HIV Infections; Humans; Male; Middle Aged; Nelfinavir; Oxazines; Retrospective Studies; Ritonavir; Seizures

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Oxazines; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Viral Load; Viremia; Zidovudine

The increasing interest in applying therapeutic drug monitoring (TDM) to antiretroviral therapy is related to the observed interindividual variation in antiretroviral pharmacokinetics that results in a wide range of drug exposure from fixed-dosing regimens and the rapid evolution in the availability of phenotypic assays that generate a target 50% inhibitory concentration (e.g., IC(50)) as a basis for adjusting individual antiretroviral dosages. To facilitate the application of TDM, a method for the simultaneous determination of eight species has been developed. This method is used to quantitate efavirenz and the following protease inhibitors: amprenavir, indinavir, lopinavir, nelfinavir and its active metabolite (M8), ritonavir, and saquinavir. The method using reversed-phase high-performance liquid chromatography (RP-HPLC) was validated. Detection is effected using a photodiode-array detector (PDA) scanning at four different wavelengths. This method allows for detection of all analytes to a lower limit of quantitation of 0.1 to 0.2 microg/mL with an interday variation in CV ranging from 3.5% to 10.4%. The method is being applied to a TDM program that is currently being implemented in the authors' laboratory.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Furans; Heparin; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oxazines; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides

We developed a simple HPLC method for the simultaneous determination of lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) to evaluate the efficiency of co-administration of LPV/RTV and EFV in Japanese patients enrolled in a clinical study. The monitoring of LPV plasma concentration is important because co-administration of LPV/RTV with EFV sometimes decreases plasma concentrations of LPV caused by EFV activation of cytochrome P-450 3A. A solution of acetonitrile, methanol and tetramethylammonium perchlorate (TMAP) in dilute aqueous trifluoroacetic acid (TFA) has been used as the mobile phase in a HPLC method to elute LPV and RTV. We found that a solvent ratio of 45 : 5 : 50 (v/v/v) of acetonitrile/methanol/0.02 M TMAP in 0.2% TFA optimized separation of LPV, RTV and EFV. A column temperature of 30 degrees C was necessary for the reproducibility of the analyses. Standard curves were linear in the range 0.060 to 24.06 micro g/ml for LPV, 0.010 to 4.16 micro g/ml for RTV, and 0.047 to 37.44 micro g/ml for EFV. Coefficients of variation (CVs) of LPV, RTV and EFV in intraday and interday assays ranged from 1.5 to 4.0%, 2.5 to 16.8% and 1.0 to 7.7%, respectively. Accuracies ranged from 100 to 110%, 101 to 116% and 99 to 106% for LPV, RTV and EFV, respectively. The extraction recoveries were 77-87, 77-83 and 81-91% for LPV, RTV and EFV, respectively.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Monitoring; Humans; Lopinavir; Oxazines; Pyrimidinones; Reference Standards; Reproducibility of Results; Ritonavir; Sensitivity and Specificity

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Oxazines; Ritonavir; Thailand; Viral Load

Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady-state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV-infected Thai subjects who used this nucleoside-sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study.. At week 4 of the study, 12-hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV-infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed.. All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L. h) (95% confidence interval [CI], 39.8-52.5), 0.32 mg/L (95% CI, 0.24-0.44), and 11.1 mg/L (95% CI, 9.4-13.0), respectively. A >10-fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5-3.7) and 2.1 mg/L (95% CI, 1.6-2.6), respectively.. Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment-naive patients.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV-1; Humans; Indinavir; Male; Oxazines; Ritonavir

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load

Human immunodeficiency virus (HIV) protease inhibitors are prone to drug interactions with other agents. As individuals with HIV infection live longer, the clinical significance of many interactions is becoming recognized. A 51-year-old man with HIV infection who was receiving extended-release nifedipine developed symptomatic orthostasis and heart block after starting antiretroviral therapy that included nelfinavir. He experienced dizziness, fatigue, and hypotension and developed complete heart block with a junctional escape rhythm. Electrocardiogram abnormalities abated within 24 hours of discontinuing antiretroviral therapy. The patient developed orthostatic symptoms after restarting nelfinavir. He was switched successfully to an efavirenz-based regimen. Subsequent administration of antiretroviral therapy containing ritonavir and indinavir with extended-release nifedipine resulted in recurrence of his orthostatic symptoms. Discontinuation of atenolol, and nifedipine dosage reduction by 50% were effective in managing his orthostatic changes. Careful monitoring by clinicians is necessary when concomitant administration of HIV protease inhibitors are prescribed with other agents that are metabolized through the cytochrome P450 system.

Topics: Alkynes; Anti-HIV Agents; Antihypertensive Agents; Benzoxazines; Cyclopropanes; Delayed-Action Preparations; Drug Interactions; HIV Protease Inhibitors; Humans; Hypotension, Orthostatic; Male; Middle Aged; Nelfinavir; Nifedipine; Oxazines; Ritonavir

A sensitive and selective liquid chromatographic assay has been developed for the determination of the six currently protease inhibitors approved by the U.S. Food & Drug Administration (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) plus the M8 active metabolite of nelfinavir and the nonnucleoside reverse transcription inhibitor efavirenz in a single run. Pretreatment of 1-mL plasma sample spiked with internal standard was made by a solid-phase extraction procedure using a polymeric reversed-phase sorbent. Liquid chromatography was performed using a narrow-bore C18 reversed-phase column and gradient elution. Double ultraviolet detection at 265 nm (amprenavir) and at 210 nm (all other assayed drugs and internal standard) was used. Calibration curves were linear in the range 25 to 10,000 ng/mL, and the assay has been validated over the range 25 to 5,000 ng/mL. Average accuracies at four concentrations were in the range 92.4% to 103.0% and 94.4% to 103.0% for within-day and between-day, respectively, and the coefficients of variation were less than 8%. Mean absolute recoveries varied from 72.8% (ritonavir) to 93.7% (indinavir). No metabolite of the protease inhibitors was found to coelute with the drugs of interest or with the internal standard. At this time, among the tested drugs, especially all the currently licensed nucleosides and the other nonnucleoside reverse transcription inhibitor nevirapine that can be used in combination with the protease inhibitors, none was found to interfere with the assay.

Topics: Alkynes; Benzoxazines; Carbamates; Chromatography, Liquid; Cyclopropanes; Drug Monitoring; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oxazines; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides

A selective and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the determination of the six human immunodeficiency virus (HIV)-protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and the non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethyl ether, the six protease inhibitors and the two non-nucleoside reverse transcriptase inhibitors are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer 50 mmol/L pH 5.65. A sequential ultraviolet detection (5-minute sequence set at 240 nm for nevirapine acquisition, 22-minute sequence set at 215 nm for other antiretroviral drugs acquisition followed by a sequence set at 260 nm for internal standard acquisition) allowed for simultaneous quantitation of the six protease inhibitors, nevirapine, and efavirenz. Calibration curves were linear in the range 100 ng/mL to 10,000 ng/mL. The limit of quantitation was 50 ng/mL for all drugs except nevirapine (100 ng/mL). Average accuracy at four concentrations ranged from 88.2% to 110.9%. Both interday and intraday coefficients of variation were less than 11% for all drugs. The extraction recoveries were greater than 62%. This method is simple and shows a good specificity with respect to commonly co-prescribed drugs. This method allows accurate therapeutic monitoring of amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz, and nevirapine.

Topics: Alkynes; Benzoxazines; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Monitoring; Furans; HIV Infections; Humans; Indinavir; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides

Since antiretroviral drugs are known to inhibit many cytochrome P450 isoforms, the inhibition of CYP2B6 by non-nucleoside reverse transcriptase inhibitors and viral protease inhibitors was studied in vitro in human liver microsomes using bupropion hydroxylation as the CYP2B6 index reaction. Mean IC(50) values (microM) for inhibition of bupropion hydroxylation were: nelfinavir (2.5), ritonavir (2.2), and efavirenz (5.5). The reaction was only weakly inhibited by indinavir, saquinavir, amprenavir, delavirdine, and nevirapine. The inhibition of bupropion hydroxylation in vitro by nelfinavir, ritonavir, and efavirenz indicates inhibitory potency versus CYP2B6 and suggests the potential for clinical drug interactions.

Topics: Alkynes; Anti-HIV Agents; Antidepressive Agents, Second-Generation; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Bupropion; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; HIV Protease Inhibitors; Humans; Hydroxylation; Inhibitory Concentration 50; Microsomes, Liver; Nelfinavir; Oxazines; Oxidoreductases, N-Demethylating; Reverse Transcriptase Inhibitors; Ritonavir

Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Oxazines; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Triglycerides

An analytical technique using liquid chromatography (LC) coupled with electrospray-mass spectrometry (ESI--MS) has been developed for the simultaneous determination of five protease inhibitors (PIs): saquinavir, indinavir, ritonavir, nelfinavir, and amprenavir; and three non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, and efavirenz, in human plasma. This assay allows the elution and identification of these drugs in a single run (10 minutes) using a linear gradient with water and acetonitrile. The procedure involves liquid--liquid extraction. High-performance liquid chromatography (HPLC) separation was achieved on a C18 reversed-phase column, with a linear gradient elution followed by mass spectrometry detection. The calibration curves, obtained by automatic process peak area integration, show a good linearity in a range of concentrations between 20 and 10,000 ng/mL (40--10,000 ng/mL for efavirenz). The limit of detection was approximately 10 ng/mL for seven drugs (25 ng/mL for efavirenz). The coefficients of variation (CV) were always less than 15% for both intraday and interday precision for each compound. The recovery of the eight drugs ranged from 88.5% to 100%. This novel LC/ESI--MS assay provides an excellent method for simultaneous quantitative monitoring of different components of the highly active antiretroviral treatments (HAARTs) in patients treated simultaneously with PIs and NNRTIs, and it has been successfully applied to therapeutic drug monitoring and pharmacokinetic studies.

Topics: Alkynes; Benzoxazines; Carbamates; Chromatography, Liquid; Cyclopropanes; Delavirdine; Drug Monitoring; Furans; HIV Protease Inhibitors; Humans; Indinavir; Mass Spectrometry; Nelfinavir; Nevirapine; Oxazines; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sensitivity and Specificity; Sulfonamides

To compare the effectiveness of initial highly active antiretroviral therapy with either: a single protease inhibitor (PI); ritonavir (RTV)/saquinavir (SQV); or efavirenz (EFV) plus nucleoside reverse transcriptase inhibitors.. Cohort study.. Urban HIV clinic.. Five-hundred and forty-five HIV-1-infected individuals with minimal antiretroviral exposure who started combination therapy with > or = 3 antiretroviral drugs and > or = 1 NRTI to which they had not previously been exposed (single PI, 416; RTV/SQV, 68; EFV, 61).. HIV-1 RNA < 400 copies/ml within 8 months of starting therapy; time to HIV-1 RNA rebound to > 1000 copies/ml in the subset of patients achieving initial viral suppression; change in CD4 cell count from baseline within 12 months of starting therapy.. By intent-to-treat analysis, initial viral suppression was achieved by 72% of patients in the EFV group, compared to 49% in the single PI group (P = 0.001) and 51% in the RTV/SQV group (P = 0.019). Among patients who achieved initial viral suppression, time to viral rebound was similar in the three groups. Durable viral suppression (> or = 3 consecutive HIV-1 RNA levels < 400 copies/ml for > 6 months) was achieved by 53% of patients in the EFV group, 26% in the single PI group, and 29% in the RTV/SQV group (P < 0.05 for both comparisons with EFV). The median CD4 cell count increase was 139 x 10(6) cells/l, and was similar in the three groups.. In agreement with a recent clinical trial, use of initial EFV-based combination antiretroviral therapy was associated with higher rates of viral suppression than PI-based therapy in a clinical cohort.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Urban Population

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Clinical Trials as Topic; Cyclopropanes; Drug Resistance, Microbial; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Phenotype; Ritonavir; Saquinavir; Treatment Failure

As part of an on-going study on the suitability of a formal therapeutic drug monitoring (TDM) of antiviral drugs for improving the management of HIV infection, a high-performance liquid chromatography method has been developed to quantify simultaneously in plasma five HIV protease inhibitors (PIs) (i.e., indinavir, amprenavir, saquinavir, ritonavir, nelfinavir) and the novel non-nucleoside reverse transcriptase inhibitor efavirenz. After viral inactivation by heat (60 degrees C for 60 min), plasma (600 microl), with clozapine added as internal standard, is diluted 1:1 with phosphate buffer, pH 7 and subjected to a solid-phase extraction on a C18 cartridge. Matrix components are eliminated with 2 x 500 microl of a solution of 0.1% H3PO4 neutralised with NaOH to pH 7. PIs and efavirenz are eluted with 3 x 500 microl MeOH. The resulting eluate is evaporated under nitrogen at room temperature and is reconstituted in 100 microl 50% MeOH. A 40-microl volume is subjected to HPLC analysis onto a Nucleosil 100, 5 microm C18 AB column, using a gradient elution of MeCN and phosphate buffer adjusted to pH 5.15 and containing 0.02% sodium heptanesulfonate: 15:85 at 0 min-->30:70 at 2 min-->32:68 at 8 min-->42:58 at 18 min-->46:54 at 34 min, followed by column cleaning with MeCN-buffer, pH 5.15 (90:10), onto which 0.3% AcOH is added. Clozapine, indinavir, amprenavir, saquinavir, ritonavir, efavirenz and nelfinavir are detected by UV at 201 nm at a retention time of 8.2, 13.0, 16.3, 21.5, 26.5, 28.7 and 31.9 min, respectively. The total run time for a single analysis is 47 min, including the washing-out and reequilibration steps. The calibration curves are linear over the range 100-10,000 ng/ml. The absolute recovery of PIs/efavirenz is always higher than 88%. The method is precise with mean inter-day relative standard deviations within 2.5-9.8% and accurate (range of inter-day deviations -4.6 to +4.3%). The in vitro stability of plasma spiked with PIs/efavirenz at 750, 3000 and 9000 ng/ml has been studied at room temperature, -20 degrees C and +60 degrees C. The method has been validated and is currently applied to the monitoring of PIs and efavirenz in HIV patients. This HPLC assay may help clinicians confronted to questionable compliance, side effects or treatment failure in elucidating whether patients are exposed to adequate circulating drug levels. The availability of such an assay represents an essential step in elucidating the utility of a formal TDM for the opt

Topics: Alkynes; Benzoxazines; Calibration; Carbamates; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Stability; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Oxazines; Reproducibility of Results; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sulfonamides

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Drug Therapy, Combination; HIV Infections; Humans; Hypercholesterolemia; Hypertriglyceridemia; Indinavir; Middle Aged; Nausea; Oxazines; Ritonavir

Topics: Alkynes; Anti-HIV Agents; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Drug Therapy, Combination; Furans; HIV Infections; Humans; Oxazines; Oxidoreductases, N-Demethylating; Ritonavir; Sulfonamides

Topics: Alkynes; Anti-HIV Agents; Anticonvulsants; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamazepine; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Middle Aged; Mixed Function Oxygenases; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Seizures

Topics: Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Cyclopropanes; Drug Interactions; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Viral Load

Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Oxazines; Patient Selection; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Viral Load; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Therapy, Combination; Humans; Indinavir; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir; Stavudine

DuPont Merck opened an expanded access program for Sustiva (DMP 266). The program is open to AIDS patients with T-cell counts less than 50 who are failing other antiretroviral therapies. Little data exists on the safety of the drug and there are cross-resistance issues. Adefovir (Preveon) is available through Gilead's unlimited expanded access program for persons with T-cell counts below 50 and viral load greater than 30,000. Unlike Sustiva, an NNRTI, adefovir is a nucleotide analogue. Adefovir appears to be effective against several viruses; however, early reports suggest significant side effects, including kidney damage. Contact information is included for both programs.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir

Anti-HIV therapy research continues to show promising results and a research update is presented on the following antiviral topics: efavirenz (DMP 266, Sustiva), indinavir (Crixivan), indinavir plus ritonavir (Norvir), hard vs. soft gel saquinavir, nelfinavir (Viracept) cross-resistance, and T-20 (pentafuside). Tables present regimen results, including viral load drop and CD4 cell increases. Difficulties in preventing viral resistance are also discussed. Situations to avoid include using dosing schedules that do not sufficiently suppress the virus, waiting for viral load to return to pre-treatment levels before switching drugs, and not switching drugs to at least two new potent compounds when changing combination therapy. The challenge for patients who have failed previous drug therapies is to develop strategies that allow them to extend the effectiveness of their options long enough for at least two new potent drugs to become available.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dosage Forms; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Oxazines; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir