pyrimidinones and HIV-Infections

The combination of antiretroviral (ARV) therapies introduced at the end of the 1990s profoundly changed the natural history of human immunodeficiency virus (HIV) infection. Liver diseases are one of the three primary causes of 'non-AIDS-related' death in people living with HIV for three reasons: the high prevalence of hepatotropic viral co-infections, the hepatotoxicity of ARV drugs and new emerging liver diseases, including nodular regenerative hyperplasia and hepatitis E virus infection. The impact of HIV infection on the natural history of hepatitis C virus (HCV) or hepatitis B virus (HBV)/HIV co-infection has markedly changed in the past few decades with the progress made in ARV treatment and the improved definition of therapeutic strategies for HCV or HBV. Initially, HIV had a negative impact on hepatotropic infections. Today, HIV does not appear to significantly modify the natural history of HCV and HBV infection. This is associated with fair immune restoration, viral suppression associated with analogues having dual activity against HBV and HIV and with the increasing efficacy of antiviral treatments against HCV. A significant decline is expected in the morbidity and mortality associated with chronic liver infection in co-infected patients. Nevertheless, today, there are three major issues: (i) improving preventive measures including vaccination and risk reduction; (ii) screening patients infected with HBV or HCV and evaluating the impact of chronic infection on the liver and finally; (iii) early screening of hepatocellular carcinoma whose occurrence is higher and that evolves more rapidly in co-infected than in mono-infected patients.

Topics: Adenine; Antiviral Agents; Deoxycytidine; Disease Progression; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B; Hepatitis C; Hepatitis Viruses; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

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

Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M(2) protein or the enzyme neuraminidase. Combination therapy with Interferon-α and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti-human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M(2) inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.

Topics: Acyclovir; Adenine; Amantadine; Antiviral Agents; Comorbidity; Drug Therapy, Combination; Foscarnet; Ganciclovir; Guanine; Hepatitis; Hepatitis B, Chronic; Hepatitis C; Herpesviridae Infections; HIV Infections; Humans; Influenza, Human; Interferons; Lamivudine; Nucleosides; Oligopeptides; Organophosphonates; Oseltamivir; Proline; Protease Inhibitors; Pyrimidinones; Ribavirin; Telbivudine; Thymidine; Valacyclovir; Valganciclovir; Valine; Virus Replication; Zanamivir

Lopinavir/ritonavir (Kaletra®) is an orally administered coformulated ritonavir-boosted protease inhibitor (PI) comprising lopinavir and low-dose ritonavir. It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults, adolescents and children. Lopinavir/ritonavir is available as a tablet, soft-gel capsule and an oral solution for patients with difficulty swallowing. In well designed, randomized clinical trials, lopinavir/ritonavir, in combination with other antiretroviral therapies (ART), provided durable virological suppression and improved immunological outcomes in both ART-naive and -experienced adult patients with virological failure. Furthermore, lopinavir/ritonavir demonstrated a high barrier to the development of resistance in ART-naive patients. More limited data indicate that it is effective in reducing plasma HIV-1 RNA levels in paediatric patients. Lopinavir/ritonavir has served as a well established benchmark comparator for the noninferiority of other ritonavir-boosted PI regimens. Although generally well tolerated, lopinavir/ritonavir is associated with generally manageable adverse gastrointestinal side effects and hypertriglyceridaemia and hypercholesterolaemia, which may require coadministration of lipid-lowering agents to reduce the risk of coronary heart disease. Lopinavir/ritonavir, in combination with other ART agents, is a well established and cost-effective treatment for both ART-naive and -experienced patients with HIV-1 infection and, with successful management of adverse events, continues to have a role as an effective component of ART regimens for the control of HIV-1 infection.

Topics: Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Combinations; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir

Several national and international guidelines recommend the use of antiretroviral therapy containing a protease inhibitor (PI) with ritonavir (RTV) boosting for human immunodeficiency virus (HIV)-infected treatment-naïve patients. RTV-boosted PIs such as lopinavir (LPV/r), atazanavir (ATV + RTV), darunavir (DRV + RTV), fosamprenavir (FPV + RTV), and saquinavir (SQV + RTV) are usually recommended in regimens for initial therapy. The guideline recommendations are generally based on the clinical efficacy of the regimens. A broadened perspective of assessing the evidence related to selection of a PI for optimal first-line therapy might consider additional factors for evaluation, such as effectiveness in actual clinical practice and cost-effectiveness of individual drugs in formulating recommendations. Among the guideline-recommended PIs, LPV/r is one of the earliest PIs approved, has been a well-recognized boosted PI for treatment-naïve patients in all guidelines, and demonstrates the most evidence on long-term clinical and economic effectiveness. Studies have shown its efficacy in various controlled and real-world settings in different populations, the relationship of adherence to virologic efficacy, and the implications of resistance when used in sequence with other PI regimens. In the absence of published evidence for other guideline-recommended PIs that will greatly facilitate a fully transparent, comparative effectiveness evaluation, the cumulative evidence from this broader perspective indicates all PIs should not be viewed as equally safe and effective across all patients for initial therapy, nor should any single PI within the class be considered preferred for all treatment-naïve patients.

Topics: Drug Administration Schedule; Drug Combinations; Drug Synergism; Drug-Related Side Effects and Adverse Reactions; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Practice Guidelines as Topic; Pyrimidinones; Ritonavir

To assess the efficacy of ritonavir-boosted protease inhibitor monotherapy.. Systematic review of all protease inhibitor-monotherapy studies published in peer-reviewed journals or presented at conferences to date. Data of randomized controlled trials were pooled to yield common odds ratios.. Twenty-two protease inhibitor-monotherapy studies were identified. In the intent-to-treat analysis, 395 out of 582 (67.9%) patients had undetectable HIV-RNA at the end of follow-up. In the six randomized controlled trials (all lopinavir/ritonavir monotherapy), the risk of therapy failure was greater on monotherapy: 121 out of 364 (33.2%) patients on monotherapy against 64 out of 280 (22.9%) patients on HAART [pooled odds ratio 1.48 (95% confidence interval 1.02-2.13, P = 0.037)]. Regarding patients with successfully resuppressed HIV-RNA upon (re-)introducing nucleoside reverse transcriptase inhibitors (NRTIs) as nonfailures, the risk of therapy failure was comparable: 98 out of 364 (26.9%) against 64 out of 280 (22.9%) patients [odds ratio 1.05 (95% confidence interval 0.72-1.53, P = 0.81)].. The overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to HAART. The efficacy improves in patients started on monotherapy after suppressed HIV-RNA for at least 6 months. Ten percent of patients have viral rebound with HIV-RNA levels between 50 and 500 copies/ml. Possible explanations are lack of HIV suppression in particular cells or compartments, alternative resistance mechanisms, and nonadherence. Once proven that reintroduction of NRTIs, in patients with loss of viral suppression, is safe and effective, a broader use of simplification of HAART to protease inhibitor monotherapy might be justified. This review supports that the majority of patients with prolonged viral suppression on HAART can successfully be treated with protease inhibitor monotherapy. Arguments for this strategy are NRTI/NNRTI side effects, NRTI/NNRTI resistance, and costs.

Topics: Atazanavir Sulfate; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

To review the evidence on the clinical effectiveness and cost-effectiveness of non-occupational postexposure prophylaxis (PEP) for HIV.. Eleven electronic databases were searched from inception to December 2007.. Selected studies were assessed, subjected to data extraction using a standard template and quality assessment using published criteria. Studies were synthesised using a narrative approach with full tabulation of results from all included studies.. One clinical effectiveness study meeting the inclusion criteria was identified, a cohort study of PEP in a high-risk HIV-negative homosexual male cohort in Brazil. The quality of the study was generally weak. Seroincidence in the cohort as a whole (2.9 per 100 person-years) was very similar to that expected in this population (3.1 per 100 person-years, p > 0.97), despite the seroconversion to HIV being 1/68 in the PEP group and 10/132 in the group not receiving PEP. High-risk sexual activities declined over time for both PEP and non-PEP users. Four economic evaluations met the inclusion criteria of the review. The methodological quality of the studies was mixed. The studies are constrained by a lack of published data on the clinical effectiveness of PEP after non-occupational exposure, with effectiveness data derived from one study of occupational PEP. Their generalisability to the UK is not clear. Results suggest that PEP following non-occupational exposure to HIV was cost saving for men who have unprotected receptive anal intercourse with men, whether the source partner is known to be HIV positive or not; heterosexuals after unprotected receptive anal intercourse; and intravenous drug users sharing needles with a known HIV-positive person. PEP following non-occupational exposure to HIV was cost-effective for all male-male intercourse (unprotected receptive and insertive anal intercourse, unprotected receptive oral sex, and 'other') and was possibly cost-effective for intravenous drug users and high-risk women. Four additional studies were identified giving further information about adverse events associated with PEP after non-occupational exposure to HIV. The majority of participants experienced adverse events with the most common being nausea and fatigue. Rates were generally higher in participants receiving triple therapy than in participants receiving dual therapy. Completion of PEP therapy was variable, ranging from 24% to 78% of participants depending on type of therapy. Toxicity was the main reason for discontinuation of treatment.. It is not possible to draw conclusions on the clinical effectiveness of non-occupational PEP for HIV because of the limited evidence available. The review of cost-effectiveness suggests that non-occupational PEP may be cost-effective, especially in certain population subgroups; however, the assumptions made and data sources used in the cost-effectiveness studies mean that their results should be used with caution.

Topics: Anti-HIV Agents; Cost-Benefit Analysis; Databases, Bibliographic; Drug Combinations; Drug Therapy, Combination; HIV Infections; HIV Seropositivity; Humans; Lamivudine; Lopinavir; Premedication; Pyrimidinones; Ritonavir; Substance Abuse, Intravenous; Time Factors; Treatment Outcome; Unsafe Sex; Zidovudine

With the introduction of combination antiretroviral therapy (cART), there have been dramatic reductions in mortality and morbidity of HIV-1-infected patients. Protease inhibitor-based regimens remain a cornerstone of cART owing to their potency and high genetic barrier to resistance. The comparison of atazanavir/ritonavir in naive subjects in combination with tenofovir-emtricitabine versus lopinavir/ritonavir in combination with tenofovir-emtricitabine to assess safety and efficacy (CASTLE) study is a noninferiority trial in which the efficacy, safety and tolerability of atazanavir-ritonavir and lopinavir-ritonavir were compared in antiretroviral therapy-naive patients. The aim of this paper is to review the CASTLE study and the role of atazanavir-ritonavir as an initial treatment in HIV-1-infected patients.

Topics: Adenine; Anti-HIV Agents; Atazanavir Sulfate; Clinical Trials, Phase III as Topic; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Lopinavir; Multicenter Studies as Topic; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Tenofovir; Treatment Outcome

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease formulated with ritonavir. Numerous clinical trials have shown that lopinavir/ritonavir (LPV/r) is highly effective as a component of highly active antiretroviral therapy (HAART) regimens for HIV-1 infection.. In this article we provide an overview of the properties of LPV/r and the experience with its use in HIV-infected adults and adolescents.. We reviewed the literature and selected the most important published articles on LPV/r and the latest posters/communications presented in conferences, with particular attention to the clinical efficacy and tolerability of LPV/r in HIV-1 infected patients.. LPV/r is highly effective as a component of HAART regimens for HIV-1 infection. There is considerable experience with the drug in both treatment-naive and treatment-experienced patients. In general, LPV/r is well tolerated and its high genetic barrier to resistance favours long-term efficacy.

Topics: Antiretroviral Therapy, Highly Active; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Patient Compliance; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir

Chronic hepatitis B virus infection affects approximately 10% of HIV-infected patients. There are an estimated 4 million patients with HIV/HBV coinfection. HIV infection has a deleterious effect on the natural history of chronic hepatitis B and increases the risk of progression to cirrhosis and terminal liver disease. Since the widespread use of highly active antiviral therapy (HAART), liver disease has emerged as one of the main causes of morbidity and mortality in HIV-positive patients. Therefore, all patients with HIV/HBV coinfection should be evaluated for treatment of hepatitis B, independently of the CD4 lymphocyte count. Six drugs are currently authorized for the treatment of chronic hepatitis B: standard interferon-alpha (2a and 2b), pegylated interferon alpha-2a, lamivudine, adefovir, entecavir and telbivudine. Other drugs with activity against HBV, such as tenofovir and emtricitabine, are used for the treatment of HIV infection. In patients not requiring HAART, treatment of hepatitis B should preferably consist of drugs without activity against HIV, such as pegylated interferon or adefovir. In contrast, in patients requiring HAART, a combination of drugs with activity against both viruses should be used, such as lamivudine, emtricitabine and tenofovir, with the aim of achieving maximal viral suppression and avoiding the development of resistance. Patients with HIV/HBV coinfection require periodic clinical and virological monitoring. Patients with cirrhosis should undergo ultrasonography and alphafetoprotein determination every 6 months for the early detection of hepatocellular carcinoma.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Comorbidity; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B; Hepatitis B Vaccines; Hepatitis B virus; HIV; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Virus Replication

Darunavir, previously known as TMC-114, is a new protease inhibitor (PI) with a high affinity for the HIV-1 protease and strong ability to inhibit its action, even in mutated forms. Consequently, this drug is considered to have great intrinsic potency and a high genetic barrier. At the time of writing, data on the tolerability and safety of darunavir come mainly from studies of late rescue therapy (POWER, DUET), which have included more than 1,600 patients. Recent data, relating to shorter time periods, are also available from studies in early treatment-experienced patients (TITAN) and in treatment-naïve patients (ARTEMIS), increasing experience to a further 600 patients. Lastly, more than 4,000 patients who have received darunavir through the Expanded Access Program have allowed the drug's generally good safety and tolerability profile to be defined. In the studies performed to date, darunavir has been well tolerated, with a better profile than that of the PIs used in control groups in terms of adverse effects such as diarrhea, gastrointestinal tolerability and lipid alterations. Moreover, to date, no unexpected severe adverse effects have been reported.

Topics: Adult; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Darunavir; Drug Therapy, Combination; Dyslipidemias; Female; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Lopinavir; Male; Multicenter Studies as Topic; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Salvage Therapy; Sulfonamides

The resistance profile of darunavir (DRV) was initially explored using pooled week 24 data from POWER 1, 2, and 3 at the recommended dose of DRV (n=467) with the subsequent addition of data from the placebo arm without etravirine (ETR) of DUET 1 and 2 (n=604). The two strongest predictors of virological response were firstly baseline phenotype expressed as the darunavir fold change in 50% effective concentration (EC(50)), with phenotypic clinical cut-offs of 10 and 40 being established for diminished response and loss of response, respectively, and secondly, the DRV score 2006 of 11 mutations in 10 positions: V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V, recently revised (DRV score 2007) with removal of G73S and addition of T74P. The presence of three or more mutations was associated with a diminished virological response in both the 2006 and 2007 lists but slightly better prediction was observed with the 2007 list. Each of the above-mentioned mutations was associated with a mean of at least 10 mutations of the International AIDS Society's (IAS) list. Moreover, good genophenotypic correlation was found, corroborating a progressive reduction in fold change with the progressive accumulation of mutations from both lists. In multiresistant patients in the POWER and DUET studies, the most commonly selected mutations upon DRV failure were those in the DRV score, especially V32I and I54L. Similar mutations were selected by patients from TITAN, who showed a much lower level of resistance; however, these mutations were selected much less frequently in the few virological failures described. Furthermore, virological failure and mutations were much less frequent in the DRV arm than in the lopinavir arm. Lastly, no protease mutations were found upon DRV failure in treatment-naive patients in the ARTEMIS study, an effect already known in enhanced proteases.

Topics: Adult; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Darunavir; Dose-Response Relationship, Drug; Drug Resistance, Viral; Female; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Lopinavir; Male; Multicenter Studies as Topic; Mutagenesis, Site-Directed; Mutation, Missense; Nitriles; Phenotype; Point Mutation; Pyridazines; Pyrimidines; Pyrimidinones; Randomized Controlled Trials as Topic; Sulfonamides

The development of antiretroviral therapy (ART) with current triple drug combinations has dramatically reduced morbidity and mortality in HIV-infected patients. However, there is a need for less toxic treatments without sacrificing efficacy, as well as for less expensive drugs to facilitate universal access to this therapy. The protease inhibitors (PI) administered with ritonavir have a favorable pharmacokinetic profile and high genetic barrier and consequently are ideal candidates for use in monotherapy, thus avoiding the toxicity and cost associated with nucleoside analogs, as well as preserving drugs for future options. The promising results of studies performed with lopinavir/ritonavir (LPV/r) in induction-maintenance regimens in patients without prior failure to PIs encourage research into the cost-effectiveness of LPV/r in monotherapy from the beginning of ART. The few studies performed in this context seem to indicate the following: a) LPV/r monotherapy achieves undetectable viral loads in a large proportion of treatment-naïve patients, b) future treatment options are not compromised in patients not achieving undetectable viral loads since the likelihood of resistance mutations is low and treatment intensification achieves suppression of viral replication, and c) strategies for early detection can probably be considered in patients who will not achieve complete suppression with LPV/r monotherapy. Nevertheless, before LPV/r monotherapy can be considered a first-line option, new studies with larger samples and longer follow-up are required. These studies should pay particular attention to viral replication in areas where PI show less penetration.

Topics: Clinical Trials as Topic; Cost-Benefit Analysis; Drug Combinations; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Treatment Outcome; Viral Load; Virus Replication

Simplification of triple antiretroviral therapy to lopinavir/ritonavir (LPV/r) monotherapy in patients with well-controlled viremia for prolonged periods (more than 6 months) without prior failure with a protease inhibitor has been proposed as a strategy that could reduce the toxicity and costs of antiretroviral therapy in the long term while also preserving other therapeutic options. The results of several studies are currently available, some of which had a large number of patients and follow-up of up to 4 years. These studies indicate that this strategy is safe and efficacious, thus allowing its clinical use when indicated. This strategy may be especially useful in reducing the costs of treatment in countries with scarce economic resources. The role of LPV/r monotherapy in the prevention and management of lipodystrophy and in improving the selection of patients with an optimal risk-benefit ratio remains to be defined.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Cost Control; Developing Countries; Drug Combinations; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Multicenter Studies as Topic; Pilot Projects; Prospective Studies; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Treatment Outcome; Viral Load; Viremia; Virus Replication

Monotherapy with LPV/r maintains blocked viral replication when used as a simplification strategy from antiretroviral therapy with a boosted protease inhibitor and two nucleoside analogs in patients with an undetectable viral load for at least 6 months. This simplification strategy can be recommended to patients in these circumstances and who are able to maintain near perfect adherence. As recommended by the GESIDA guidelines, LPV/r monotherapy could be offered to patients with undetectable viral loads but who show symptoms or laboratory abnormalities attributable to nucleoside analog toxicity, or co-morbidities such as liver disease or nephropathy; LPV/r monotherapy could also be offered to patients who simply wish to take a lower number of pills. This strategy reduces treatment toxicity and costs, without jeopardizing the patient's future.

Topics: Clinical Trials as Topic; Cost-Benefit Analysis; Drug Combinations; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Mitochondria; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Treatment Outcome; Viral Load; Virus Replication

Although guidelines for the treatment of HIV-infected patients recommend triple drug antiretroviral therapy, because of the toxicity of these regimens, the complexity of treatment and its costs, other therapeutic options are desirable. Several clinical trials have shown that lopinavir/ritonavir (LPV/r) as a simplification strategy in antiretroviral therapy in HIV-infected patients who maintain suppression of viral replication while receiving conventional treatment regimens is safe and is associated with less toxicity than that due to prolonged exposure to protease inhibitors and nucleoside analogs. The present review summarizes the main results of the various retrospective studies on LPV/r as a simplification strategy of antiretroviral therapy in daily clinical practice.

Topics: Antiretroviral Therapy, Highly Active; Drug Combinations; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Lopinavir; Practice Guidelines as Topic; Pyrimidinones; Retrospective Studies; Ritonavir; Treatment Outcome; Viral Load; Virus Replication

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

Nine clinical trials have analyzed whether the use of lopinavir-ritonavir (LPV/r) monotherapy could be a valid alternative to triple antiretroviral therapy. Four of these clinical trials included an analysis of risk factors for virological failure. The MONARK study evaluated monotherapy in treatment-naïve patients. The M03-613 trial evaluated monotherapy after a period of induction therapy with triple combination antiretroviral therapy. The study by Sprinz et al and the OK studies evaluated monotherapy as maintenance of virological suppression. The efficacy of monotherapy varied according to the scenario. In the scenario of induction-maintenance, the factors related to virological failure were suboptimal adherence and low baseline CD4 counts. In the scenario of maintenance, the factors related to virological failure were suboptimal adherence, nadir CD4 count and low hemoglobin. In treatment-naive patients, the risk of virological failure increased in patients who did not achieve a viral load of less than 400 copies/ml 4 weeks after initiating treatment and in those infected with non-B subtypes (a factor that was probably also related to suboptimal adherence).

Topics: Anemia; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Combinations; Hemoglobins; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Multicenter Studies as Topic; Patient Compliance; Pilot Projects; Prospective Studies; Pyrimidinones; Randomized Controlled Trials as Topic; Risk Factors; Ritonavir; Treatment Outcome; Viral Load

Treatment with lopinavir/ritonavir (LPV/r) monotherapy has been shown to be an effective alternative, especially in the maintenance of patients previously treated with combination therapy and prolonged virological suppression. LPV/r monotherapy is associated with a greater number of low-level viremia episodes than combination therapy, without resistance mutations being detected in the majority of patients. The incidence of the development of major resistance mutations in the OK pilot and OK04 studies was very low: 0.51 per 100 patients-year, and was mainly related to mutations in positions 46, 54 and 82, which have not compromised other therapeutic options. The contribution of low-level resistance mutations to loss of virological control seems small, and no different from that observed in combination therapy. However, this phenomenon should be studied in larger, long-term trials.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Combinations; Drug Resistance, Multiple, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Incidence; Lopinavir; Mutation, Missense; Pilot Projects; Point Mutation; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Viremia

The present article briefly reviews the main types of pharmacoeconomic analyses that evaluate the costs associated with HIV infection and the efficiency of antiretroviral therapy in general. The results of several pharmacoeconomic analyses applied to the selection of antiretroviral drugs in distinct clinical scenarios are also presented. Finally, we analyze the advantages, in terms of efficiency, of lopinavir/ritonavir as induction-maintenance therapy, both in terms of saving the direct costs of treatment and in possibly reducing the costs due to the management of the adverse effects of nucleoside analogs.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Cost Control; Cost-Benefit Analysis; Direct Service Costs; Drug Combinations; Drug Costs; Drug-Related Side Effects and Adverse Reactions; European Union; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Prescription Fees; Pyrimidinones; Ritonavir; Treatment Outcome

Maintenance monotherapy with lopinavir/ritonavir (LPV/r) is a safe and effective strategy in the short and medium term. To evaluate its effectiveness in the long term, the question of whether a theoretical decrease in the potency of treatment could reduce suppression of viral replication in reservoirs or in biological compartments where LPV/r penetration is lower must be answered. LPV/r penetrates fairly well in the most impenetrable reservoir, the central nervous system. However, the ability to penetrate reservoirs is not essential to achieve efficacy, since the main battlefield in the fight against HIV is the plasma compartment. What can be achieved in this compartment with antiretroviral therapy can be faithfully extrapolated to cerebrospinal fluid and almost always to seminal fluid. What occurs in lymphoid tissue and in intestinal mucosa, whose physiopathology is intensely initiated at the beginning of the disease, is more obscure and difficult to interpret. The marginal problems that might be generated by some reservoirs that harbor HIV and are relatively impermeable to LPV/r would be of little importance in simplification therapy, which is only offered as maintenance monotherapy with LPV/r to clinically stable patients with good immunological and virological control.

Topics: Anti-HIV Agents; Drug Combinations; Female; Genitalia, Male; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Lymphocytes; Lymphoid Tissue; Male; Organ Specificity; Pyrimidinones; Ritonavir; Tissue Distribution; Virus Replication

Lopinavir is a protease inhibitor (PI) for the treatment of HIV infection that was specifically designed to overcome the shortcomings of earlier agents in this class. It is the only PI coformulated with ritonavir, whose pharmacological boosting effect results in a highly potent, well-tolerated, clinically effective antiretroviral agent with a high genetic barrier to resistance. Lopinavir/ritonavir is a recommended first-line option for antiretroviral-naive patients initiating PI-based therapy, and has an equally important role in the management of treatment-experienced individuals. Its favorable pharmacological and clinical characteristics have recently prompted investigators to explore its potential novel applications in HIV monotherapy and double-boosted regimens.

Topics: Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir

Recommendations for a highly active antiretroviral therapy in either pretreated patients or symptomatic patients with an AIDS-defining event include at least one protease inhibitor. The majority of currently available protease inhibitors are coadministrated with low-dose ritonavir, a pharmacoenhancer that significantly increases protease inhibitor plasma concentrations. In the class of protease inhibitors lopinavir plus ritonavir is the only coformulation. This coformulation was designed to overcome the problems of earlier agents of this class of drugs concerning unfavorable pharmacokinetics with a higher frequency of dosing and therapy failure. The pharmacoenhancing effect of ritonavir on lopinavir resulted in a highly potent, clinically effective antiretroviral drug with a high genetic barrier to viral resistance. Safety concerns have taken a backseat, focusing instead on the favorable efficacy of lopinavir, which recently led to the evaluation of its use in boosted double-protease-inhibitor regimens, as a once-daily application and even in HIV monotherapy. Nevertheless, since HIV infection became a chronic but controllable disease, side effects like metabolic disorders and cardiovascular disease have begun to draw increased attention in the long-term treatment with protease inhibitors. Coformulated lopinavir/ritonavir is available as a soft gelatin capsule (133.33/33.33 mg), liquid formulation (80/20 mg/ml) and recently approved melt-extrusion tablet (200/50 mg). Lopinavir/ritonavir is recommended for first- and second-line therapy in HIV-1 infection, in children as well as adolescents and adults.

Topics: Animals; Drug Combinations; Drug Evaluation, Preclinical; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir

Despite the unprecedented pace of development of drugs for the treatment of a viral disease and the unquestionable efficacy of antiretroviral therapy, there is a need for less toxic and cheaper regimens that could simplify the treatment of HIV infection without sacrificing efficacy. The favorable pharmacokinetic profile and the high genetic barrier of boosted protease inhibitors make them ideal candidates for use as monotherapy. Given the encouraging results of available studies on lopinavir/ritonavir monotherapy in patients with no prior failure with protease inhibitors, it may be warranted to conduct trials to investigate the cost-effectiveness of lopinavir/ritonavir monotherapy as second-line therapy in resource-constrained settings where virologic monitoring is not feasible. In addition, larger trials with longer follow up, with particular attention to the potential consequences of viral replication in sites where the penetration of protease inhibitors may be poor, are needed before this strategy can be considered for routine use.

Topics: Drug Combinations; Drug Resistance, Multiple, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

Inhibition of viral assembly (protease inhibitors) and of fusion of viral and target membranes (fusion inhibitors) are general approaches to antiviral treatment, not specific for HIV. Nonetheless, the agents that induce these phenomena are most often specific for a given virus or virus family. Drugs developed for HIV treatment were reevaluated for use against severe acute respiratory syndrome-coronavirus (SARS-CoV) during and after the epidemic in 2003, in view of the absence of any other available treatment. Of the protease and entry inhibitors approved for treating HIV-infected patients, none was effective against SARS-CoV, although in vitro activity against this virus was reported for the protease inhibitor lopinavir/ritonavir, in results that have not been confirmed in the most recent studies. The epidemiologic methods used to assess this drug's efficacy are not robust. Preliminary results for SARS treatment with protease and entry inhibitors, although at early stages of development, are promising.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Clinical Trials as Topic; Cohort Studies; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Protease Inhibitors; Pyrimidinones; Ribavirin; Ritonavir; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Viral Fusion Proteins

Coformulated lopinavir/ritonavir (Kaletra) is a boosted protease inhibitor (PI) containing lopinavir and low-dose ritonavir. It is approved for use in combination with other antiretroviral drugs for the treatment of HIV infection in adults, adolescents and children aged >or=6 months (in the US) or >or=2 years (in the EU).Lopinavir/ritonavir-based antiretroviral therapy (ART) is generally well tolerated and has shown durable virological efficacy in clinical trials in ART-naive and -experienced patients with virological failure. Lopinavir/ritonavir is one of the preferred PIs for first-line treatment of HIV infection in adults, adolescents and children, according to US and British guidelines, reflecting its comparatively better virological efficacy than nelfinavir and low incidence of de novo resistance during long-term treatment. Lopinavir/ritonavir-based treatment may produce a more effective virological response than other PI-based regimens in single PI-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients. In PI- and NNRTI-experienced patients, atazanavir/saquinavir was inferior to lopinavir/ritonavir; further well designed trials are required to determine the comparative efficacy of lopinavir/ritonavir versus other PIs such as ritonavir-boosted atazanavir, or fosamprenavir or tipranavir in these patients. Lopinavir/ritonavir is more likely than atazanavir (alone or boosted) or nelfinavir to cause hypertriglyceridaemia and is associated with a higher incidence of hypercholesterolaemia than atazanavir (alone or boosted). The new lopinavir/ritonavir tablet coformulation offers a reduced pill count and lack of food interaction, and ART-naive patients in the US and Canada, who are not receiving efavirenz, nelfinavir, nevirapine or amprenavir, may benefit from convenient once-daily administration of lopinavir/ritonavir. Thus, lopinavir/ritonavir is a convenient, effective option for use in the treatment of HIV infection in ART-naive and -experienced adults, adolescents and children.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

In the current era of HIV treatment, the toxicity profiles of antiretroviral drugs have increasingly emerged as a basis for selecting initial antiretroviral regimens as well as a reason for switching therapy in treatment-experienced patients. In this respect, an intensive research effort involving clinical research as well as basic science research over the past six years, has focused on the cluster of metabolic and body composition abnormalities that have come to be termed the 'lipodystrophy syndrome'. These data have now provided a clear and clinically relevant understanding of the individual profiles of drugs within the nucleoside analogue reverse transcriptase inhibitor , HIV protease inhibitor and non-nucleoside analogue reverse transcriptase inhibitor drug classes, and have provided a rational basis for assessing and monitoring these adverse effects in clinical practice. In this review, current and emerging drug toxicities are considered with an emphasis on lipodystrophy complications.

Topics: Adenine; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cardiovascular Diseases; Cyclopropanes; Drug Monitoring; Drug Therapy, Combination; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Kidney Diseases; Lopinavir; Metabolic Syndrome; Nevirapine; Organophosphonates; Oxazines; Pyrimidinones; Risk Factors; Tenofovir

Kaletra, a fixed-dose co-formulation of lopinavir/ritonavir, was the first boosted protease inhibitor developed for the treatment of HIV-infection. In September 2000, the US FDA granted Kaletra fast-track approval as data showed a higher efficacy in the treatment of HIV-infection than standard protease inhibitors of that time. Although potency was of major concern in the early years of highly active antiretroviral therapy (HAART), presently, with the perspective of HIV-infection becoming a chronic but well controllable disease, other issues begin to draw increased attention in the long-term management of HIV-infected patients. Among general health issues such as cardiovascular disease, metabolic disorders or hepatitis co-infection, the long-term toxicity and safety of HAART is an important concern when choosing antiretroviral drugs for each individual patient. In this review, the authors report on the safety of lopinavir/ritonavir in the treatment of HIV-infected patients, and focus on special patient groups and relevant safety issues.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Approval; Drug Interactions; HIV Infections; Humans; Lopinavir; Pyrimidinones; Safety

Protease inhibitor-based antiretroviral therapy has been shown to decrease the morbidity and mortality associated with human immunodeficiency virus type 1 (HIV-1) infection. However, many of the available agents in this class suffer shortcomings, including poor tolerability, difficult dosing regimens, and variable drug concentrations which may lead to generation of viral resistance. Lopinavir/ritonavir (Kaletra) has been designed specifically to address some of these shortcomings. Excellent therapeutic efficacy has been documented for lopinavir/ritonavir in multiple clinical trials in both antiretroviral-naive and -experienced patients. Development of resistance is a rare event in persons initiating therapy with lopinavir/ritonavir as their first protease inhibitor. The main side effects associated with lopinavir/ritonavir are gastrointestinal disturbances and elevations of serum lipids. Current antiretroviral therapy guidelines list lopinavir/ritonavir as the consensus first-line protease inhibitor recommended in the initial therapeutic regimen in persons infected with HIV-1.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir

The importance of combination antiretroviral therapy in HIV-infection has been well established. However, many available agents suffer shortcomings that limit their clinical value, including adverse effects, difficult dosing requirements and rapid development of resistance. Lopinavir/ritonavir (Kaletra) is a member of the protease inhibitor class, specifically designed to address some of these deficits. The drug is a coformulation of lopinavir with low-dose ritonavir, exploiting a favourable drug-drug interaction between the two that yields sustained increases in plasma levels of lopinavir. In large-scale clinical trials, lopinavir/ritonavir has demonstrated superior therapeutic efficacy when compared with other protease inhibitors. It exerts potent antiviral activity in both treatment-naive and experienced patients with an acceptable incidence of adverse effects. De novo development of resistance has not been described in large clinical trials with patients naive to antiretroviral therapy. Lopinavir/ritonavir has recently been approved for once-daily dosing in antiretroviral-naive patients.

Topics: Administration, Oral; CD4 Lymphocyte Count; Contraindications; Cytochrome P-450 CYP3A Inhibitors; Dosage Forms; Drug Approval; Drug Combinations; Drug Interactions; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Darunavir; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy; Sulfonamides

There are currently (July, 2002) six protease inhibitors approved for the treatment of HIV infection, each of which can be classified as peptidomimetic in structure. These agents, when used in combination with other antiretroviral agents, produce a sustained decrease in viral load, often to levels below the limits of quantifiable detection, and a significant reconstitution of the immune system. Therapeutic regimens containing one or more HIV protease inhibitors thus provide a highly effective method for disease management. The important role of protease inhibitors in HIV therapy, combined with numerous challenges remaining in HIV treatment, have resulted in a continued effort both to optimize regimens using the existing agents and to identify new protease inhibitors that may provide unique properties. This review will provide an overview of the discovery and clinical trials of the currently approved HIV protease inhibitors, followed by an examination of important aspects of therapy, such as pharmacokinetic enhancement, resistance and side effects. A description of new peptidomimetic compounds currently being investigated in the clinic and in preclinical discovery will follow.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Dipeptides; Furans; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Models, Molecular; Molecular Mimicry; Molecular Structure; Nelfinavir; Oligopeptides; Organophosphates; Peptides; Phenylbutyrates; Pyridines; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides; Urethane

Topics: Administration, Inhalation; Adult; Androstadienes; Antiviral Agents; Asthma; Biological Availability; Cushing Syndrome; Cytochrome P-450 Enzyme Inhibitors; Drug Therapy, Combination; Fluticasone; Glucocorticoids; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

Topics: Carbamates; Drug Resistance, Viral; Furans; Genetic Linkage; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Phenotype; Pyrimidinones; Sulfonamides

Topics: Atazanavir Sulfate; Drug Administration Schedule; HIV Infections; Humans; Indinavir; Lopinavir; Oligopeptides; Protease Inhibitors; Pyridines; Pyrimidinones; Randomized Controlled Trials as Topic; Saquinavir

As the HIV pandemic enters its third decade, more sophisticated and efficacious therapies are continually being developed. This article provides an in-depth review of the first coformulated boosted protease inhibitor available on the world market, lopinavir/ritonavir (Kaletra). Included in this review is an overview of the current market place, the chemistry, pharmacokinetics, clinical efficacy and side-effect profile of lopinavir/ritonavir. In addition, an expert opinion and commentary on the clinical applications of this drug is provided.

Topics: Adult; Animals; Anti-Retroviral Agents; HIV Infections; Humans; Lopinavir; Pyrimidinones

Sam Jin is investigating SJ-3366, a non-nucleoside reverse transcriptase inhibitor (NNRTI), for the potential treatment of HIV infection [302450]. As well as acting as an NNRTI, SJ-3366 also interferes with HIV-1 entry via an intermediate target formed after virus-cell attachment [341146], [363900]. As of June 1998, Sam Jin had been awarded a patent for SJ-3366 in South Africa, with applications pending in 22 other countries [302450].

Topics: HIV Infections; HIV Reverse Transcriptase; Humans; Patents as Topic; Pyrimidinones; Reverse Transcriptase Inhibitors

Despite major advances in HIV research, eradication of HIV from the body is not yet possible. However, current antiretroviral (ARV) therapy can achieve disease control via viral suppression below the limits of detection of currently available assays. This has led to a marked decline in morbidity and mortality associated with the development of opportunistic infections and malignancies. Since viral suppression appears to be the most achievable goal of current therapy, there arises a need for new and more potent ARV agents in order to maintain viral suppression. Many of the currently available protease inhibitors (PIs) have a high protein-binding ability, short plasma half-life [1] and pharmacokinetic interactions with food or other drugs [2]. This can result in sub-optimal plasma drug concentrations, which may allow the virus to break through and replicate, leading to the development of resistant mutants [1]. Lopinavir/ritonavir (LPV/r; Kaletra, Abbott Laboratories) is a new PI consisting of a co-formulation of lopinavir and low-dose ritonavir. The sub-therapeutic dose of ritonavir (a potent cytochrome P450 [CYP] 3A4 inhibitor) inhibits the metabolism of lopinavir, resulting in higher lopinavir concentrations than when lopinavir is administered alone [3]. This pharmacokinetic interaction is associated with a high lopinavir trough level:wild type median effective concentration (EC(50)) ratio and good general tolerability when compared with other currently licensed PIs [4]. The concept of pharmacokinetic enhancement - boosting - is not new as ritonavir has previously been utilised in this context with other PIs. The relationship between plasma and intracellular drug levels has yet to be clarified. What has been ascertained from pharmacokinetic studies thus far is the correlation between ARV trough plasma concentrations (C(min)) and virological outcome [5,6]. LPV/r exemplifies how the pharmacokinetic profile of a drug can be modified to attain sufficient C(min) to suppress pheno- and genotypically resistant viral strains, as well as provide a pharmacological barrier to the emergence of resistance [7]. LPV/r reduces pill-burden and aids compliance, as shown by encouraging results in the treatment of both ARV-naive and -experienced patients.

Topics: Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones

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

The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV-infected pregnant women receiving lopinavir/ritonavir (LPV/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum.. Women were enrolled in the study who were receiving the LPV/r tablet as part of their routine prenatal care. Demographic and clinical data were collected and LPV plasma (total) and ultrafiltrate (unbound) concentrations were determined in the first, second and third trimesters using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Postpartum sampling was performed where applicable. Antepartum and postpartum trough concentrations (C(trough) ) were compared independently [using analysis of variance (anova)] and on a longitudinal basis (using a paired t-test).. Forty-six women were enrolled in the study (38 Black African). Forty women initiated LPV/r treatment in pregnancy. Median (range) gestation at initiation was 25 (15-36) weeks and median (range) baseline CD4 count and viral load were 346 (14-836) cells/μL and 8724 (<50-267408) HIV-1 RNA copies/mL, respectively. Forty women (87%) had LPV concentrations above the accepted minimum effective concentration for wild-type virus (MEC; 1000 ng/mL). Geometric mean (95% confidence interval [CI]) total LPV concentrations in the first/second [3525 (2823-4227) ng/mL; n=16] and third [3346 (2813-3880) ng/mL; n=43] trimesters were significantly lower relative to postpartum [5136 (3693-6579) ng/mL; n=12] (P=0.006). In a paired analysis (n=12), LPV concentrations were reduced in the third trimester [3657 (2851-4463) ng/mL] vs. postpartum (P=0.021). No significant differences were observed in the LPV fraction unbound (fu%). Conclusions The above target concentrations achieved in the majority of women and similarities in the fu% suggest standard dosing of the LPV/r tablet is appropriate during pregnancy. However, reduced LPV concentrations in the second/third trimesters and potentially compromised adherence highlight the need for TDM-guided dose adjustment in certain cases.

Topics: Adult; Anti-HIV Agents; Chromatography, High Pressure Liquid; Drug Monitoring; Female; HIV Infections; HIV-1; Humans; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Ritonavir; Young Adult

To evaluate strategies to reduce HIV-1 transmission through breastfeeding, a multicentre study including a nested randomized controlled trial was implemented in five research sites in West, East and South Africa (The Kesho Bora Study). The aim was to optimize the use of antiretroviral (ARV) drugs during pregnancy, delivery and breastfeeding to prevent mother-to-child transmission of HIV-1 (PMTCT) and to preserve the health of the HIV-1-infected mother. The study included long-term ARV treatment for women with advanced disease, and short-course ARV prophylaxis stopped at delivery for women with early disease. Women with intermediate disease participated in a randomized controlled trial to compare safety and efficacy of triple-ARV prophylaxis prolonged during breastfeeding with short-course ARV prophylaxis stopped at delivery. Between January 2005 and August 2008 a total of 1140 women were enrolled. This paper describes the study design, interventions and protocol amendments introduced to adapt to evolving scientific knowledge, international guidelines and availability of ARV treatment. The paper highlights the successes and challenges during the conduct of the trial. The Kesho Bora Study included one of the few randomized controlled trials to assess safety and efficacy of ARV prophylaxis continued during breastfeeding and the only randomized trial to assess maternal prophylaxis started during pregnancy. The findings have been important for informing international and national guidelines on MTCT prevention in developing countries where, due to poverty, lack of reliable and affordable supply of replacement feed and stigma associated with HIV/AIDS, HIV-infected women have little or no option other than to breastfeed their infants. (ISRCTN71468401).

Topics: Africa, Eastern; Africa, Southern; Africa, Western; Anti-Retroviral Agents; Breast Feeding; Child, Preschool; Clinical Protocols; Cohort Studies; Delivery, Obstetric; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Mothers; Nevirapine; Pregnancy; Pyrimidinones; Research Design; Ritonavir; Zidovudine

The purpose of this study was to determine if switching to an Lopinavir/ritonavir (LPV/r)-containing regimen resulted in greater immune reconstitution in patients with immunologic failure despite complete viral suppression with highly active antiretroviral therapy (HAART). Twenty patients with partial or no immune response to HAART despite viral suppression were enrolled. Ten were randomized to stay on their current regimen and 10 were randomized to LPV/r plus their current NRTI backbone. T cell subsets, ex vivo apoptosis, and the percent of circulating cells with detectable intracellular HIV-1 RNA were measured. The mean increase in CD4(+) count at 6 months was 116/mm(3) (172-288) for the LPV/r-containing arm versus 32/mm(3) (264-296) for continuation regimens (p = 0.03). The number of patients with an increase ≥50 cells/mm(3) was also greater in the LPV/r arm (7/9 versus 2/10, p = 0.01). This paralleled a decrease in ex vivo apoptosis of naive CD4(+) T cells at 6 months (21.7-11.0% for the LPV/r arm versus 17.3-18.9% for the continuation arm, p = 0.04) and memory cells (21.1-14.1% for LPV/r versus 20.2-17.9% for continuation arm, NSS). Switching patients to an LPV/r-containing regimen improved CD4(+) counts in patients with prior immunologic failure, and this may be due to an effect of LPV/r on apoptosis.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

To examine whether the overall results of the CASTLE study pertain to both genders, we analysed the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir in 277 female and 606 male patients in the open-label, multinational trial over 96 weeks. The trial is registered with ClinicalTrials.gov, number NCT00272779.. Treatment-naive patients aged ≥ 18 years with HIV-1 RNA ≥ 5000 copies/mL were randomized to receive either atazanavir/ritonavir 300/100 mg once daily or lopinavir/ritonavir 400/100 mg twice daily, with fixed-dose tenofovir/emtricitabine 300/200 mg once daily.. At week 96, confirmed virological response rates (HIV RNA <50 copies/mL; intent-to-treat analysis) were higher in women and men receiving atazanavir/ritonavir than those receiving lopinavir/ritonavir and lower in women than men in both treatment arms (67% of women and 77% of men on atazanavir/ritonavir and 63% of women and 71% of men on lopinavir/ritonavir). These differences were not observed in the on-treatment analysis. Mean change in CD4 cell count from baseline to week 96 was 265 cells/mm(3) for women and 269 cells/mm(3) for men on atazanavir/ritonavir and 298 cells/mm(3) for women and 286 cells/mm(3) for men on lopinavir/ritonavir. Discontinuation rates were higher in women than men in each treatment arm (22% of women and 15% of men on atazanavir/ritonavir and 29% of women and 18% of men on lopinavir/ritonavir). In women and men, grade 2-4 nausea and diarrhoea were more frequent in the lopinavir/ritonavir group; jaundice and hyperbilirubinaemia occurred more frequently in the atazanavir/ritonavir group.. Once-daily atazanavir/ritonavir is an effective and well-tolerated therapeutic option for women and men with HIV-1 infection. The sex-based differences in response may be due to higher discontinuation rates in women.

Topics: Adult; Aged; Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Sex Factors

Given the decline in mortality among HIV-infected patients, it has become increasingly important to consider delayed disease-related and/or anti-HIV therapy-related adverse effects, such as lipodystrophy, when choosing initial therapy. Data from the MONARK trial allowed for comparison of the potential lipodystrophic effects of lopinavir/ritonavir (LPV/r) monotherapy with those of triple therapy with LPV/r plus zidovudine (ZDV) and lamivudine (3TC). This was a randomized, open-label, multinational study that included 136 antiretroviral-naive HIV-infected patients. A portion of study patients underwent evaluations of limb and trunk fat tissue by dual-energy x-ray absorptiometry at baseline and after 48 weeks of treatment (and 96 weeks in some patients). Sixty-three patients had paired absorptiometry data at baseline and week 48 (13 patients at week 96). At week 48, median change in limb fat was -63 g on LPV/r monotherapy versus -703 g on LPV/r + ZDV/3TC triple therapy (p=0.014). The proportion of patients with fat loss (>20% loss in limb fat) was significantly lower with LPV/r monotherapy (4.9% versus 27.3%; p=0.018). Changes in trunk fat did not differ significantly between treatments. Nonetheless, limb fat and trunk fat varied in the same direction with both treatments. The decrease in arm lean mass was also significantly less in patients receiving LPV/r monotherapy. Only treatment type emerged as a significant predictor of fat loss (odds ratio, 7.06; 95% CI, 1.11-78.69). These results suggest that LPV/r, and possibly other protease inhibitors, may not be the main contributor to lipoatrophy in HIV-infected patients receiving triple therapy.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Body Fat Distribution; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Zidovudine

To investigate the longitudinal pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r) in HIV-infected infants initiating combination antiretroviral therapy (cART) between 2 weeks and 6 months of age.. A prospective, open-label, multicenter Phase I/II study of LPV/r-based cART at a dose of 300/75 mg/m(2)/dose LPV/r twice daily. Intensive pharmacokinetic sampling at 12 months of age and quarterly predose LPV concentrations were collected and safety, virologic and immunologic responses were monitored every 4-12 weeks up to 252 weeks.. Thirty-one HIV-infected infants enrolled into two age cohorts, 14 days to <6 weeks and 6 weeks to <6 months; 29 completed ≥48 weeks of follow-up (median = 123 weeks, range 4-252). At 12 months of age, median LPV area under the curve was comparable for both age cohorts and similar to older children and adults. At week 48, 22 of 31 patients (71%) had HIV-1 RNA <400 copies/ml and 11 of 15 (73%) had <50 copies/ml; 29 of 31 achieved HIV-1 RNA <400 copies/ml on study treatment and 19 (66%) remained durably suppressed until the end of study; viral suppression correlated with a higher percentage of predose time points exceeding the LPV target of 1 μg/ml (92 vs. 71%, P = 0.002).. LPV/r at 300/75 mg/m(2)/dose as part of a cART regimen resulted in viral suppression through 96 weeks of treatment in >65% of young infants. Due to initially low LPV exposure in infants <6 weeks of age, frequent dose adjustment for weight gain is advisable and consideration should be given to studying a higher dose for very young infants.

Topics: Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Infant, Newborn; Lopinavir; Male; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load

In the Phase III ARTEMIS Trial, treatment-naive patients received once-daily darunavir/ritonavir (DRV/r) 800/100 mg (n = 343) or lopinavir/ritonavir (LPV/r) 800/200 mg (total daily dose; n = 346) plus fixed-dose tenofovir disoproxil fumarate/emtricitabine. The primary outcome measure was non-inferiority of DRV/r versus LPV/r (HIV type-1 [HIV-1] RNA<50 copies/ml). Here, a detailed 96-week resistance analysis is presented.. Virological failures (VFs) were defined as patients who had lost (rebounders) or who had never achieved (never suppressed) HIV-1 RNA < 50 copies/ml after week 12. Genotypic and phenotypic determinations were performed on plasma samples with HIV-1 RNA ≥ 50 copies/ml. The end point was defined as the last on-treatment visit with available genotype and/or phenotype.. The VF rate was significantly lower in DRV/r (12%, n = 40) versus LPV/r patients (17%, n = 59; P = 0.0437). Among DRV/r patients, 24 rebounded and 16 were never suppressed, whereas among LPV/r patients, 33 rebounded and 26 were never suppressed. Transient HIV-1 RNA increases (≥ 50 copies/ml) occurred in 50% (n = 12) DRV/r and 48% (n = 16) LPV/r rebounders; these viral levels returned to undetectable by end point without any changes to the study regimen. No major (primary) protease inhibitor (PI) resistance-associated mutations (RAMs) developed in VFs with an available genotype at baseline and end point, and almost all developing minor PI RAMs were polymorphic. At end point, all VFs with available phenotypes at baseline and end point remained susceptible to all PIs, including study PIs.. The VF rate was lower with DRV/r than LPV/r. The findings of this resistance analysis confirmed the lack of development of major PI RAMs and the preservation of phenotypic susceptibility to all PIs in patients with VF.

Topics: Adenine; Adult; Anti-HIV Agents; Darunavir; Deoxycytidine; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Female; Genetic Association Studies; HIV Infections; HIV-1; Humans; Lopinavir; Male; Mutation; Organophosphonates; Polymorphism, Genetic; Pyrimidinones; Ritonavir; RNA, Viral; Sulfonamides; Tenofovir; Treatment Failure; Viral Load

The number of patients on second-line highly active antiretroviral therapy (HAART) regimens is increasing in resource-limited settings. We describe the outcomes after 24 months for patients on LPV/r-based second-line regimens followed up by the ESTHER programme in Phnom Penh, Cambodia.. Seventy patients who initiated second-line HAART regimens more than 24 months earlier were included, and immuno-virological data analyzed. HIV RNA viral load was determined by real-time RT-PCR. HIV-1 drug resistance was interpreted according to the ANRS algorithm.. Of the 70 patients, two were lost to follow up, three died and 65 (92.8%) remained on second-line treatment after 24 months of follow up (median duration of treatment: 27.4 months). At switch to second-line, the median CD4 T cell count was 106 cells/mm³ and the median viral load was 4.7 Log10. Second-line regimens prescribed were ddI/3TC/LPV/r (65.7%), ddI/TDF/LPV/r (10.0%), ddI/AZT/LPV/r (8.6%) and TDF/3TC/LPV/r (7.1%). The median CD4 T cell gain was +258 cells/mm³ at 24 months (n = 63). After 24 months of follow up, 92.3% (60/65) of the patients presented undetectable viral loads, giving an overall treatment success rate of 85.7% (CI: 75.6- 92.0) in intent-to-treat analysis.. These data suggest that a LPV/r-based second-line regimen is associated with a high rate of virological suppression and immune reconstitution after 24 months of follow up in Cambodia.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cambodia; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cohort Studies; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Treatment Outcome; Viral Load

Rifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C(0)) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC(0-12)), C(0), C(12), maximum concentration of drug in serum (C(max)), or half-life (t(1/2)) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; Tablets

The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral-naïve patients.. A total of 136 antiretroviral-naïve patients, with a CD4 cell count above 100 cells/microL and a plasma HIV RNA below 100,000 HIV-1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n = 83) or lopinavir/ritonavir + zidovudine/lamivudine (n = 53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent-to-treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n = 83), and then focused on patients who had an HIV RNA < 50 copies/mL at week 48 (n = 56).. At week 96, 39 of 83 patients (47%) had HIV RNA < 50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA > 400 copies/mL. Focusing on the 56 patients with an HIV RNA < 50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA < 50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI-associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96.. By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA < 50 copies/mL at week 96. The occurrence in some patients of low-level viraemia (50-500 copies/mL) may increase the risk of drug resistance. First-line lopinavir/ritonavir monotherapy cannot be systematically recommended.

Topics: Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Intention to Treat Analysis; Lamivudine; Lopinavir; Male; Medication Adherence; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Outcome; Zidovudine

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

Once-daily atazanavir/ritonavir demonstrated similar antiviral efficacy to twice-daily lopinavir/ritonavir over 48 weeks, with less gastrointestinal disturbance and a better lipid profile, in treatment-naive patients.. International, multicenter, open-label, 96-week noninferiority randomized trial of atazanavir/ritonavir 300/100 mg once daily vs lopinavir/ritonavir 400/100 mg twice daily, each in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily, in antiretroviral-naive, HIV-1-infected patients. The primary end point was the proportion of patients with HIV RNA <50 copies/mL at 48 weeks. Results through 96 weeks are reported.. Of 883 patients enrolled, 440 were randomized to atazanavir/ritonavir and 443 to lopinavir/ritonavir. At week 96, more patients receiving atazanavir/ritonavir achieved HIV RNA <50 copies/mL (74% vs 68%, P < 0.05) in the intent-to-treat analysis. On both regimens, 7% of subjects were virologic failures by 96 weeks. Bilirubin-associated disorders were greater in patients taking atazanavir/ritonavir. Treatment-related gastrointestinal adverse events were greater in patients taking lopinavir/ritonavir. Mean changes from baseline in fasting total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides at week 96 were significantly higher with lopinavir/ritonavir (P < 0.0001).. Noninferiority of atazanavir/ritonavir to lopinavir/ritonavir was confirmed at 96 weeks. Atazanavir/ritonavir had a better lipid profile and fewer gastrointestinal adverse events than lopinavir/ritonavir.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Deoxycytidine; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lipids; Lopinavir; Male; Middle Aged; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome; Viral Load; Young Adult

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

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

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

To compare the safety and antiviral activity of once (QD) or twice (BID) daily lopinavir/ritonavir (LPV/r) in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-experienced subjects.. Subjects failing treatment with HIV-1 RNA > 1000 copies per milliliter received LPV/r tablets 800/200 mg QD (n = 300) or 400/100 mg BID (n = 299) with investigator-chosen nucleoside/nucleotide reverse transcriptase inhibitors. Efficacy was determined by the intent-to-treat time to loss of virologic response (ITT-TLOVR) algorithm. Safety, tolerability, adherence, impact of baseline protease mutations on virologic response, and emergence of resistance on therapy were assessed.. Demographics were comparable across groups. By intent-to-treat time to loss of virologic response, 166 QD subjects (55.3%) and 155 BID subjects (51.8%) were responders at week 48 (P = 0.413), with similar mean increases in CD4 T-cell count. QD subjects demonstrated better adherence than BID subjects. The occurrence of treatment-related moderate/severe adverse events was comparable for all events except nausea, which was reported more frequently among BID-treated subjects. Emergence of new protease resistance mutations on treatment was similarly infrequent in both groups.. LPV/r dosed QD resulted in increased treatment adherence and was as efficacious as BID LPV/r while providing similar safety, tolerability, and limited resistance evolution.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Medication Adherence; Middle Aged; Nausea; Pyrimidinones; Ritonavir; Viral Load; Young Adult

The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4(+) counts compared to no therapy.. Participants not on continuous ART with > or = 300 CD4(+) cells/mm(3) were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4(+) counts, HIV RNA, and HIV progression events were collected monthly.. A total of 267 participants were randomized. At week 32, the mean CD4(+) count was 134 cells greater in the IL-2 alone group (p<0.001), and 133 cells greater in the IL-2 plus ART group (p<0.001) compared to the no therapy group. Twelve participants in the IL-2 groups compared to 1 participant in the group assigned to no therapy experienced an opportunistic event or died (HR 5.84, CI: 0.59 to 43.57; p = 0.009).. IL-2 alone or with peri-cycle HAART increases CD4(+) counts but was associated with a greater number of opportunistic events or deaths compared to no therapy. These results call into question the immunoprotective significance of IL-2-induced CD4(+) cells.. ClinicalTrials.gov NCT00110812.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Carbamates; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; Fever; Furans; HIV Infections; Humans; Interleukin-2; Lopinavir; Male; Nausea; Oligopeptides; Opportunistic Infections; Organophosphates; Pyridines; Pyrimidinones; Ritonavir; Sulfonamides; Treatment Outcome

Dosing frequency is an important determinant of regimen effectiveness. Methods. To compare efficacy of once-daily (QD) versus twice-daily (BID) antiretroviral therapy, we randomized human immunodeficiency virus (HIV)-positive, treatment-naive patients to lopinavir-ritonavir (LPV/r) administered at a dosage of 400 mg of lopinavir and 100 mg of ritonavir BID (n = 160) or 800 mg of lopinavir and 200 mg of ritonavir QD (n = 161), plus either emtricitabine 200 mg QD and extended-release stavudine at a dosage of 100 mg QD or tenofovir at a dosage of 300 mg QD. Randomization was stratified by screening HIV RNA level <100,000 copies/mL versus > or = 100,000 copies/mL. The primary efficacy end point was sustained virologic response (SVR; defined as reaching and maintaining an HIV RNA level <200 copies/mL) through week 48.. Subjects were 78% male, 33% Hispanic, and 34% black. A total of 82% of subjects completed the study, and 71% continued to receive the initially assigned dosage schedule. The probability of SVR did not differ significantly for the BID versus QD comparison, with an absolute proportional difference of 0.03 (95% confidence interval [CI], -0.07 to 0.12). The comparison depended on the screening RNA stratum (P=.038); in the higher RNA stratum, the probability of SVR was significantly better in the BID arm than in the QD arm: 0.89 (95% CI, 0.79-0.94) versus 0.76 (95% CI, 0.64-0.84), a difference of 0.13 (95% CI, 0.01-0.25). Lopinavir trough plasma concentrations were higher with BID dosing. Adherence to prescribed doses of LPV/r was 90.6% in the QD arm versus 79.9% in the BID arm (P<.001). Conclusions. Although subjects assigned to QD regimens had better adherence, overall treatment outcomes were similar in the QD and BID arms. Subjects with HIV RNA levels > or =100,000 copies/mL had better SVR with BID regimens at 48 weeks, which suggests a possible advantage in this setting for more frequent dosing. Clinical trial registration. ClinicalTrials.gov registration number: NCT00036452.

Topics: Anti-Retroviral Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Lopinavir; Male; Proportional Hazards Models; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

South African guidelines recommend protease-inhibitor-based antiretroviral therapy (ART) with lopinavir-ritonavir for human immunodeficiency virus (HIV)-infected children <36 months of age. We investigated factors associated with viral suppression and mortality among young children initiating ART.. Treatment-naive, ART-eligible, HIV-infected children (aged 6-104 weeks) were enrolled in an ART strategies trial in South Africa and initiated protease-inhibitor-based ART. Mortality and the probability of viral suppression (defined as HIV RNA load of <400 copies/mL) by 39 weeks after ART initiation were investigated.. Of 254 children who initiated ART, 99 (39%) were cotreated for tuberculosis during follow-up. The mortality rate was 14%. Factors predicting mortality were lower pre-ART weight-for-age z score and higher HIV RNA load. By 39 weeks, 84% of surviving children achieved viral suppression. Children who were not cotreated for tuberculosis were more likely to achieve viral suppression (94.8%) than were children who were receiving cotreatment at ART initiation (74.2%) or who started tuberculosis cotreatment after ART initiation (51.6%; P < .001). Other factors predicting lower probability of viral suppression were lower pre-ART weight- and length-for-age z score, higher HIV RNA load, and World Health Organization disease stage.. High rates of viral suppression can be achieved among infants and young children who initiate protease-inhibitor-based ART. Cotreatment for tuberculosis reduced viral suppression. How best to treat HIV-infected children who require tuberculosis treatment warrants urgent investigation.

Topics: Antiretroviral Therapy, Highly Active; Antitubercular Agents; Child, Preschool; Drug Therapy, Combination; Ethionamide; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Isoniazid; Kaplan-Meier Estimate; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; RNA, Viral; South Africa; Tuberculosis, Pulmonary; Viral Load

Lipoatrophy can complicate thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI)-based antiretroviral therapy (ART). Lipoatrophy may be less likely with ART including ritonavir-boosted lopinavir (LPV/r). Small, placebo-controlled studies found that uridine (in tNRTI recipients) and pravastatin improved HIV lipoatrophy over 12 weeks. Today, most patients with lipoatrophy receive non-tNRTI-based ART; the effect of uridine in such patients is unknown.. We performed a prospective, randomized trial in lipoatrophic adults with plasma HIV RNA<50 HIV-1 RNA copies/mL on tNRTI-sparing ART including LPV/r. Patients received uridine [36 g three times a day (tid) on 10 consecutive days per month; n=10], pravastatin [40 mg every night (nocte); n=12], uridine plus pravastatin (n=11) or neither (n=12) for 24 weeks. The primary endpoint was mean change in limb fat mass as assessed by dual-energy X-ray absorptiometry (DEXA). With 20 patients per intervention, the study had 80% power to detect a mean difference between a treatment and the control of 0.5 kg, assuming a standard deviation of 0.9 and an alpha threshold equal to 5% (two-sided).. Of 45 participants (all men, with median age 49.5 years and median limb fat 2.6 kg), two discontinued pravastatin and one participant stopped both pravastatin and uridine. The difference between the mean changes in limb fat mass for uridine vs. no uridine was 0.03 kg [95% confidence interval (CI) -0.35, +0.28; P=0.79]. The respective difference for pravastatin was -0.03 kg (95% CI -0.29, +0.34; P=0.84). Pravastatin slightly decreased total cholesterol (0.44 mmol/L; P=0.099). Visceral adipose tissue measured by computed tomography did not change significantly.. In this population and at the doses used, neither uridine nor pravastatin for 24 weeks significantly increased limb fat mass.

Topics: Absorptiometry, Photon; Adiposity; Adult; Anti-Retroviral Agents; Anticholesteremic Agents; Dideoxynucleosides; Drug Therapy, Combination; Extremities; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Male; Middle Aged; Pravastatin; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Uridine

To study the impact of protease inhibitor monotherapy on the HIV-1 blood reservoir in 72 antiretroviral-naive patients.. This was evaluated for 72 antiretroviral-naive patients included in the on-treatment analysis of the MONARK trial; 46 patients receiving lopinavir/ritonavir monotherapy and 26 patients receiving a triple therapy. HIV-DNA was quantified in whole blood, using real-time PCR.. The decrease in HIV-DNA after 48 weeks of lopinavir/ritonavir monotherapy was similar to the decrease observed with triple therapy including lopinavir/ritonavir (-0.77 versus -0.69 log copies/10(6) leucocytes, respectively; P = 0.91). The HIV-DNA decrease was also similar in patients with a virological response in both arms (-0.69 versus -0.69 log copies/10(6) leucocytes, respectively). Interestingly, non-responders had a significantly higher baseline HIV-DNA load than responders in the monotherapy arm; 3.16 versus 2.86 log copies/10(6) leucocytes, respectively (P = 0.05).. The MONARK data indicate that a lopinavir/ritonavir monotherapy regimen is potent against HIV blood reservoirs in antiretroviral-naive patients after 1 year of treatment, in comparison with a standard-of-care highly active antiretroviral therapy. This impact should be evaluated with other boosted protease inhibitor monotherapies.

Topics: Anti-HIV Agents; Blood Cells; DNA, Viral; HIV Infections; HIV-1; Humans; Lopinavir; Polymerase Chain Reaction; Pyrimidinones; Ritonavir; Viral Load

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

Initial viral decay rate may be useful when comparing the relative potency of antiretroviral regimens. Two hundred twenty-seven ART-naïve patients were randomized to receive efavirenz (EFV) (n = 74), lopinavir/ritonavir (LPV/r) (n = 77), or atazanavir/ritonavir (ATV/r) (n = 79) in combination with two NRTIs. The most frequently used NRTI combinations in the EFV and ATV/r groups were the nonthymidine analogues tenofovir and emtricitabine or lamivudine (70% and 68%, respectively) and, in the LPV/r group, lamivudine and the thymidine analogue zidovudine (89%). HIV-1 RNA was monitored during the first 28 days after treatment initiation. Phase 1 and 2 decay rate was estimated in a subset of 157 patients by RNA decrease from days 0 to 7, and days 14 to 28. One-way ANOVA and subsequent Tukey's post hoc tests were used for groupwise comparisons. Mean (95% CI) HIV-1 RNA reductions from days 0 to 28 were 2.59 (2.45-2.73), 2.42 (2.27-2.57), and 2.13 (2.01-2.25) log(10) copies/ml for the EFV-, LPV/r-, and ATV/r-based treatment groups, respectively, with a significantly larger decrease in the EFV-based group at all time points compared with ATV/r (p < 0.0001), and with LPV/r at days 7-21 (p < 0.0001-0.03). LPV/r gave a greater RNA decrease compared with ATV/r from day 14 (p = 0.02). Phase 1 decay rate was significantly higher in the EFV group compared with LPV/r (p = 0.003) or ATV/r (p < 0.0001). No difference was found in phase 2 decrease. EFV-based treatment gave a more rapid decline in HIV-1 RNA than did either of the boosted protease inhibitor-based regimens. The observed differences may reflect different inherent regimen potencies.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

Most ritonavir-boosted protease inhibitor (PI)-based antiretroviral regimens offer comparable levels of virological efficacy. Thus, the tolerability of the regimen becomes a distinguishing factor with implications for patient quality of life (QoL), treatment adherence, and clinical outcome. This article describes results from the CASTLE study (comparing once-daily atazanavir/ritonavir [ATV/RTV] with twice-daily lopinavir/ritonavir [LPV/RTV], both in combination with fixed-dose tenofovir/emtricitabine, in treatment-naive HIV-infected patients) and an evaluation of the impact of gastrointestinal (GI) complications of treatment on patient QoL, as measured by the irritable bowel syndrome (IBS) QoL questionnaire (IBS-QoL). Changes in IBS-QoL from baseline over time (to week 24) were classified as: "Improvement" (> or =2-point positive change from baseline), "No change" (<2-point change), or "Worsening" (> or =2-point negative change). Data were collected on GI adverse events (AEs) and use of GI medications. Of the 599 patients with IBS-QoL-evaluable data through week 24, fewer patients in the ATV/RTV group than in the LPV/RTV group experienced grade 2-4 treatment-related GI AEs including diarrhea (3% versus 10%), nausea (5% versus 7%), and vomiting (<1% on both arms). Nearly three times as many patients receiving LPV/RTV used GI medications. ATV/RTV was associated with an increase in overall IBS-QoL scores and more patients receiving ATV/RTV than LPV/RTV experienced improvement in IBS-QoL through week 24. In contrast to LPV/RTV, ATV/RTV treatment was associated with earlier and more positive improvements in QoL scores across CD4 sub-groups. Differences in the health-related QoL profile between ATV/RTV and LPV/RTV may be important when selecting PI-based antiretroviral regimens.

Topics: Adenine; Adult; Aged; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; Gastrointestinal Diseases; HIV Infections; HIV-1; Humans; Irritable Bowel Syndrome; Lopinavir; Male; Medication Adherence; Middle Aged; Oligopeptides; Organophosphonates; Prospective Studies; Pyridines; Pyrimidinones; Quality of Life; Ritonavir; Surveys and Questionnaires; Tenofovir; Young Adult

To examine how treatment adherence differences in ARTEMIS (96 week analysis) affected clinical outcome, and to assess factors impacting adherence.. ARTEMIS is a Phase III trial, in HIV-1-infected treatment-naive patients, comparing efficacy and safety of once-daily darunavir/ritonavir (800/100 mg) versus lopinavir/ritonavir (800/200 mg total daily dose), each with a fixed-dose background tenofovir and emtricitabine regimen. Self-reported treatment adherence was assessed using the Modified Medication Adherence Self-Report Inventory (M-MASRI). In post-hoc analyses, mean adherence from weeks 4-96 was used to assess overall adherence for each patient, and transformed into a binary variable (>95% , adherent; < or = 95% , suboptimally adherent).. Overall adherence was high: 83% of darunavir/ritonavir-treated patients and 78% of lopinavir/ritonavir-treated patients were >95% adherent. The difference in virological response rate for adherent versus suboptimally adherent patients was smaller for darunavir/ritonavir (6% difference: 82% versus 76%, P = 0.3312) than for lopinavir/ritonavir (25% difference: 78% versus 53%, P < 0.0001). In suboptimally adherent patients, a higher virological response rate was seen with darunavir/ritonavir (76%) versus lopinavir/ritonavir (53%) (P < 0.01). Suboptimally adherent patients (both treatment groups) reported more adverse events (AEs), including gastrointestinal AEs, than adherent patients. Darunavir/ritonavir had a lower rate of AEs, including gastrointestinal AEs, than lopinavir/ritonavir, in adherent and suboptimally adherent patients.. Suboptimal adherence had no significant effect on the virological response rate with once-daily darunavir/ritonavir treatment. In contrast, the lopinavir/ritonavir response rate was significantly reduced in suboptimally adherent patients compared with adherent patients. Once-daily darunavir/ritonavir resulted in a higher virological response rate in suboptimally adherent patients compared with lopinavir/ritonavir.

Topics: Adult; Anti-HIV Agents; Darunavir; HIV Infections; HIV-1; Humans; Lopinavir; Medication Adherence; Pyrimidinones; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

To evaluate the long-term safety and effectiveness of lopinavir/ritonavir (LPV/r) in a population-based cohort of HIV-1-infected children.. All children enrolled in the Swiss Mother and Child HIV Cohort Study, treated with LPV/r-based combination antiretroviral treatment (cART) between November 2000 and October 2008, were included.. 88 children (25 (28%) protease inhibitor (PI)-naive, 16 (18%) ART-naive) were analysed (251 patient-years on LPV/r). After 48 weeks on LPV/r, 70 children had a median (interquartile range (IQR)) decrease in HIV-1 viral load of 4.25 log (5.45-3.17; PI-naive, n=17) and 2.53 (3.68-1.38; PI-experienced, n=53). Median (IQR) increase in CD4 count was 429 (203-593; PI-naive) and 177 (21-331; PI-experienced) cells/microl. These effects remained stable throughout 192 weeks for 25 children. Treatment was stopped for viral rebound in seven and suspected toxicity in 12 children.. Long-term treatment with LPV/r-based cART is safe and effective in HIV-1-infected children.

Topics: Adolescent; CD4 Lymphocyte Count; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load

To evaluate the pharmacokinetics and HIV viral load response following initiation during the third trimester of pregnancy of zidovudine plus standard-dose lopinavir boosted with ritonavir (LPV/r), twice daily, until delivery for the prevention of mother-to-child transmission of HIV.. Prospective study nested within a multicenter, three-arm, randomized, phase III prevention of mother-to-child transmission of HIV trial in Thailand (PHPT-5, ClinicalTrials.gov Identifier: NCT00409591).. Women randomized to receive 300 mg zidovudine and 400/100 mg LPV/r twice daily from 28 weeks' gestation, or as soon as possible thereafter, until delivery had intensive steady-state 12-h blood sampling performed. LPV/r pharmacokinetic parameters were calculated using noncompartmental analysis. Rules were defined a priori for a LPV/r dose escalation based on the proportion of women with an LPV area under the concentration-time curve (AUC) below 52 microg h/ml (10th percentile for LPV AUC in nonpregnant adults). HIV-1 RNA response was assessed during the third trimester.. Thirty-eight women were evaluable; at entry, median (range) gestational age was 29 (28-36) weeks, weight 59.5 (45.0-91.6) kg, CD4 cells count 442 (260-1327) cells/microl and HIV-1 RNA viral load 7818 (<40-402 015) copies/ml. Geometric mean (90% confidence interval) LPV AUC, Cmax and Cmin were 64.6 (59.7-69.8) microg h/ml, 8.1 (7.5-8.7) microg/ml and 2.7 (2.4-3.0) microg/ml, respectively. Thirty-one of 38 (81%) women had an LPV AUC above the AUC target. All women had a HIV-1 viral load less than 400 copies/ml at the time of delivery.. A short course of zidovudine plus standard-dose LPV/r initiated during the third trimester of pregnancy achieved adequate LPV exposure and virologic response.

Topics: Adult; CD4-Positive T-Lymphocytes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Pregnancy; Pregnancy Trimester, Third; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Thailand; Viral Load; Young Adult; Zidovudine

Sustained viral suppression with antiretroviral therapy improves clinical outcomes for HIV-infected individuals. Study M05-730 evaluated the long-term antiviral activity, safety, tolerability, emergence of resistance, and compliance with once-daily (QD) versus twice-daily (BID) lopinavir/ritonavir (LPV/r) combination therapy in treatment-naïve, HIV-1-infected subjects through 96 weeks. Antiretroviral-naïve subjects with HIV-1 RNA levels >1000 copies/ml were randomized to LPV/r QD (N = 333) or BID (N = 331) with tenofovir DF and emtricitabine. Through 96 weeks, 77 subjects from each group discontinued prematurely; adverse or HIV-related events contributed to discontinuation of 36 subjects overall, with no significant differences between treatment groups. At 96 weeks, 216 QD subjects (64.9%) and 229 BID subjects (69.2%) had HIV-1 RNA <50 copies/ml (p = 0.249) by intent-to-treat analysis. Evaluation of the time to virologic failure indicated that 85.0% and 80.7% of QD and BID subjects, respectively, maintained virologic suppression through 96 weeks (p = 0.638). QD subjects demonstrated greater adherence levels. There were no significant differences in virologic response when subjects were analyzed according to baseline disease state. Emergence of postbaseline resistance mutations occurred at similar low rates in each dosing group. Diarrhea was the most common moderate-to-severe drug-related adverse event reported; the most common Grade 3+ laboratory abnormalities were elevations of total cholesterol and triglycerides, occurring with similar incidence regardless of LPV/r dosing frequency. QD dosing of LPV/r was associated with similar durability of viral suppression and low rates of genotypic resistance and treatment-limiting adverse events as compared with BID dosing in treatment-naïve subjects through 96 weeks of treatment.

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Emtricitabine; HIV Infections; HIV-1; Humans; Lopinavir; Organophosphonates; Pyrimidinones; Ritonavir; Tenofovir

this study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain.. a randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis.. ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P <0.001) and 2.6-fold (range 1.9- to 3.3-fold; P <0.001). The mean (± SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P <0.001) and 5.7 ± 0.9 h (P <0.001), respectively. Both ritonavir (P <0.001) and lopinavir/ritonavir (P <0.05) increased the self-reported drug effect of oxycodone.. ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects.

Topics: Adult; Analgesics, Opioid; Area Under Curve; Cross-Over Studies; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Finland; HIV Infections; HIV Protease Inhibitors; Humans; Linear Models; Lopinavir; Male; Oxycodone; Pain; Pyrimidinones; Reference Values; Ritonavir; Time Factors; Young Adult

Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. However, efficacy of LPV/r-MT in compartments remains to be shown.. Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system [cerebrospinal fluid (CSF)] and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml.. The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/microl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02).. Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/microl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.

Topics: Adult; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Semen; Time Factors; Treatment Failure; Viral Load

Protease inhibitor (PI)-based therapy is recommended for infants infected with human immunodeficiency virus (HIV) who were exposed to nevirapine for prevention of mother-to-child HIV transmission. However, there are limitations of continuing PI-based therapy indefinitely and reuse of nevirapine has many advantages.. To test whether nevirapine-exposed infants who initially achieve viral suppression with PI-based therapy can maintain viral suppression when switched to nevirapine-based therapy.. Randomized trial conducted between April 2005 and May 2009 at a hospital in Johannesburg, South Africa, among 195 children who achieved viral suppression less than 400 copies/mL for 3 or more months from a cohort of 323 nevirapine-exposed children who initiated PI-based therapy before 24 months of age.. Control group children continued to receive ritonavir-boosted lopinavir, stavudine, and lamivudine (n = 99). Switch group children substituted nevirapine for ritonavir-boosted lopinavir (n = 96).. Children were followed up for 52 weeks after randomization. Plasma HIV-1 RNA of greater than 50 copies/mL was the primary end point. Confirmed viremia greater than 1000 copies/mL was used as a criterion to consider regimen changes for children in either group (safety end point).. Plasma viremia greater than 50 copies/mL occurred less frequently in the switch group (Kaplan-Meier probability, 0.438; 95% CI, 0.334-0.537) than in the control group (0.576; 95% CI, 0.470-0.668) (P = .02). Confirmed viremia greater than 1000 copies/mL occurred more frequently in the switch group (0.201; 95% CI, 0.125-0.289) than in the control group (0.022; 95% CI, 0.004-0.069) (P < .001). CD4 cell response was better in the switch group (median CD4 percentage at 52 weeks, 34.7) vs the control group (CD4 percentage, 31.3) (P = .004). Older age (relative hazard [RH], 1.71; 95% CI, 1.08-2.72) was associated with viremia greater than 50 copies/mL in the control group. Inadequate adherence (RH, 4.14; 95% CI, 1.18-14.57) and drug resistance (RH, 4.04; 95% CI, 1.40-11.65) before treatment were associated with confirmed viremia greater than 1000 copies/mL in the switch group.. Among HIV-infected children previously exposed to nevirapine, switching to nevirapine-based therapy after achieving viral suppression with a ritonavir-boosted lopinavir regimen resulted in lower rates of viremia greater than 50 copies/mL than maintaining the primary ritonavir-boosted lopinavir regimen.. clinicaltrials.gov Identifier: NCT00117728.

Topics: Anti-HIV Agents; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Male; Maternal Exposure; Nevirapine; Protease Inhibitors; Pyrimidinones; RNA, Viral; Stavudine; Treatment Outcome; Viremia

Pharmacokinetic (PK) interactions between lopinavir/ritonavir (LPV/r) and transdermally delivered ethinyl estradiol (EE) and norelgestromin (NGMN) are unknown.. Using a standard noncompartmental PK analysis, we compared EE area under the time-concentration curve (AUC) and NGMN AUC during transdermal contraceptive patch administration in HIV-1-infected women on stable LPV/r to a control group of women not on highly active antiretroviral therapy (HAART). In addition, EE AUC after a single dose of a combination oral contraceptive pill including EE and norethindrone was measured before patch placement and was compared with patch EE AUC in both groups. Contraceptive effects on LPV/r PKs were estimated by measuring LPV/r AUC at baseline and during week 3 of patch administration.. Eight women on LPV/r, and 24 women in the control group were enrolled. Patch EE median AUC0-168 h was 45% lower at 6010.36 pg·h·mL in those on LPV/r versus 10911.42 pg·h·mL in those on no HAART (P = 0.064). Pill EE median AUC0-48 hours was similarly 55% lower at 344.67 pg·h·mL in those on LPV/r versus 765.38 pg·h·mL in those on no HAART (P = 0.003). Patch NGMN AUC0-168 h however, was 138.39 ng·h·mL, 83% higher in the LPV/r group compared with the control AUC of 75.63 ng·h·mL (P = 0.036). After 3 weeks on the patch, LPV AUC0-8 h decreased by 19%, (P = 0.156).. Although PKs of contraceptive EE and NGMN are significantly altered with LPV/r, the contraceptive efficacy of the patch is likely to be maintained. Larger studies are indicated to fully assess contraceptive efficacy versus risks of the transdermal contraceptive patch when co-administered with protease inhibitors.

Topics: Adolescent; Adult; Contraceptives, Oral, Combined; Drug Combinations; Drug Interactions; Estrogens; Ethinyl Estradiol; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Middle Aged; Norgestrel; Oximes; Pyrimidinones; Ritonavir; Transdermal Patch; United States

We evaluated a monotherapy maintenance regimen with lopinavir/ritonavir versus continuing current combined antiretroviral treatment (cART) in HIV patients with suppressed plasma HIV-1 RNA.. This was an open-label, non-inferiority, multicentre trial in 23 sites in France. Adults were randomized if they had no history of virological failure while receiving a protease inhibitor, maintained HIV-1 RNA <50 copies/mL for at least 6 months and did not change cART during the last 3 months. The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 (non-inferiority margin set at -12%) with missing data and treatment modification considered as failure. The trial has been registered in ClinicalTrials.gov under the identifier NCT00140751.. At Week 48, 84% (73/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group [difference, -4.0%, lower limit of 90% two-sided confidence interval (CI) for difference, -12.4%]. In secondary analysis with success defined as plasma HIV-1 RNA <400 copies/mL, 87% (76/87) of patients in the lopinavir/ritonavir monotherapy group were virologically suppressed compared with 88% (87/99) in the cART group (difference, -0.5%, lower limit of 90% two-sided CI for difference, -8.5%). If antiretroviral treatment intensification was taken into account, 91% (79/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group (difference, +2.9%, lower limit of 90% two-sided CI for difference, -4.5%). Failures of lopinavir/ritonavir monotherapy did not show acquired resistance mutations in the protease gene.. Lopinavir/ritonavir monotherapy did not achieve non-inferiority versus cART for maintaining plasma HIV-1 RNA <50 copies/mL. Nevertheless, the incidence of virological failure was low (mostly with HIV-1 RNA <400 copies/mL) and easily managed by treatment intensification.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; France; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus.. In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir–emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death.. A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P=0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died.. In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir–emtricitabine was superior to nevirapine plus tenofovir–emtricitabine for initial antiretroviral therapy. (Funded by the National Institute of Allergy and Infectious Diseases and the National Research Center; ClinicalTrials.gov number, NCT00089505.).

Topics: Adenine; Adult; Anti-HIV Agents; Anti-Retroviral Agents; CD4 Lymphocyte Count; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Kaplan-Meier Estimate; Linear Models; Lopinavir; Nevirapine; Organophosphonates; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Ritonavir; Statistics, Nonparametric; Tenofovir; Treatment Failure; Young Adult

Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown.. We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board.. A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events.. Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Kaplan-Meier Estimate; Lopinavir; Male; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Failure

Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals.. HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2.. A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant.. In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.

Topics: Adenine; Adipose Tissue; Adult; Anti-HIV Agents; Blood Glucose; Carbamates; Confidence Intervals; Drug Administration Schedule; Drug Combinations; Dyslipidemias; Furans; HIV Infections; HIV-1; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Lopinavir; Male; Organophosphates; Organophosphonates; Pyrimidinones; Ritonavir; Sulfonamides; Tenofovir

The effect of HIV type-1 (HIV-1) subtype on in vitro susceptibility and virological response to darunavir (DRV) and lopinavir (LPV) was studied using a broad panel of primary isolates, and in recombinant clinical isolates from treatment-naive, HIV-1-infected patients in the Phase III trial, AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS).. Patients received DRV/ritonavir (DRV/r) 800/100 mg once daily (n=343) or LPV/ritonavir (LPV/r) 800/200 mg total daily dose (n=346), plus a fixed daily dose of emtricitabine and tenofovir disoproxil fumarate.. DRV demonstrated high antiviral activity against a broad panel of HIV-1 major group (M) and outlier group (O) primary isolates in peripheral blood mononuclear cells, with a median 50% effective concentration (EC(50)) of 0.52 nM. Most (61%) patients in ARTEMIS harboured HIV-1 subtype B; other prevalent subtypes were C (13%) and CRF01_AE (17%); 9% harboured other subtypes. Median EC(50) values (interquartile range) for DRV were 1.79 nM (1.3-2.6) for subtype B, 1.12 nM (0.8-1.4) for C and 1.27 nM (1.0-1.7) for CRF01_AE. Virological response to DRV/r (HIV-1 RNA<50 copies/ml [intent-to-treat, time-to-loss of virological response algorithm]) was 81%, 87% and 85% for patients with subtype B, C and CRF01_AE infections, respectively. Similar results were observed in the LPV/r treatment group.. In vitro susceptibility to DRV was comparable across HIV-1 subtypes in a broad panel of primary isolates and in recombinant clinical isolates. Once daily DRV/r 800/100 mg and LPV/r 800/200 mg were highly effective in ARTEMIS irrespective of the HIV-1 subtype studied, confirming their broad anti-HIV-1 activity.

Topics: Adamantane; Adult; Analysis of Variance; Atazanavir Sulfate; Carbamates; Darunavir; Drug Resistance, Viral; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Microbial Sensitivity Tests; Molecular Typing; Nelfinavir; Neuraminidase; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Saquinavir; Sulfonamides; Viral Load

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

Guidelines recommend that when soft-gelatin capsules of lopinavir/ritonavir are co-administered with CYP3A4-inducing agents, doses should be increased to 4 capsules (533 mg/133 mg) twice daily. No evidence is available to guide dosing of lopinavir/ritonavir in tablet formulation in this setting. A single-center study is conducted to compare the pharmacokinetics of high-dose lopinavir/ritonavir in 34 patients on stable HAART regimens including 4 soft-gelatin capsules twice daily who then switch to 3 tablets (600 mg/150 mg) twice daily. Median C(min) on soft-gelatin capsule and tablets is 4700 ng/mL (interquartile range [IQR] 2310, 6000 ng/mL) and 5640 ng/mL (IQR 4290, 8080 ng/mL), respectively, for those on inducing agents (n = 17). For patients not on inducing agents (n = 17), median C(min) on soft-gelatin capsule and tablets is 5170 ng/mL (IQR 3640, 6210 ng/mL) and 5640 ng/mL (IQR 4290, 8080 ng/mL), respectively. Among treatment-experienced patients on lopinavir/ritonavir capsules 533/133 mg twice daily, a switch to tablets 600/150 mg twice daily produces comparable pharmacokinetics, regardless of whether they receive concomitant CYP3A4-inducing antiretroviral agents.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Capsules; Cytochrome P-450 CYP3A; Drug Combinations; Drug Therapy, Combination; Enzyme Induction; Female; Gelatin; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Tablets

Preliminary studies suggest that the new film-coated tablet formulation of lopinavir/ritonavir (LPV/r-fct) could cut down the rate of adverse gastrointestinal symptoms of the conventional lopinavir/ritonavir soft gelatine capsules (LPV/r-sgc).. To ascertain the difference in the rate of adverse gastrointestinal symptoms in patients who switch from LPV/r-sgc to LPV/r-fct.. An uncontrolled, open, prospective study including a pre/post comparison using the Gastrointestinal Symptom Rating Scale (GSRS) modified to the characteristics of the protease inhibitors.. Seventy patients were included, with a mean time of treatment, with the new formulation of 77 days [confidence interval (CI) 95%: 70 to 84]. The total GSRS score was 26.96 (CI 95%: 25.02 to 28.89) in the prechange survey and 26.27 (CI 95%: 24.08 to 28.47) in the postchange survey, with a mean difference of 0.69 points (CI 95%: -1.18 to 2.55, P = 0.47). None of the questions obtained the objective of a difference of at least 2 points, previously set as a clinically significant difference. Only 1 patient dropped the study due to gastrointestinal toxicity.. Our study has unearthed no clinically significant differences in the gastrointestinal tolerance profile of (LPV/r-sgc) and (LPV/r-fct), measuring this tolerance level by application of the GSRS scale.

Topics: Adult; Aged; Drug Combinations; Female; Gastrointestinal Tract; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5- or R5X4-tropic virus.. A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed.. This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability.. While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.

Topics: Adult; Aged; Benzoates; Diketopiperazines; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Piperazines; Pyrimidinones; Receptors, CCR5; Ritonavir; RNA, Viral; Spiro Compounds; Young Adult

With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r).. A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants > or =14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 microg/mL and area under the curve (AUC) <170 microg hr/mL.. Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure.. Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.

Topics: Area Under Curve; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

Lopinavir/ritonavir (LPV/r)-dosed twice daily has demonstrated durable efficacy in antiretroviral-naive and protease inhibitor (PI) -experienced patients. Study M05-730 compared LPV/r tablets dosed once daily vs. twice daily in antiretroviral-naive subjects.. Six hundred sixty-four subjects were randomized to LPV/r soft gel capsules (SGCs) once daily, SGC twice daily, tablets once daily, and tablets twice daily, all with tenofovir and emtricitabine once daily. At week 8, all SGC-treated subjects were switched to tablets, maintaining randomized dose frequency. The primary efficacy analysis used an intent-to-treat, noncompleter = failure approach to assess noninferiority of the LPV/r once-daily group compared with the twice-daily group.. At week 48, 77% of once-daily-dosed subjects vs. 76% of twice-daily-dosed subjects had HIV-1 RNA <50 copies per milliliter (P = 0.715; 95% confidence interval for difference: 5% to 8%). Response rates were numerically similar between the once-daily and twice-daily groups among subjects with baseline HIV-1 RNA > or = 100,000 copies per milliliter (75% once daily vs. 74.6% twice daily; P > 0.999) or when analyzed by baseline CD4+ T-cell count (<50, 50 to <200, and > or = 200 cells/mm3). Rates of discontinuation and adverse events, including diarrhea, were similar between arms. Among subjects with protocol-defined virologic rebound through week 48, no new PI resistance mutations were detected.. At 48 weeks, the antiviral response in the LPV/r once-daily group was noninferior to the twice-daily group when coadministered with tenofovir and emtricitabine in antiretroviral-naive subjects. Efficacy was comparable between the once-daily and twice-daily groups regardless of baseline HIV-1 RNA or CD4+ T-cell count. Safety and tolerability of once-daily and twice-daily dosing was also comparable. No new PI resistance mutations were detected upon virologic rebound.

Topics: Adult; Capsules; Drug Administration Schedule; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Tablets

Topics: Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Male; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load; Zidovudine

Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC(0-4)), the maximum concentration of the drug (C(max)), and the residual concentration of the drug at the end of the dosing interval (C(trough)) for plasma and the AUC(0-4) and C(trough) for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC(0-4) was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and C(trough) values for women.

Topics: Adenine; Adult; Anti-HIV Agents; Area Under Curve; Cross-Sectional Studies; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Middle Aged; Organophosphonates; Pilot Projects; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome

Previous studies have demonstrated that lopinavir/ritonavir monotherapy maintained plasma HIV-1 RNA suppression in a large proportion of antiretroviral naive subjects. However, more subjects receiving lopinavir/ritonavir monotherapy experienced confirmed virologic rebound >50 copies/ml compared to a standard three-drug HAART regimen. In this study, we sought to determine the factors associated with maintenance of virologic suppression in subjects receiving lopinavir/ritonavir monotherapy. Antiretroviral-naive HIV-1-infected volunteers were randomized 2:1 to initiate a lopinavir/ritonavir-based combination regimen followed by simplification to lopinavir/ritonavir monotherapy or an efavirenz-based triple combination therapy and followed for 96 weeks. Potential predictors of time to loss of virologic response included baseline demographics, baseline HIV-1 RNA levels, baseline CD4(+) T cell counts, adherence as determined by 4-day subject recall, duration of HIV-1 RNA <50 copies/ml prior to simplification, and lopinavir concentrations. By the Cox proportional hazards model, higher reported adherence levels and higher baseline CD4(+) T cell counts were associated with a greater likelihood of maintaining virologic suppression while receiving lopinavir/ritonavir monotherapy. Lopinavir concentrations, including trough concentrations, were not significantly associated with virologic outcomes. This analysis suggests that adherence and higher baseline CD4(+) T cell counts may help to predict who will sustain virologic suppression with lopinavir/ritonavir monotherapy. The data also suggest that measuring lopinavir concentrations is not useful in predicting virologic response in these patients.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Medication Adherence; Plasma; Pyrimidinones; Ritonavir; Time Factors; Treatment Outcome; Viral Load; Zidovudine

Switching a thymidine analogue to a non-thymidine analogue or changing to a nucleoside-sparing regimen has been shown to partially reverse peripheral lipoatrophy. The current study evaluated both approaches.. Subjects at 15 AIDS Clinical Trial Group sites receiving thymidine analogue stavudine- or zidovudine-containing regimens with plasma HIV RNA < or =500 copies/mL and lipoatrophy were prospectively randomized to: (i) switch the thymidine analogue to abacavir; (ii) discontinue all antiretrovirals and switch to lopinavir/ritonavir plus nevirapine (LPV/r+NVP); or (iii) delay switching for 24 weeks (ClinicalTrials.gov identifier: NCT00028314). Single-slice computer tomography of mid-thigh and abdominal fat and metabolic and virological/immunological parameters were measured at baseline and weeks 24 and 48.. Among the 101 patients enrolled, there were significant subcutaneous thigh fat and subcutaneous abdominal tissue (SAT) increases over time and decreases in visceral adipose tissue to total adipose tissue (VAT:TAT) ratios for both interventions, and a decrease in VAT for abacavir. CD4 increased in the LPV/r+NVP arm. LPV/r+NVP had a significantly shorter time to grade 3 or higher toxicity (P = 0.007), but discontinuation rates were similar. Glucose levels did not change, but insulin decreased in the LPV/r+NVP arm. Lipids tended to increase in the LPV/r+NVP arm.. Switching stavudine or zidovudine to a non-thymidine analogue or changing to a nucleoside reverse transcriptase inhibitor-sparing regimen is associated with qualitatively similar improvements in thigh fat, SAT and VAT:TAT ratio at 48 weeks. Abacavir also resulted in VAT reductions and LPV/r+NVP resulted in CD4 count increases.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Intra-Abdominal Fat; Lopinavir; Male; Middle Aged; Nevirapine; Pyrimidinones; Radiography, Abdominal; Stavudine; Thigh; Viral Load; Zidovudine

MONARK is a pilot randomized trial comparing the safety and efficacy of lopinavir/ritonavir (LPV/r) monotherapy to a standard triple-drug regimen as initial therapy. The primary endpoint was virological response (VR) defined as viral load (VL)<400 copies/ml at week 24 and VL<50 copies/ml at week 48. The objective of this study was to determine prognostic factors of VR in patients receiving LPV/r monotherapy.. Baseline characteristics, including demographics, HIV type-1 (HIV-1) subtype (B versus non-B), early VR up to week 4, LPV trough concentrations and compliance were investigated as prognostic factors for VR in patients receiving LPV/r monotherapy. Logistic regression was used to search for variables significantly associated with the occurrence of VR.. VR was achieved in 53 out of 83 patients randomized to the LPV/r arm. The on-treatment analysis, using a multivariate model, indicated that having VL<400 copies/ml at week 4 and harbouring HIV-1 subtype B were independently associated with an increased probability of VR. No difference in early VL reduction was evidenced between patients harbouring B or non-B subtypes. The latter patients had more difficulty in adherence to therapy than the former patients. The intention-to-treat analysis showed similar results.. HIV-1 RNA measured at baseline or at week 4 and HIV-1 subtype (B versus non-B) were independent predictive factors of VR in patients starting therapy with LPV/r alone. Although based on a small sample size, results of this study showed that adherence to therapy is lower in patients harbouring non-B subtypes and appears to be a key factor of VR in the context of protease inhibitor monotherapy.

Topics: Adult; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Medication Adherence; Pilot Projects; Predictive Value of Tests; Prognosis; Pyrimidinones; Ritonavir; RNA, Viral; Viral Load

The OK04 trial has shown that 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy with 2 nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, it is still uncertain if this experimental strategy can maintain suppression in the long term.. Patients entered this noninferiority trial (upper limit 95% confidence interval: +12%) with no history of virological failure while receiving a protease inhibitor and receiving 2 nucleosides plus lopinavir/ritonavir, with HIV RNA <50 copies per milliliter for more than 6 months. Primary end point was percent of patients without therapeutic failure, defined as confirmed HIV RNA >500 copies per milliliter with exclusion of monotherapy patients who resuppressed to <50 copies per milliliter after resuming baseline nucleosides, or loss to follow-up, or change of randomized therapy other than reinduction.. Through 96 weeks, percentage of patient without therapeutic failure was 87% (monotherapy, n = 100) vs. 78% (triple therapy, n = 98; 95% confidence interval: -20% to +1.2%). Percentage with HIV RNA <50 copies per milliliter (intention to treat, missing = failure, reinduction = failure): 77% (monotherapy) vs. 78% (triple therapy). Low-level viral rebound was more frequent in the monotherapy group. Twelve patients in the monotherapy group (12%) needed reinduction with nucleosides. Discontinuations due to adverse events were significantly more frequent in the triple therapy group (8%) than in the monotherapy group (0%); P = 0.003.. At 96-week lopinavir/ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy. Incidence of adverse events leading to treatment discontinuation was significantly lower with monotherapy. (ClinicalTrials.gov number, NCT00114933).

Topics: Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Middle Aged; Nucleosides; Pyrimidinones; Ritonavir

To evaluate the efficacy and safety of switching from boosted lopinavir (LPV/r) to boosted atazanavir (ATV/r) in virologically suppressed HIV-1-infected patients versus continuing LPV/r.. Forty-eight weeks analysis of a randomized, open-label, noninferiority trial including patients with virological suppression (< or = 200 copies/mL for > or = 6 months) on LPV/r-containing triple highly active antiretroviral therapy. Patients (n = 248) were randomized 1:1 either to continue LPV/r twice a day (n = 127) or to switch to ATV/r every day (ATV/r; n = 121), with no change in nucleoside reverse transcriptase inhibitor backbone. Those known to have >4 protease inhibitor (PI)-associated mutations and/or who had failed >2 PI-containing regimens were excluded.. Baseline characteristics were balanced. 30% harboured > or = 1 PI-associated mutation (10% harboured > or = 1 major mutation). Treatment failure at 48 weeks (primary end point) occurred in 20% (25 of 127) of the LPV/r arm and in 17% (21 of 121) of the ATV/r arm (difference -2.3%; 95% confidence interval: -12.0 to 8.0; P = 0.0018). Virological failure occurred in 7% (9 of 127) of the LPV/r arm and in 5% (6 of 121) of the ATV/r arm (difference -2.1%; 95% confidence interval: -8.7% to 4.2%, P < 0.0001 for noninferiorating). CD4 changes from baseline were similar in each arm (approximately 40 cells/mm). Adverse event rate leading to study drug discontinuation was 5% in both arms. Median fasting triglycerides and total cholesterol decreased significantly in the ATV/r arm (-53 and -19 mg/dL, respectively versus -4 and -4 mg/dL in the LPV/r arm; P < 0.001 in both comparisons). Alanine aminotransferase/aspartate aminotransferase hepatic abnormalities were similar in the 2 arms.. Switching to ATV/r in virologically suppressed patients who were receiving a LPV/r-containing highly active antiretroviral therapy provided comparable (noninferior) efficacy and a safety profile with improved lipid parameters [ISRCTN24813210].

Topics: Adult; Alanine Transaminase; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Aspartate Aminotransferases; Atazanavir Sulfate; Drug Resistance, Viral; Drug Tolerance; Female; HIV Infections; HIV-1; Humans; Lipids; Liver; Lopinavir; Male; Middle Aged; Mutation; Oligopeptides; Pyridines; Pyrimidinones; Safety

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

We studied changes in bone mineral density (BMD) and bone turnover after initiation of combination antiretroviral therapy (cART) and the contribution of zidovudine/lamivudine (ZDV/3TC) in particular.. Randomized clinical trial comparing lopinavir/ritonavir(LPV/r) + ZDV/3TC with LPV/r + nevirapine (NVP) in 50 cART-naive men.. Dual energy X-ray absorptiometry (DXA) and quantitative computed tomography scans (QCT) were performed at baseline and 3, 12, and 24 months after cART initiation. Serum 25-hydroxy-vitamin D3, parathyroid hormone (PTH), osteocalcin, and urine deoxypyridinoline (DPD)/creatinine ratio were measured.. BMD decreased rapidly in both femoral neck and lumbar spine after cART initiation. BMD loss during 24 months measured by DXA, but not by QCT, was greater in the ZDV/3TC/LPV/r group compared to the NVP/LPV/r group [femoral neck: -6.3% +/- 1.0% (P < 0.0001) compared to -2.3% +/- 0.9% (P = 0.01), between-group P = 0.0006); lumbar spine: -5.1% +/- 0.8% (P < 0.0001) compared to -2.6% +/- 0.7% (P = 0.0006), between-group P = 0.07]. Osteocalcin [+1.60 +/- 0.32 (P < 0.0001) and +1.81 +/- 0.29 (P < 0.0001) nmol/l] and the urine DPD/creatinine ratio [+1.35 +/- 0.44 (P = 0.0029) and +1.19 +/- 0.38 nmol/mmol (P = 0.0024)] increased in both groups over 24 months, with no significant difference between groups. PTH increased to a greater degree in the NVP/LPV/r group [+2.0 +/- 0.31 pmol/l (P < 0.0001)] compared to [+0.81 +/- 0.33 pmol/l (P = 0.021) in the ZDV/3TC/LPV/r group].. BMD in both femoral neck and lumbar spine decreased rapidly after initiation of cART, in parallel to an increase in bone turnover. The greater bone loss in the ZDV/3TC/LPV/r group compared to the NVP/LPV/r group suggests that ZDV/3TC contributes to this process. The PTH increase does not explain this greater bone loss.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bone Density; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Osteoporosis; Pyrimidinones; Ritonavir; Young Adult; Zidovudine

The MONARK study was a pilot randomized trial comparing the safety and efficacy of lopinavir-ritonavir (LPV/r) monotherapy to those of LPV/r-zidovudine-lamivudine triple therapy for antiretroviral-naïve human immunodeficiency virus type 1 (HIV-1)-infected patients. Resistance testing was performed at the time of initial screening and at the time of virological failure (defined to include low-level viremia with >50 and <400 HIV-1 virus RNA copies/ml of plasma). Changes from the baseline sequences, including mutations noted on the 2008 International AIDS Society-USA list of resistance-associated protease mutations, were considered. Drug resistance testing was performed for 38 patients (5 of 53 on triple therapy and 33 of 83 on monotherapy). By week 96 (W96), virus samples from 18 of 33 patients in the monotherapy arm showed changes from baseline sequences, and 5 of these patients had viruses with major protease inhibitor (PI) resistance-associated mutations (M46I at W40, L76V at W48, M46I and L76V at W48, L10F and V82A at W72, and L76V at W84). Data on virus phenotypes detected at the time of initial screening and the time of virological failure were available for four patients in whom major PI resistance mutations developed, and these data revealed a mean increase of 2.2-fold (range, 0.75- to 4.6-fold) in the LPV 50% inhibitory concentration. All three patients in whom the L76V PI resistance mutation developed were infected with HIV-1 subtype CRF02_AG. In the triple-therapy group, no major PI resistance mutation was selected among the three patients with protease changes by W48. No association between the baseline CD4 cell count and the viral load, the W4 and final viral loads, or the final LPV trough concentration and the emergence of a major PI resistance mutation was found. Major PI resistance-associated mutations were detected in 5 (6%) of 83 patients treated with LPV/r monotherapy, suggesting that LPV/r monotherapy is an inappropriate first option. The mutation L76V may be considered in further studies of lopinavir resistance.

Topics: Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome; Zidovudine

Characterization of resistance development in virologic failure patients on the protease inhibitor darunavir administered with low-dose ritonavir (DRV/r) in the 48-week analysis of TMC114/r In Treatment-experienced pAtients Naive to lopinavir (TITAN).. TITAN is a randomized, controlled, open-label, phase III, noninferiority trial comparing the efficacy and safety of DRV/r with that of lopinavir/ritonavir (LPV/r) in HIV-1-infected, treatment-experienced, LPV-naive patients. The primary endpoint was the proportion of patients with HIV-1 RNA less than 400 copies/ml at week 48.. Patients received DRV/r 600/100 mg twice daily (n = 298) or LPV/r 400/100 mg twice daily (n = 297), and an optimized background regimen. Patients who lost or never achieved HIV-1 RNA less than 400 copies/ml after week 16 were considered virologic failure patients. Genotyping and phenotyping were performed.. The virologic failure rate in the DRV/r arm (10%, n = 31) was lower than in the LPV/r arm (22%, n = 65). Furthermore, fewer virologic failure patients in the DRV/r arm than in the LPV/r arm developed primary protease inhibitor mutations (6 vs. 20) or nucleoside reverse transcriptase inhibitor resistance-associated mutations (4 vs. 15). In addition, fewer virologic failure patients on DRV/r than on LPV/r lost susceptibility to the protease inhibitor (3 vs. 13) or nucleoside reverse transcriptase inhibitor(s) (3 vs. 14) used in the treatment regimen or to other protease inhibitors. Most DRV/r-treated virologic failure patients retained susceptibility to all protease inhibitors.. In treatment-experienced, LPV-naive patients, the overall virologic failure rate in the DRV/r arm was low and was associated with limited resistance development. These findings showed that the use of DRV/r in earlier lines of treatment was less likely to lead to cross-resistance to other protease inhibitors compared with LPV/r.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sulfonamides; Treatment Failure; Viral Load

To determine the effects of switching from lopinavir/ritonavir (LPV/r) to atazanavir/ritonavir (ATV/r) on muscle glucose uptake, glucose homeostasis, lipids, and body composition.. Fifteen HIV-infected men and women on a regimen containing LPV/r and with evidence of hyperinsulinemia and/or dyslipidemia were randomized to continue LPV/r or to switch to ATV/r (ATV 300 mg and ritonavir 100 mg daily) for 6 months. The primary endpoint was change in thigh muscle glucose uptake as measured by positron emission tomography. Secondary endpoints included abdominal visceral adipose tissue, fasting lipids, and safety parameters. The difference over time between treatment groups (treatment effect of ATV/r relative to LPV/r) was determined by repeated measures ANCOVA.. After 6 months, anterior thigh muscle glucose uptake increased significantly (treatment effect +18.2 +/- 5.9 micromol/kg per min, ATV/r vs. LPV/r, P = 0.035), and visceral adipose tissue area decreased significantly in individuals who switched to ATV/r (treatment effect -31 +/- 11 cm, ATV/r vs. LPV/r, P = 0.047). Switching to ATV/r significantly decreased triglyceride (treatment effect -182 +/- 64 mg/dl, ATV/r vs. LPV/r, P = 0.02) and total cholesterol (treatment effect -23 +/- 8 mg/dl, ATV/r vs. LPV/r, P = 0.01), whereas high-density lipoprotein and low-density lipoprotein did not change significantly. Fasting glucose also decreased significantly following switch to ATV/r (treatment effect -15 +/- 4 mg/dl, ATV/r vs. LPV/r, P = 0.002).. Switching from LPV/r to ATV/r significantly increases glucose uptake by muscle, decreases abdominal visceral adipose tissue, improves lipid parameters, and decreases fasting glucose over 6 months.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Female; Glucose; HIV Infections; HIV Protease Inhibitors; Humans; Intra-Abdominal Fat; Lipid Metabolism; Lopinavir; Male; Middle Aged; Muscle, Skeletal; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir

Lipoatrophy is known to be associated with stavudine as part of the treatment for HIV infection, but it is less clear if this serious side effect is also related to other nucleoside reverse transcriptase inhibitors like zidovudine. We aimed to determine whether zidovudine-sparing first-line antiretroviral therapy would lead to less lipoatrophy and other metabolic changes than zidovudine-containing therapy.. Fifty antiretroviral therapy-naïve HIV-1 infected men with an indication to start antiretroviral therapy were included in a randomized single blinded clinical trial. Randomisation was between zidovudine-containing therapy (zidovudine/lamivudine+lopinavir/ritonavir) and zidovudine-sparing therapy (nevirapine+lopinavir/ritonavir). Main outcome measures were body composition assessed by computed tomography and dual-energy X-ray absorptiometry scan and lipid profile before and after 3, 12, 24 months of antiretroviral therapy. In the zidovudine/lamivudine+lopinavir/ritonavir group, from 3 months onward limb fat decreased progressively by 684+/-293 grams (estimated mean+/-standard error of the mean)(p = 0.02) up to 24 months whereas abdominal fat increased, but exclusively in the visceral compartment (+21.9+/-8.1 cm(2), p = 0.008)). In contrast, in the nevirapine+lopinavir/ritonavir group, a generalized increase in fat mass was observed. After 24 months no significant differences in high density lipoprotein and total/high density lipoprotein cholesterol ratio were found between both treatment groups, but total and low density lipoprotein cholesterol levels were higher in the nevirapine+lopinavir/ritonavir group (6.1+/-0.2 versus 5.3+/-0.2 and 3.6+/-0.1 versus 2.8+/-0.1 mmol/l respectively, p<0.05). Virologic response and safety were comparable in both groups.. Zidovudine/lamivudine+lopinavir/ritonavir, but not nevirapine+lopinavir/ritonavir in antiretroviral therapy-naïve patients, is associated with lipoatrophy and greater relative intraabdominal lipohypertrophy, suggesting that zidovudine/lamivudine contributes to both these features of lipodystrophy. These findings support to no longer consider zidovudine/lamivudine as one of the preferred possible components of first-line antiretroviral therapy where alternative treatments are available.. ClinicalTrials.gov NCT 00122226.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Biomarkers; Body Composition; Glucose; HIV Infections; HIV-1; Humans; Lamivudine; Lipids; Lipodystrophy; Lopinavir; Male; Middle Aged; Pyrimidinones; Zidovudine

Present 96-week data from ongoing ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In Naive Subjects) trial.. Randomized, open-label, phase III trial of antiretroviral-naive patients with HIV-1 RNA at least 5000 copies/ml (stratified by HIV-1 RNA and CD4 cell count) receiving darunavir/ritonavir (DRV/r) 800/100 mg once daily or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose (twice daily or once daily) and fixed-dose tenofovir/emtricitabine. Primary outcome measure was noninferiority of DRV/r vs. LPV/r in virologic response (<50 copies/ml, time-to-loss of virologic response) at 96 weeks (secondary outcome: superiority).. Six hundred eighty-nine patients were enrolled. At week 96, significantly more DRV/r (79%) than LPV/r patients (71%) had viral load less than 50 copies/ml, confirming statistical noninferiority (estimated difference: 8.4%; 95% confidence interval 1.9-14.8; P < 0.001; per-protocol) and superiority (P = 0.012; intent-to-treat) in virologic response. Median CD4 cell count increases from baseline were 171 and 188 cells/microl for DRV/r and LPV/r, respectively (P = 0.57; noncompleter=failure). Overall, 4% of DRV/r patients and 9% of LPV/r patients discontinued treatment due to adverse events. Lower rates of grade 2-4 treatment-related diarrhea were seen with DRV/r (4%) vs. LPV/r (11%; P < 0.001), whereas grade 2-4 treatment-related rash occurred infrequently in both arms (3 vs. 1%, respectively; P = 0.273). DRV/r patients had smaller median increases in triglycerides (0.1 and 0.6 mmol/l, respectively, P < 0.0001) and total cholesterol (0.6 and 0.9 mmol/l, respectively; P < 0.0001) than LPV/r patients; levels remained below National Cholesterol Education Program cut-offs for DRV/r.. At week 96, once-daily DRV/r was both statistically noninferior and superior in virologic response to LPV/r, with a more favorable gastrointestinal and lipid profile, confirming DRV/r as an effective, well tolerated, and durable option for antiretroviral-naive patients.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Darunavir; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

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

Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients.. Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks.. At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups.. Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Double-Blind Method; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

Once-daily lopinavir/ritonavir (LPV/r) is not approved for treatment of HIV paediatric patients. Once daily treatment in children might serve the same goals of patient comfort and adherence as in adults.. HIV type-1-infected children aged 6 months to 18 years, who were virologically suppressed on an LPV/r-containing regimen, were eligible. Treatment 1 consisted of once-daily LPV/r 460/115 mg/m(2), plus two nucleoside reverse transcriptase inhibitors (NRTIs). Treatment 2 consisted of twice-daily LPV/r 230/57.5 mg/m(2) plus two NRTIs. Patients were randomized either to start with treatment 1 followed by treatment 2 or vice versa. Full pharmacokinetic profiles were analysed for lopinavir and ritonavir with a validated HPLC tandem mass spectrometry assay.. Seven patients (five girls and two boys) were included in the study. Median age was 9.8 years (range 5.8-15.5). For the once-daily treatment, the median (range) lopinavir 24 h area under the plasma -concentration-time curve (AUC(24 h)), maximum plasma concentration (C(max)) and 24 h plasma concentration (C(24 h)) were 214.6 h*mg/l (114.2-289.2), 13.5 mg/l (8.3-17.5) and 3.4 mg/l (0.6-7.4), respectively. For the twice-daily treatment the median (range) lopinavir 12 h area under the plasma concentration-time curve (AUC(12 h)), C(max) and 12 h plasma concentration (C(12 h)) were 80.9 h*mg/l (23.3-135.9), 9.8 mg/l (3.4-15.2) and 5.7 mg/l (1.7-9.7), respectively.. This study suggests that the pharmacokinetics of lopinavir after twice-daily and once-daily dosing are similar, with no observable difference in tolerability, in this group of patients between 5 and 15 years old.

Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Cross-Over Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

Success of antiretroviral therapy depends on high rates of adherence, but few interventions are effective. Our objective was to determine if modified directly observed therapy (mDOT) improves initial antiretroviral success.. In an open-label, randomized trial comparing mDOT (Monday-Friday for 24 weeks) and self-administered therapy with lopinavir/ritonavir soft gel capsules (800 mg/200 mg), emtricitabine (200 mg), and either extended-release stavudine (100 mg) or tenofovir (300 mg), all taken once daily, 82 participants received mDOT and 161, self-administered therapy. Participant eligibility included a plasma human immunodeficiency virus RNA level higher than 2000 copies/mL and being naïve to antiretroviral therapy. A total of 243 participants were predominantly male (79%) (median age, 38 years), with 84 Latinos (35%), 74 non-Latino blacks (30%), and 79 non-Latino whites (33%). The study was conducted at 23 AIDS Clinical Trials Group (ACTG) sites in the United States and 1 site in South Africa between October 2002 and January 2006. The primary outcome was virologic success at week 24 and secondary outcomes were virologic success, clinical progression, and adherence at week 48.. Over 24 weeks, mDOT had greater virologic success (0.91; 95% confidence interval [CI], 0.81 to 0.95) than self-administered therapy (0.84; 95% CI, 0.77 to 0.89), but the difference (0.07; lower bound 95% CI, -0.01) did not reach the prespecified threshold of 0.075. Over 48 weeks, virologic success was not significantly different between mDOT (0.72; 95% CI, 0.61 to 0.81) and self-administered therapy (0.78; 95% CI, 0.70 to 0.84) (difference, -0.06; 95% CI, -0.18 to 0.07 [P = .19]).. The potential benefit of mDOT was marginal and not sustained after discontinuation. Modified DOT should not be incorporated routinely for care of treatment-naïve human immunodeficiency virus type 1-infected patients.

Topics: Adenine; Administration, Oral; Adolescent; Adult; Aged; Anti-HIV Agents; Deoxycytidine; Dose-Response Relationship, Drug; Emtricitabine; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Organophosphonates; Pyrimidinones; Retrospective Studies; RNA, Viral; Stavudine; Tenofovir; Treatment Outcome; Young Adult

Genotypic algorithms used to predict the clinical efficacy of lopinavir/ritonavir (LPV/r) have included a range of mutation lists and efficacy endpoints. Normally, HIV clinical trials are powered to detect a difference between treatment arms of 10-12% for the endpoint of viral load suppression <50 HIV-1 RNA copies/mL. The TITAN trial evaluated LPV/r vs. darunavir/ritonavir (DRV/r) in treatment-experienced patients with viral load >1000 copies/mL. This analysis aimed to re-evaluate resistance algorithms for LPV/r in the TITAN trial.. Baseline genotype data were classified using seven genotypic resistance algorithms: International AIDS Society USA (IAS-USA) LPV mutations (current cut-off=6), Abbott 2007 mutation list (cut-off=3), ANRS mutations (cut-off=4), FDA mutations (cut-off=3), Stanford, REGA and IAS-USA major protease inhibitor (PI) mutations. Efficacy in the TITAN trial (HIV-1 RNA <50 copies/mL at week 48) was correlated with the number of mutations from each list, to show the 'efficacy advantage cut-off level': the number of mutations from each list associated with a difference in efficacy between treatment arms of at least 12%.. Multivariate logistic regression analysis identified lower genotypic cut-off levels than previously reported where there was at least 12% lower efficacy for LPV/r vs. DRV/r. These efficacy advantage cut-off levels were: IAS-USA LPV mutations, cut-off=3; Abbott 2007, cut-off=2; ANRS LPV, cut-off=3; FDA LPV mutations, cut-off=2; major IAS-USA PI mutations, cut-off=1; Stanford algorithm, cut-off=low-level LPV resistance; REGA algorithm, cut-off=intermediate-level LPV resistance. There were linear falls in HIV-1 RNA suppression rates with rising mutation counts in the TITAN, French LPV ATU, BMS-045 and RESIST trials.. The analysis identified more sensitive cut-off levels for LPV genotypic algorithms, below those currently used.

Topics: Adult; Algorithms; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Intention to Treat Analysis; Logistic Models; Lopinavir; Male; Mutation; Pyrimidinones; Ritonavir; RNA, Viral; Sensitivity and Specificity; Sulfonamides; Treatment Outcome; Viral Load

Nucleoside reverse-transcriptase inhibitor (NRTI)-related mitochondrial toxicity has been suggested as a key factor in the induction of antiretroviral-related lipoatrophy. This study aimed to evaluate in vivo the effects of NRTI withdrawal on mitochondrial parameters and body fat distribution.. A multicenter, prospective, randomized trial assessed the efficacy and tolerability of switching to lopinavir-ritonavir plus nevirapine (nevirapine group; n = 34), compared with lopinavir-ritonavir plus 2 NRTIs (control group; n = 33) in a group of human immunodeficiency virus-infected adults with virological suppression. A subset of 35 individuals (20 from the nevirapine group and 15 from the control group) were evaluated for changes in the mitochondrial DNA (mtDNA) to nuclear DNA ratio and cytochrome c oxidase (COX) activity after NRTI withdrawal. Dual-energy X-ray absorptiometry (DEXA) scans were used to objectively quantify fat redistribution over time.. The nevirapine group experienced a progressive increase in mtDNA content (a 40% increase at week 48; P = .039 for comparison between groups) and in the COX activity (26% and 32% at weeks 24 and 48, respectively; P = .01 and P = .09 for comparison between groups, respectively). There were no statistically significant between-group differences in DEXA scans at week 48, although a higher fat increase in extremities was observed in the nevirapine group. No virologic failures occurred in either treatment arm.. Switching to a nucleoside-sparing regimen of nevirapine and lopinavir-ritonavir maintained full antiviral efficacy and led to an improvement in mitochondrial parameters, which suggests a reversion of nucleoside-associated mitochondrial toxicity. Although DEXA scans performed during the study only revealed slight changes in fat redistribution, a longer follow-up period may show a positive correlation between reduced mitochondrial toxicity and a clinical improvement of lipodystrophy.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; DNA, Mitochondrial; Drug Therapy, Combination; Electron Transport Complex IV; Extremities; Female; Follow-Up Studies; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lipids; Lopinavir; Male; Middle Aged; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load

Lopinavir/ritonavir is a common protease inhibitor (PI) used for second-line regimens in children. Several studies have shown higher plasma concentrations of antiretroviral agents in Thai adults than in Caucasians, suggesting that lower doses may be used.. An open label study in 24 HIV-infected children between the age of 2 and 18 years, naive to PIs, randomized to receive either the WHO-recommended dose of lopinavir/ritonavir or a low dose (70% of the standard dose) twice daily in combination with zidovudine and lamivudine. A 12 h pharmacokinetic study was done at 4-6 weeks after starting treatment. Treatment outcomes were evaluated at week 48. The clinical trial number of the study is NCT00887120.. The medians [interquartile ranges (IQRs)] of age, body surface area, percentage CD4 and plasma HIV RNA were 9.5 years (7.0-12.3), 0.9 m(2) (0.8-1.1), 17% (11%-24%) and 4.6 log(10) copies/mL (4.1-4.9), respectively. The median (IQR) lopinavir dose was 279 mg/m(2)/dose (263-294) and 194 mg/m(2)/dose (176-206) in the standard and low-dose arms, respectively. Median (IQR) AUC(0-12) and C(trough) of lopinavir were 117.6 mg.h/L (74.0-128.5) and 4.9 mg/L (2.7-8.0) for the standard arm and 83.8 mg.h/L (56.0-112.9) and 3.4 mg/L (2.7-5.4) for the low-dose arm. One child in the low-dose arm had a lopinavir pre-dose level of <1.0 mg/L. At week 48, the median percentage CD4 was 22% (15%-28%) and 27% (21%-31%) in the standard and low-dose arms, respectively, while 50% and 83% of children had HIV RNA <50 copies/mL, respectively (P = 0.19).. Low-dose lopinavir displayed adequate pharmacokinetic parameters and good efficacy as compared with standard-dose lopinavir in Thai children. A larger study to investigate the efficacy of low-dose lopinavir is warranted.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Plasma; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV)-coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir-exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm3. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence.

Topics: Adult; Anti-Retroviral Agents; Cyclosporine; Dose-Response Relationship, Drug; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Lopinavir; Male; Middle Aged; Peptide Fragments; Pyrimidinones; Ritonavir; Tacrolimus; Treatment Outcome

Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir.. We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed.. Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C(max)) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C(max) values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C(max) values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance.. The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

Topics: Adult; Antibiotics, Antitubercular; Antiviral Agents; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Rifabutin; Ritonavir; Tuberculosis

Efavirenz and lopinavir boosted with ritonavir are both recommended as first-line therapies for patients with HIV when combined with two nucleoside reverse transcriptase inhibitors. It is uncertain which therapy is more effective for patients starting therapy with an advanced infection.. We estimated the relative effect of these two therapies on rates of virological and immunological failure within the Swiss HIV Cohort Study and considered whether estimates depended on the CD4(+) T-cell count when starting therapy. We defined virological failure as either an incomplete virological response or viral rebound after viral suppression and immunological failure as failure to achieve an expected CD4(+) T-cell increase calculated from EuroSIDA statistics.. Patients starting efavirenz (n=660) and lopinavir (n=541) were followed for a median of 4.5 and 3.1 years, respectively. Virological failure was less likely for patients on efavirenz, with the adjusted hazard ratio (95% confidence interval) of 0.63 (0.50-0.78) then multiplied by a factor of 1.00 (0.90-1.12) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. Immunological failure was also less likely for patients on efavirenz, with the adjusted hazard ratio of 0.68 (0.51-0.91) then multiplied by a factor of 1.29 (1.14-1.46) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy.. Virological failure is less likely with efavirenz regardless of the CD4(+) T-cell count when starting therapy. Immunological failure is also less likely with efavirenz; however, this advantage disappears if patients start therapy with a low CD4(+) T-cell count.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cohort Studies; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Lopinavir; Medication Adherence; Organophosphonates; Pyrimidinones; Ritonavir; Self Administration; Stavudine; Tenofovir; Treatment Outcome

Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation.. In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (C(min)) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra((R)) soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann-Whitney U test was used to compare the groups.. A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of intolerance. The median (interquartile range) lopinavir C(min) was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C(min) levels was found between Kaletra((R)), and the generic product (P=0.224). By contrast, the C(min) of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients.. The generic lopinavir/ritonavir tablet showed C(min) plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle- and low-income countries.

Topics: Adult; Drug Administration Schedule; Drug Combinations; Drugs, Generic; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrimidinones; Ritonavir; Tablets

The central nervous system may act as a sanctuary site for viral replication in the setting of low antiretroviral penetration. Data on lopinavir cerebrospinal fluid (CSF) trough concentration (C(trough)) values have yet to be reported.. To describe lopinavir CSF C(trough) values and compare them with a measure of HIV susceptibility.. In a prospective, open-label design, HIV-infected adults whose regimen included lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily for at least 4 weeks were enrolled. Each subject had 8 plasma lopinavir concentrations determined over a 12-hour dosing interval and 1 CSF lopinavir C(trough) value determined at the end of the study. Linear regression methods tested for associations between CSF or CSF to plasma concentration ratio and covariates including pharmacokinetic parameters and CSF protein.. Ten patients (7 male; median [range] +/- SD age 45.3 +/- 2.8 y) completed the study. Median (intraquartile range [IQR]) lopinavir plasma 0- to 12-hour area under the curve (AUC(0-12)) and minimum concentrations were 71.3 h x microg/mL (48.4-87.6) and 3.82 microg/mL (2.76-5.34). Median (IQR) CSF C(trough), paired plasma concentration, and time since last dose were 11,200 pg/mL (6760-16,400), 5.42 microg/mL (3.88-5.85), and 9.9 hours (9.7-10.2), respectively. Median (IQR) CSF to plasma concentration ratio was 0.225% (0.194-0.324). Lopinavir CSF C(trough) was above the median 50% inhibitory concentration (IC(50)) for wild-type HIV-1 (wtHIV-1) (1900 pg/mL) in all subjects. Lopinavir plasma AUC(0-12) (r(2) = 0.65; p = 0.009) and CSF protein (r(2) = 0.26; p = 0.006) were associated with lopinavir CSF concentration, while CSF protein (r(2) = 0.66; p = 0.008) was associated with CSF to plasma concentration ratio.. Lopinavir CSF C(trough) was above the median IC(50) for wtHIV-1 replication in all patients receiving lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily.

Topics: Adult; Area Under Curve; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Inhibitory Concentration 50; Linear Models; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; Time Factors; Virus Replication

To assess the 48-week efficacy, safety, pharmacokinetics, and resistance of double boosted protease inhibitors (PI), saquinavir (SQV), and lopinavir/ritonavir (LPV/r), in children who have failed nucleoside reverse transcription inhibitors /non-nucleoside reverse transcription inhibitors-based regimens.. Fifty children at 2 sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4, HIV-RNA viral load (VL), plasma drug concentrations and safety laboratory evaluations were monitored. Virologic failure was defined as having 2 consecutive VL >400 copies/mL after week 12 of therapy. Intention to treat analysis was performed.. Baseline data were a median age of 9.3 years (interquartile range [IQR]: 7.1-11.2), Center for Disease Control and Prevention (CDC) classification N:A:B:C 4%:14%:68%:14%, VL 4.8 log10 (IQR: 4.5-5.1), CD4 7% (IQR: 3-9.5). At 48 weeks, 3 had died of bacterial infection but no cases had progressed CDC classification. Median CD4% rise was 9 (IQR: 5-16) and median HIV RNA reduction was -2.8 log10 (IQR: -3.2 to -1.4), both P < 0.001. Thirty-nine (78%) and 32 (64%) children had VL <400 and <50 with significant differences between the 2 sites. Five children (10%) had VL failure as a result of poor adherence to the drug regimen but no one had major PI mutations. Median serum cholesterol and triglyceride increased significantly (+35 mg/dL, +37 mg/dL, respectively, both P < 0.001). Mean minimum plasma concentrations (Cmin) of LPV and SQV were 4.6 and 1.24 mg/L, respectively.. Double boosted SQV/LPV/r resulted in significant CD4 rise and VL decline at 48 weeks. Hyperlipidemia was common. Cmin of both PIs exceeded therapeutic concentrations. Poor adherence caused failure in 10%. No major PI mutations were found.

Topics: Anti-HIV Agents; Blood Chemical Analysis; CD4 Lymphocyte Count; Child; Cholesterol; Drug Resistance, Viral; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Saquinavir; Thailand; Treatment Refusal; Triglycerides; Viral Load

Liver disease may alter the pharmacokinetics of antiretrovirals and produce changes in plasma protein binding. The aim was to evaluate the pharmacokinetics of total and unbound lopinavir (LPV) in HIV-infected patients with and without hepatitis C virus (HCV) coinfection. Fifty-six HIV+ patients receiving lopinavir/ritonavir (LPV/r) (group I = 24 controls; II = 23 HIV/HCV-coinfected; III = 9 cirrhotic HIV/HCV-coinfected) were included. Total (n = 56) and unbound (n = 36) LPV pharmacokinetic parameters were determined at steady-state using validated high-performance liquid chromatography with ultraviolet detection and high-performance liquid chromatography-tandem mass spectrometry methods, respectively. Pharmacokinetic parameters (plasma concentration just before drug administration, peak concentrations in plasma, times to maximum plasma concentration, areas under the plasma concentration-time curve from 0 to 12 hours, and CL/F/kg) of both total and unbound LPV were calculated by standard noncompartmental methods and differences among groups evaluated (Kruskal-Wallis test).LPV apparent oral clearance normalized to body weight (median, interquartile range) was 55 (40-68), 59 (44-69), and 71 (53-78) mL/h/kg for groups I, II, and III, respectively (II vs. I, P = 0.52; III vs. I, P = 0.16). The areas under the plasma concentration-time curve from 0 to 12 hours were 110.4 (80.9-135.2), 103.4 (85.5-131.3), and 92.8 (87.4-116.3) microg h/mL for groups I, II, and III, respectively (II vs. I, P = 0.68; III vs. I, P = 0.71). Chronic liver impairment produced a slight, although not significant, decrease in plasma protein binding. The free-fraction of LPV increased ( approximately 21%) from 0.97% (0.80-1.06) in HIV+/HCV- patients to 1.18% (0.89-1.65) in HIV/HCV+ cirrhotic patients. The apparent oral clearance of unbound LPV (CLu/F/kg) in cirrhotic patients did not change significantly, supporting the concept that the clearance of unbound LPV in liver disease is not affected after being inhibited by low-dose ritonavir co-administration.LPV total and unbound pharmacokinetics were not affected by hepatic impairment, suggesting that no adjustment of LPV/r dose is required for HIV/HCV-coinfected patients with and without cirrhosis and moderate impairment of liver function.

Topics: Adult; Area Under Curve; Body Weight; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver Cirrhosis; Liver Function Tests; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Risk Factors; Ritonavir; Spectrophotometry, Ultraviolet; Ultrafiltration; Ultrasonography

The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) compares the efficacy and safety of once-daily darunavir/ritonavir (DRV/r) with that of lopinavir/ritonavir (LPV/r) in treatment-naive patients.. Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III, open-label trial, and randomized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitabine for 192 weeks. The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per-protocol time-to-loss of virologic response at 48 weeks.. Six hundred and eighty-nine patients were randomized and treated; mean baseline HIV-1 RNA: 4.85 log10 copies/ml and median CD4 count: 225 cells/microl. At 48 weeks, 84% of DRV/r and 78% of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (estimated difference = 5.6 [95% confidence interval -0.1-11]%), demonstrating non-inferiority of DRV/r as compared with LPV/r (P < 0.001; per-protocol time-to-loss of virologic response). Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r (79%) versus LPV/r (67%; P < 0.05). Median CD4 cell count increases (non-completer = failure; cells/mul) were 137 for DRV/r and 141 for LPV/r. DRV/r had a lower incidence of possibly treatment-related grade 2-4 gastrointestinal-related adverse events (7 versus 14%) and treatment-related moderate-to-severe diarrhea (4 versus 10%) than LPV/r. Adverse events leading to discontinuation were DRV/r: 3% and LPV/r: 7%.. DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml. DRV/r 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients.

Topics: Adult; CD4 Lymphocyte Count; Darunavir; Drug Administration Schedule; Drug Combinations; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load; Weight Gain

Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m(2) orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m(2) p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m(2) p.o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years (range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of >0.75 log(10), with a median maximal decrease in viral load of -1.57 log(10) copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 (range, 62.8 to 305.5) microg x h/ml and median LPV trough concentration (C(trough)) of 10.8 (range, 4.1 to 25.3) microg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) microg x h/ml and the median SQV C(trough) was 2.1 (range, 0.2 to 4.1) microg/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach.

Topics: Adolescent; Anti-HIV Agents; Child; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Treatment Outcome

Topics: Atazanavir Sulfate; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oligopeptides; Pyridines; Pyrimidinones; Viral Load

Recent data indicate that fosamprenavir/ritonavir as part of an initial antiretroviral regimen in HIV-1-infected patients is associated with favourable efficacy and tolerability and in the KLEAN study (kaletra versus lexiva with epivir and abacavir in antiretroviral-naive patients) it was found to be non-inferior to lopinavir/ritonavir in association with abacavir/lamivudine. In our open-label, observational study conducted in 82 therapy-nasmall yi, Ukrainianve HIV-1-infected patients followed-up for 18 months, virological and immunological efficacy was comparable in subjects receiving a fosamprenavir/ritonavir-based and a lopinavir/ritonavir-based treatment (proportions of patients with HIV RNA <50 copies/mL at month 18 were 76.9% and 74.4%, respectively, when discontinuations were counted as failures). At the same time, frequency of treatment discontinuations and adverse events were similar in both groups, whereas incidence of diarrhoea and hypertriglyceridaemia was significantly higher in lopinavir-treated patients than in fosamprenavir-treated ones (53.5% vs. 25.6% and 69.8% vs. 43.6%, respectively; P < 0.01). In subjects with virological failure, no viral protease resistance mutations were detected by genotype analysis.

Topics: Adult; Anti-HIV Agents; Carbamates; Diarrhea; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease; HIV-1; Humans; Hypertriglyceridemia; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Failure; Treatment Outcome

Topics: Adult; Blood Glucose; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Insulin Resistance; Lipids; Lopinavir; Male; Pyrimidinones; Risk Factors; Ritonavir

Standard-of-care for HIV-infected patients consists of combining three antiretroviral drugs. However, other therapeutic strategies could be beneficial given long-term toxicity and quality of life (QOL) issues associated with taking multiple antiretroviral drugs for many years. In the prospective, open label, randomized, pilot monotherapy antiretroviral Kaletra (MONARK) trial among antiretroviral-naive patients, lopinavir/ritonavir (LPV/r) monotherapy was found to be less suppressive for HIV RNA than a standard triple-drug therapy of LPV/r plus zidovudine/lamivudine (on-treatment analysis after 48 weeks). We present data from the MONARK trial concerning QOL and patient-reported symptoms.. Patient-reported symptoms were collected at baseline and at weeks 4, 12, 24 and 48 using a list of 22 symptoms. QOL was assessed at baseline, week 24 and week 48 using the six-domain World Health Organization QOL short form questionnaire for HIV-infected individuals including an evaluation of global health perception.. Patients treated with the standard triple-drug therapy reported significantly more symptoms over 48 weeks of treatment than patients treated with LPV/r monotherapy (incidence rate ratio [95% confidence interval] 1.3 [1.1, 1.6] P=0.001 and 1.4 [1.2, 1.7] P=0.0004 for the total number of symptoms and the number of symptoms causing discomfort, respectively). No baseline differences and no significant changes were observed in the six QOL scores. The percentage of patients with a positive perception of their global health status increased significantly in the monotherapy arm from 32% at baseline to 67% at week 48 (P<0.0001).. These results suggest that the number of self-reported symptoms could be used as a treatment-sensitive measure of patients' well-being in clinical trials.

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Pyrimidinones; Quality of Life; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Viral Load; Zidovudine

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

Topics: Atazanavir Sulfate; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Tablets; Viral Load

Atazanavir/ritonavir is as effective as lopinavir/ritonavir, with a more favourable lipid profile and less gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations directly in treatment-naive patients.. In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were randomly assigned to receive atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg twice daily (n=443), in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation was done with a computer-generated centralised randomisation schedule and was stratified by baseline levels of HIV RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48. The main efficacy analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00272779.. At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1.7%, 95% CI -3.8 to 7.1). Mean increases from baseline in CD4 cell count were similar (203 cells per muL in the atazanavir/ritonavir group vs 219 cells per muL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2-4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2-4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3-4 increases in total bilirubin were seen in 146 (34%) of 435 patients on atazanavir/ritonavir and in one (<1%) of 431 patients on lopinavir/ritonavir.. In treatment-naive patients, atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia.

Topics: Adult; Aged; Atazanavir Sulfate; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Viral Load

Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients.. To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds.. HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques.. A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as alpha1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the I(max) [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision.. A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.

Topics: Adult; Cross-Sectional Studies; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Models, Biological; Pyrimidinones; Ritonavir

Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Oligopeptides; Pyridines; Pyrimidinones; Sex Factors; Viral Load

Thymidine-based nucleoside analogue reverse transcriptase inhibitors and some protease inhibitors of HIV are associated with lipoatrophy, relative central fat accumulation and insulin resistance. The latter associations have not been well evaluated prospectively in adults commencing antiretroviral therapy. We studied the effects of protease inhibitor-based antiretroviral regimens on body composition, insulin sensitivity and adipocytokine levels.. 48-week substudy of a randomized, open-label, three-arm trial.. Hospital and community HIV clinics.. 140 HIV-infected adults naive to antiretroviral therapy.. Tipranavir/ritonavir [500/200 mg twice a day (TPV/r200)] or [500/100 mg twice a day (TPV/r100)] or lopinavir/ritonavir [400/100 mg twice a day (LPV/r)], each with tenofovir + lamivudine.. Body composition [dual-energy x-ray absorptiometry for limb fat; L4, abdominal computed tomography for visceral adipose tissue (VAT)]; and fasting metabolic parameters. The primary analysis was change in limb fat mass in each TPV/r group vs. LPV/r.. Limb fat increased in all three groups: LPV/r (1.17 kg) versus TPV/r200 (0.83 kg; P = 0.16) and TPV/r100 (0.41 kg; P = 0.07). VAT decreased in all groups: LPV/r (-3 cm) vs. TPV/r200 (-9 cm; P = 0.04) and TPV/r100 (-6 cm; P = 0.40). No significant change in insulin sensitivity was observed, including by oral glucose tolerance testing. The increase in leptin levels was significantly correlated with the increase in limb fat mass (r = 0.67; P < 0.0001). Despite increased limb fat, adiponectin levels increased, but significantly more with TPV/r200 (+6010 ng/ml; P < 0.0001) or TPV/r100 (+4497 ng/ml; P = 0.002) when compared with LPV/r (+1360 ng/ml).. Unlike many other antiretroviral regimens, TPV/r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks.

Topics: Adiponectin; Adult; Body Composition; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Lopinavir; Male; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

In countries with a high seroprevalence of human immunodeficiency virus type 1 (HIV-1), HIV infection contributes significantly to infant mortality. We investigated antiretroviral-treatment strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial.. HIV-infected infants 6 to 12 weeks of age with a CD4 lymphocyte percentage (the CD4 percentage) of 25% or more were randomly assigned to receive antiretroviral therapy (lopinavir-ritonavir, zidovudine, and lamivudine) when the CD4 percentage decreased to less than 20% (or 25% if the child was younger than 1 year) or clinical criteria were met (the deferred antiretroviral-therapy group) or to immediate initiation of limited antiretroviral therapy until 1 year of age or 2 years of age (the early antiretroviral-therapy groups). We report the early outcomes for infants who received deferred antiretroviral therapy as compared with early antiretroviral therapy.. At a median age of 7.4 weeks (interquartile range, 6.6 to 8.9) and a CD4 percentage of 35.2% (interquartile range, 29.1 to 41.2), 125 infants were randomly assigned to receive deferred therapy, and 252 infants were randomly assigned to receive early therapy. After a median follow-up of 40 weeks (interquartile range, 24 to 58), antiretroviral therapy was initiated in 66% of infants in the deferred-therapy group. Twenty infants in the deferred-therapy group (16%) died versus 10 infants in the early-therapy groups (4%) (hazard ratio for death, 0.24; 95% confidence interval [CI], 0.11 to 0.51; P<0.001). In 32 infants in the deferred-therapy group (26%) versus 16 infants in the early-therapy groups (6%), disease progressed to Centers for Disease Control and Prevention stage C or severe stage B (hazard ratio for disease progression, 0.25; 95% CI, 0.15 to 0.41; P<0.001). Stavudine was substituted for zidovudine in four infants in the early-therapy groups because of neutropenia in three infants and anemia in one infant; no drugs were permanently discontinued. After a review by the data and safety monitoring board, the deferred-therapy group was modified, and infants in this group were all reassessed for initiation of antiretroviral therapy.. Early HIV diagnosis and early antiretroviral therapy reduced early infant mortality by 76% and HIV progression by 75%. (ClinicalTrials.gov number, NCT00102960.)

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Infant; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; Treatment Failure; Zidovudine

The ARTEMIS study compared the efficacy of darunavir/ritonavir at once-daily doses of 800/100 mg versus once- or twice-daily doses of lopinavir/ritonavir, together with 300 mg of tenofovir and 200 mg of emtricitabine, both in once-daily doses, in treatment-naive patients. The results at 48 weeks show that darunavir/ritonavir is not inferior to lopinavir/ritonavir; the increase in CD4 count observed with both regimens was similar. Darunavir/ritonavir was superior to lopinavir/ritonavir in patients with high viral loads (>100,000 copies/mL). The use of darunavir/ritonavir was associated with a lower proportion of grades 2-4 adverse effects, especially gastrointestinal effects such as diarrhea and with a lower frequency of lipidic adverse effects, such as increased triglyceride and total cholesterol levels. Once-daily darunavir/ritonavir may be an option in first-line antiretroviral therapy, with the added advantage of a reduced dose of ritonavir and high efficacy in patients with elevated viral loads.

Topics: Adult; CD4 Lymphocyte Count; Darunavir; Drug Therapy, Combination; Dyslipidemias; Female; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

Lopinavir/ritonavir (LPV/r) has been the gold standard in first line rescue treatment for many years. No other boosted protease inhibitor (PI/r) has managed to demonstrate that it is superior to LPV/r. In this regard, the TITAN study compared the efficacy and safety of darunavir (DRV/r) in 595 patients, at a dose of 600/100 mg two times a day against the normal LPV/r dose, combined with at least 2 other optimised antiretroviral drugs. The efficacy of the treatment at 48 weeks (VL<400 copies/mL) was significantly higher in the DRV/r goup compared to the LPV/r group, both in the analysis by protocol (77% vs. 68%), the non-inferiority of DRV/r being demonstrated (estimated difference +9%, 95% CI 2-16), and by intention to treat (77% vs. 67%), the superiority of DRV/r being demonstrated (estimated difference 10%, 95% CI 2-17%). The incidence of diarrhoea and increase in triglycerides was higher in the LPV/r group. The differences in efficacy of both treatments in favour of DRV/r started to be seen from a basal primary mutation in the protease, with these differences increasing as the number of these mutations increased. In patients with virological failure, DRV/r protected the protease and reverse transcriptase against mutations, thus preserving future therapeutic options. We have some theoretical and clinical data available that enables us to consider the possibility of administering DRV/r once a day in some patients with a few mutations in the protease and in those where this dosing regime is considered important. With the results of the TITAN study, DRV/r must be considered the new gold standard in first line rescue, at least in those patients with a primary mutation in the protease.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Darunavir; Diarrhea; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prognosis; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy; Sulfonamides

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Lopinavir; Mutation; Protease Inhibitors; Pyrimidinones; Ritonavir; Sulfonamides

We determined the effects of lopinavir/ritonavir on tenofovir renal clearance. Human immunodeficiency virus-infected subjects taking tenofovir disoproxil fumarate (TDF) were matched on age, race, and gender and were enrolled into one of the following two groups: group 1: subjects taking TDF plus lopinavir/ritonavir plus other nucleoside reverse transcriptase inhibitors (NRTIs); group 2: subjects taking TDF plus NRTIs and/or non-NRTIs but no protease inhibitors. Twenty-four-hour blood and urine collections were carried out in subjects for tenofovir quantification. Drug transporter genotype associations with tenofovir pharmacokinetics were examined. In 30 subjects, median (range) tenofovir apparent oral clearance, renal clearance, and fraction excreted in urine were 34.6 l/h (20.6-89.5), 11.3 l/h (6.2-22.6), and 0.33 (0.23-0.5), respectively. After adjusting for renal function, tenofovir renal clearance was 17.5% slower (P=0.04) in subjects taking lopinavir/ritonavir versus those not taking a protease inhibitor, consistent with a renal interaction between these drugs. Future studies should clarify the exact mechanism and whether there is an increased risk of nephrotoxicity.

Topics: Adenine; Administration, Oral; Adult; Antiretroviral Therapy, Highly Active; Case-Control Studies; Drug Interactions; Female; Genotype; HIV Infections; HIV Protease Inhibitors; Humans; Kidney; Lopinavir; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Organic Anion Transport Protein 1; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome

Atazanavir seems to be a protease inhibitor (PI) with a more favourable metabolic profile. Information regarding the potential benefit of replacing lopinavir/ritonavir by atazanavir in HIV-infected patients with prolonged viral suppression is scarce. If proved, this strategy could be particularly attractive for the subset of patients with greater cardiovascular risk.. SLOAT was a prospective, open, comparative trial in which patients receiving lopinavir/ritonavir-based regimens and having undetectable plasma HIV-RNA for longer than 24 weeks were randomized to continue on the same therapy or switch to atazanavir. Outcomes in viral rebound, CD4 counts, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and glucose were compared in both groups of patients at 48 weeks of follow-up.. A total of 189 patients were recruited and took at least the first dose of the assigned treatment arm. Overall, 102 switched to atazanavir (49 on 400 mg once daily, and 53 on 300 mg plus 100 mg of ritonavir once daily due to concomitant tenofovir use) and 87 continued on lopinavir/ritonavir. All patients received the PI along with two nucleoside analogues. Virological failure occurred in 12 patients switched to atazanavir and 9 continuing on lopinavir/ritonavir. A reduction (P < 0.001) in median total cholesterol (-19 mg/dL) and triglycerides (-80 mg/dL) was observed after 48 weeks of atazanavir switching, whereas no significant changes occurred in the lopinavir/ritonavir arm. Greater reductions in total cholesterol and triglycerides were seen in patients switched to atazanavir without ritonavir boosting.. The replacement of lopinavir/ritonavir by atazanavir provides an overall significant reduction in total cholesterol and triglycerides, without increased risk of virological failure.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Blood Glucose; CD4 Lymphocyte Count; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Lopinavir; Male; Middle Aged; Oligopeptides; Prospective Studies; Pyridines; Pyrimidinones; RNA, Viral; Treatment Outcome

Prior attempts to reduce the number of drugs needed to maintain viral suppression in patients with suppressed HIV replication while receiving three antiretroviral drugs have been unsuccessful.. In 205 patients with suppressed HIV replication on lopinavir-ritonavir and two nucleosides, this randomized, open-label, non-inferiority clinical trial compared the strategies of continuation of triple therapy versus lopinavir-ritonavir monotherapy followed by reinduction with two nucleosides if virological rebound occurred without genotypic resistance to lopinavir-ritonavir. The primary endpoint was proportion of patients without therapeutic failure, defined as confirmed HIV RNA higher than 500 copies/mL (with exclusion of patients receiving monotherapy who resuppressed to < 50 copies/mL after resuming baseline nucleosides), or loss to follow-up, or change of randomized therapy other than reinduction.. At week 48, the percentage of patients without therapeutic failure was 94% in the monotherapy group versus 90% in the triple therapy group (difference,-4%; upper limit of 95% confidence interval for difference, 3.4%). The percentage of patients with HIV RNA 50 copies/mL at 48 weeks by intention-to-treat, missing data or reinductions considered as failures, were 85% in the monotherapy group versus 90% in the triple therapy group (P = 0.31; 95% upper limit of 95% confidence interval for difference, 14%).. In this trial, 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was non-inferior to continuation of two nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, episodes of low level viremia were more common in patients receiving monotherapy.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nucleosides; Pyrimidinones; Ritonavir; RNA, Viral; Spain; Treatment Outcome; Viral Load

Patients with antiretroviral therapy (ART)-associated lipodystrophy frequently have disturbances in glucose metabolism associated with insulin resistance. It is not known whether changes in body composition are necessary for the development of these disturbances in ART-naive patients starting treatment with different combination ART regimens.. Glucose metabolism and body composition were assessed before and after 3 months of ART in a prospective randomized clinical trial of HIV-1-positive ART-naive men taking lopinavir/ritonavir within either a nucleoside reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine/lamivudine; n = 11) or a NRTI-sparing regimen (nevirapine; n = 9). Glucose disposal, glucose production and lipolysis were measured after an overnight fast and during a hyperinsulinaemic-euglycaemic clamp using stable isotopes. Body composition was assessed by computed tomography and dual-energy X-ray absorptiometry.. In the NRTI-containing group, body composition did not change significantly in 3 months; insulin-mediated glucose disposal decreased significantly (25%; P < 0.001); and fasting glycerol turnover increased (22%; P < 0.005). Hyperinsulinaemia suppressed glycerol turnover equally before and after treatment. The disturbances in glucose metabolism were not accompanied by changes in adiponectin or other glucoregulatory hormones. In contrast, glucose metabolism did not change in the NRTI-sparing arm. Glucose disposal significantly differed over time between the arms (P < 0.01).. Treatment for 3 months with a NRTI-containing, but not a NRTI-sparing, regimen resulted in a 25% decrease in insulin-mediated glucose disposal and a 22% increase in fasting lipolysis. In the absence of discernable changes in body composition, NRTI may directly affect glucose metabolism, the mechanism by which remains to be elucidated.

Topics: Adiponectin; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Glucose; Glycerol; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperinsulinism; Insulin Resistance; Lamivudine; Lipid Metabolism; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Time Factors; Treatment Outcome; Zidovudine

To investigate pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r)-based therapy in HIV-1-infected infants 6 weeks to 6 months of age.. A prospective, multicenter, open-label trial of 21 infants with HIV-1 RNA > 10 000 copies/ml and treated with LPV/r 300/75 mg/m twice daily plus two nucleoside reverse transcriptase inhibitors. Intensive pharmacokinetic sampling was performed at 2 weeks and predose concentrations were collected every 8 weeks; safety and plasma HIV-1 RNA were monitored every 4-12 weeks for 24 weeks.. Median age at enrollment was 14.7 weeks (range, 6.9-25.7) and 19/21 completed > or= 24 weeks of study. Although LPV/r apparent clearance was slightly higher than in older children, the median area under the concentration-time curve 0-12 h (67.5 mug.h/ml) was in the range reported from older children taking the recommended dose of 230/57.5 mg/m. Predose concentrations stabilized at a higher level after the first 2 weeks of study. In as-treated analysis at week 24, 10/19 (53%) had plasma HIV-1 RNA < 400 copies/ml (median change, -3.33 log10 copies/ml); poor adherence contributed to delayed viral suppression, which improved with longer follow-up. Three infants (14%) had transient adverse events of grade 3 or more that were possibly related to study treatment but did not require permanent treatment discontinuation.. Despite higher clearance in infants 6 weeks to 6 months of age, a twice daily dose of 300/75 mg/m LPV/r provided similar exposure to that in older children, was well tolerated and provided favorable virological and clinical efficacy.

Topics: Antiretroviral Therapy, Highly Active; Brazil; CD4 Lymphocyte Count; Child, Preschool; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Treatment Outcome; United States

This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pharmacokinetics. We measured activities of CYP3A, CYP2D6, and P-glycoprotein in 28 patients before and during ART using a cocktail phenotyping approach. Activities, demographics, and genetic polymorphisms in CYP3A, CYP2D6, and P-glycoprotein were tested as covariates. Oral midazolam clearance (overall CYP3A activity) decreased to 0.19-fold (90% confidence interval (CI), 0.15-0.23), hepatic midazolam clearance and intestinal midazolam availability changed to 0.24-fold (0.20-0.29) and 1.12-fold (1.00-1.26), respectively. In CYP2D6 extensive metabolizers, the plasma ratio AUC(dextromethorphan)/AUC(dextrorphan) increased to 2.92-fold (2.31-3.69). Digoxin area under the curve (AUC)(0-12) (P-glycoprotein activity) increased to 1.81-fold (1.56-2.09). Covariates had no major influence on lopinavir and ritonavir pharmacokinetics. In conclusion, CYP3A, CYP2D6, and P-glycoprotein are profoundly inhibited in patients receiving ritonavir boosted lopinavir. The covariates investigated are not useful for a priori dose selection.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Drug Synergism; Female; HIV Infections; HIV Protease Inhibitors; Humans; Intestinal Mucosa; Intestines; Liver; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir

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

Guidelines for the use of antiretroviral agents for HIV-1 infection recommend combining at least three agents. The toxicity, cost, and complexity of such regimens warrant the search for other options.. MONARK is a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in HIV-infected patients with HIV-RNA levels less than 100,000 copies/ml. The primary endpoint was the proportion of patients with HIV-1-RNA levels below 400 copies/ml at week 24 and below 50 copies/ml at week 48.. Eight-three and 53 patients were randomly assigned and exposed in the monotherapy and triple-drug groups, respectively. At week 48, by an intent-to-treat analysis, 53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in the triple-drug group achieved the primary endpoint (P = 0.19). The on-treatment analysis indicates that 80 and 95% of patients reached the primary endpoint in the monotherapy and triple-drug groups, respectively (P = 0.02). In the monotherapy arm, protease inhibitor-associated resistance mutations were seen in three of the 21 patients qualifying for genotypic resistance testing, with a modest impact on lopinavir susceptibility. None of the serious reported adverse events were considered to be related to study treatment.. Our results suggest that lopinavir/ritonavir monotherapy demonstrates lower rates of virological suppression when compared with lopinavir/ritonavir triple therapy and therefore should not be considered as a preferred treatment option for widespread use in antiretroviral-naive patients.

Topics: Adult; Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease; HIV-1; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Zidovudine

The inhibitory quotient (IQ) of human immunodeficiency virus (HIV) protease inhibitors (PIs), which is the ratio of drug concentration to viral susceptibility, is considered to be predictive of the virological response. We used several approaches to calculate the IQs of amprenavir and lopinavir in a subset of heavily pretreated patients participating in the French National Agency for AIDS Research (ANRS) 104 trial and then compared their potentials for predicting changes in the plasma HIV RNA level. Thirty-seven patients were randomly assigned to receive either amprenavir (600 mg twice a day [BID]) or lopinavir (400 mg BID) plus ritonavir (100 or 200 mg BID) for 2 weeks before combining the two PIs. The 90% inhibitory concentration (IC(90)) was measured using a recombinant assay without or with additional human serum (IC(90+serum)). Total and unbound PI concentrations in plasma were measured. Univariate linear regression was used to estimate the relation between the change in viral load and the IC(90) or IQ values. The amprenavir phenotypic IQ values were very similar when measured with the standard and protein binding-adjusted IC(90)s. No relationship was found between the viral load decline and the lopinavir IQ. During combination therapy, the amprenavir and lopinavir genotypic IQ values were predictive of the viral response at week 6 (P = 0.03). The number of protease mutations (< 5 or > or = 5) was related to the virological response throughout the study. These findings suggest that the combined genotypic IQ and the number of protease mutations are the best predictors of virological response. High amprenavir and lopinavir concentrations in these patients might explain why plasma concentrations and the phenotypic IQ have poor predictive value.

Topics: Adult; Aged; Carbamates; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; France; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Phenotype; Prognosis; Pyrimidinones; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brazil; Carbamates; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pilot Projects; Prospective Studies; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome

Data are scarce on the long-term efficacy of lopinavir/ritonavir monotherapy for the maintenance of HIV suppression. Four years of results of patients randomized to monotherapy in the Only Kaletra (OK) pilot clinical trial are presented.. Twenty-one HIV-infected patients with suppressed HIV replication (<50 copies/mL) for at least 6 months and without previous failure while receiving a protease inhibitor-based regimen started lopinavir/ritonavir monotherapy. Follow-up was performed within the OK pilot clinical trial during the first 2 years and according to routine clinical practice during the 3rd and 4th years.. Fourteen patients (67%) remain on monotherapy and with RNA <50 copies/mL (intention-to-treat analysis, with missing patients scored as failures). Five patients (24%) had virological rebound and all of them were successfully re-suppressed by adding two nucleosides. No major protease inhibitor mutations were found.. Our data support the long-term efficacy and safety of lopinavir/ritonavir monotherapy for the maintenance of HIV suppression, a finding that must be confirmed in larger studies.

Topics: Adult; Drug Resistance, Viral; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Longitudinal Studies; Lopinavir; Male; Mutation; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

New strategies such as boosted-protease inhibitor (PI) monotherapy are being investigated. However, a concern remains regarding the efficacy of this strategy in viral sanctuaries such as the male genital tract. More than 80% of untreated HIV-infected men have detectable HIV-RNA in semen and such a strategy could favour local selection of resistant variants, given the poor penetration of most PIs in semen.. To evaluate the impact of a first-line lopinavir/ritonavir alone or standard triple combination on HIV-1 shedding in the genital tract.. HIV-1-infected men enrolled in the Monark randomized trial were eligible for the present study after 48 weeks of a first-line lopinavir/ritonavir alone or in combination with zidovudine and lamivudine. Single-paired samples of blood and semen were collected at week 48. Blood plasma HIV-RNA and seminal plasma HIV-RNA were measured at week 48. Lopinavir and ritonavir concentrations were measured in blood and in semen at week 48 by high-performance liquid chromatography.. Ten patients were included: five of them received lopinavir/ritonavir monotherapy and five received a triple combination. At week 48, all patients had blood plasma HIV-RNA <1.7 log(10) copies/mL. Median lopinavir and ritonavir concentrations were within the expected therapeutic target range in blood plasma (4896 and 130.5 ng/mL, respectively), whereas both lopinavir and ritonavir were undetectable in all seminal plasma samples (<30 ng/mL). All 10 patients had undetectable seminal plasma HIV-RNA at week 48 (<2.3 log(10) copies/mL).. No local viral production was evident in semen, despite the local absence of therapeutic antiretroviral drug concentrations in the five patients receiving lopinavir/ritonavir alone.

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Genitalia, Male; HIV Infections; HIV-1; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Plasma; Pyrimidinones; Ritonavir; RNA, Viral; Semen; Time Factors; Virus Shedding; 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

Topics: Brazil; CD4 Lymphocyte Count; Drug Combinations; Drug Resistance, Multiple; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Time; Time Factors; Treatment Outcome

Topics: Adenine; Adult; Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lopinavir; Middle Aged; Organophosphonates; Pilot Projects; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

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

We report the results of the extended follow-up at one year of a randomized trial evaluating the virological efficacy of a salvage therapy combining lopinavir and amprenavir with either 200 or 400 mg/day ritonavir, along with optimized nucleoside reverse transcriptase inhibitors, in patients carrying multidrug-resistant isolates. The combination of amprenavir, lopinavir and ritonavir (400 mg/day) is durably potent, yielding a sustained virological response (HIV RNA < 50 copies) in 39% of cases.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Carbamates; Drug Resistance, Multiple, Viral; Follow-Up Studies; Furans; HIV Infections; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir; Salvage Therapy; Sulfonamides

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

To describe outcomes in patients starting first-line antiretroviral regimens including lopinavir/ritonavir (LPV/r) in a routine clinic setting.. Previously naïve patients starting LPV/r-containing antiretroviral therapy were included in the study. Virological failure was defined as the first of two viral loads >500 HIV-1 RNA copies/mL more than 6 months after starting LPV/r. Cumulative percentages experiencing virological failure were calculated using Kaplan-Meier methods.. A total of 195 individuals had a median follow-up time of 1.7 years. At 48 weeks, 87.9, 77.4 and 71.6% of patients with pretreatment CD4 counts of <50, 50-200 and >200 cells/microL, respectively, remained on LPV/r. By 48, 72 and 96 weeks, 2.2, 3.0 and 5.0% of patients, respectively, had experienced virological failure, ignoring treatment changes but censoring follow-up at discontinuation of all antiretrovirals; these percentages became 24.0, 33.7 and 42.3% when LPV/r discontinuation was considered as virological failure. Censoring those who stopped LPV/r with a viral load <50 copies/mL and considering as virological failures those who stopped LPV/r with a viral load >50 copies/mL gave 12.1, 14.6 and 17.0% virological failure at 48, 72 and 96 weeks, respectively. Median CD4 count increases at 24, 48 and 72 weeks were 167, 230 and 253 cells/microL, respectively.. Few patients experienced virological failure whilst on a LPV/r-based regimen, although it was not uncommon for patients in our clinic with higher baseline CD4 counts to discontinue LPV/r.

Topics: Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; London; Lopinavir; Male; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load

To assess the safety, efficacy and metabolic toxicity of lopinavir/ritonavir + saquinavir or zidovudine/lamivudine and evaluate the pharmacokinetics of lopinavir/ritonavir + saquinavir.. HIV-1-infected, antiretroviral-naive subjects were randomized to lopinavir/ritonavir (400/100 mg) twice daily + saquinavir (800 mg) or zidovudine/lamivudine (150/300 mg) in a Phase II, 48 week study. Subjects receiving lopinavir/ritonavir + zidovudine/lamivudine initiated escalating doses of saquinavir (400, 600 and 800 mg) weekly for 3 weeks.. By intent-to-treat (non-completer = failure) analysis, 10/16 (63%) lopinavir/ritonavir + saquinavir-treated and 7/14 (50%) lopinavir/ritonavir + zidovudine/lamivudine-treated subjects achieved plasma HIV-1 RNA <50 copies/mL (P=0.713) at week 48. Safety, tolerability, metabolic changes and truncal fat increases were similar between groups. Small decreases in the lower extremity fat in the zidovudine/lamivudine group (-6%) and a statistically significant increase in the lower extremity fat in the saquinavir group (+19%) were observed. Lopinavir/ritonavir co-administered with saquinavir 600 or 800 mg twice daily produced saquinavir concentrations similar to those previously reported for saquinavir/ritonavir 1000/100 mg twice daily.. Treatment regimens had similar efficacy and tolerability. Metabolic parameters suggested lipoatrophy in the zidovudine/lamivudine treatment group. Saquinavir 600 and 800 mg twice daily produced concentrations similar to those previously reported for saquinavir/ritonavir 1000/100 mg twice daily.

Topics: Adult; Anti-HIV Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Saquinavir; Zidovudine

To develop a computer-based system for modelling and interpreting plasma antiretroviral concentrations for therapeutic drug monitoring (TDM).. Data were extracted from a prospective TDM study of 199 HIV-infected patients (CCTG 578). Lopinavir (LPV) and efavirenz (EFV) pharmacokinetic (PK) parameters were modelled using a Bayesian method and interpreted by an expert committee of HIV specialists and pharmacologists who made TDM recommendations. These PK models and recommendations formed the knowledge base to develop an artificial intelligence (AI) system that could estimate drug exposure, interpret PK data and generate TDM recommendations. The modelled PK exposures and expert committee TDM recommendations were considered optimum and used to validate results obtained by the AI system.. A group of patients, 67 on LPV, 46 on EFV and three on both drugs, were included in this analysis. Correlations were high for LPV and EFV estimated trough and 4 h post-dose concentrations between the Al estimates and modelled values (r > 0.79 for all comparisons; P < 0.0001). Although trough concentrations were similar, significant differences were seen for mean predicted 4 h concentrations for EFV (4.16 microg/ml versus 3.89 microg/ml; P = 0.02) and LPV (7.99 microg/ml versus 8.79 microg/ml; P < 0.001). The AI and expert committee TDM recommendations agreed in 53 out of 69 LPV cases [kappa (kappa) = 0.53; P < 0.001] and 47 out of 49 EFV cases (kappa = 0.91; P < 0.001).. The AI system successfully estimated LPV and EFV trough concentrations and achieved good agreement with expert committee TDM recommendations for EFV- and LPV-treated patients.

Topics: Adult; Algorithms; Alkynes; Anti-Retroviral Agents; Artificial Intelligence; Bayes Theorem; Benzoxazines; California; Computer Systems; Cyclopropanes; Drug Monitoring; Drug Therapy, Combination; Expert Systems; Female; Fuzzy Logic; HIV Infections; Humans; Lopinavir; Male; Models, Biological; Practice Guidelines as Topic; Prospective Studies; Pyrimidinones; Reproducibility of Results

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

Several genotypic resistance algorithms have been proposed for quantitation of the degree of phenotypic resistance to the human immunodeficiency virus (HIV) protease inhibitor (PI) lopinavir (LPV), including the original LPV mutation score. In this study, we retrospectively evaluated 21 codons in HIV protease known to be associated with PI resistance in a large antiretroviral agent-experienced observational patient cohort, "Autorisation Temporaire d'Utilization" (ATU), to assess whether a more optimal algorithm could be derived by using virologic response data from patients treated with LPV in combination with ritonavir (LPV/r). Five of the 11 mutations constituting the LPV mutation score were not associated with a virologic response, while 4 additional mutations not included in this score demonstrated an association. Therefore, the LPV ATU score, which includes mutations at codons 10, 20, 24, 33, 36, 47, 48, 54, 82, and 84, was constructed and shown in two different types of multivariable analyses of the ATU cohort to be a better predictor of the virologic response than the LPV mutation score. The LPV ATU score was also more strongly associated with a virologic response when it was applied to independent clinical trial populations of PI-experienced patients receiving LPV/r. This study provides the basis for a new genotypic resistance algorithm that is useful for predicting the antiviral activities of LPV/r-based regimens in PI-experienced patients. The refined algorithm may be useful in making clinical treatment decisions and in refining genetic and pharmacologic methods for assessing the activity of LPV/r.

Topics: Adult; Algorithms; Analysis of Variance; Cohort Studies; Female; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Logistic Models; Lopinavir; Male; Middle Aged; Mutation; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral

The aim of this study was to determine the impact of sex on the pharmacokinetics of lopinavir/ritonavir. Interaction between lopinavir/ritonavir and tenofovir was also evaluated. Steady-state plasma samples were obtained from virologically suppressed HIV-infected patients on lopinavir/ritonavir 800/200-mg soft gel capsule taken once daily. Drug assays were performed by high-performance liquid chromatography. Pharmacokinetic parameters estimated by noncompartmental method were reported as 90% confidence intervals (CIs) about the geometric mean ratio (GMR). There were 9 males and 11 females. No sex differences were observed in lopinavir/ritonavir pharmacokinetics profile. The GMR(sex) (women compared with men) for lopinavir area under the concentration-time curve (AUC(24)), maximum concentration (C(max)), and minimum concentration (C(min)) was 0.95 (90% CI, 0.70-1.29), 0.88 (90% CI, 0.67-1.15), and 1.27 (90% CI, 0.60-2.66), respectively. Similarly, the GMR(sex) for ritonavir AUC(24), C(max), and C(min) was 0.84 (90% CI, 0.57-1.24), 0.79 (90% CI, 0.50-1.22), and 1.02 (90% CI, 0.58-1.80), respectively. Tenofovir coadministration led to a reduction in lopinavir/ritonavir plasma exposure, giving a lopinavir GMR(tenofovir) for C(max) of 0.72 (90% CI, 0.57-0.93) and AUC(24) of 0.74 (90% CI, 0.56-0.98), respectively. No difference in lopinavir/ritonavir plasma concentrations between sexes was demonstrated in this study. However, tenofovir coadministration lowered lopinavir/ritonavir plasma exposure.

Topics: Adenine; Adult; Area Under Curve; Capsules; Chromatography, High Pressure Liquid; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sex Factors; Tenofovir

The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week efficacy and safety of darunavir-ritonavir with that of lopinavir-ritonavir in treatment-experienced, lopinavir-naive patients.. Patients received optimised background regimen plus non-blinded treatment with darunavir-ritonavir 600/100 mg twice daily or lopinavir-ritonavir 400/100 mg twice daily. The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877.. Of 595 patients randomised and treated, 187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir-ritonavir than lopinavir-ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2-16). Fewer virological failures treated with darunavir-ritonavir than with lopinavir-ritonavir developed primary protease inhibitor mutations (21% [n=6] vs 36% [n=20]) and nucleoside analogue-associated mutations (14% [n=4] vs 27% [n=15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir-ritonavir and 89 (30%) lopinavir-ritonavir patients.. In lopinavir-naive, treatment-experienced patients, darunavir-ritonavir was non-inferior to lopinavir-ritonavir treatment in terms of our virological endpoint, and should therefore be considered as a treatment option for this population.

Topics: Adult; Antiretroviral Therapy, Highly Active; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Sulfonamides

Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals.. HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm (1) or lopinavir/ritonavir (400/100 mg twice daily; arm (2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI).. Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900-21,807) and 15,136 (13,339-17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298-18,628) and 10,471 (9,270-11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252-54,666) and 28,840 (19,213-43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084-75,509) and 63,096 (48,128-82,718) ng.h/ml.. No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.

Topics: Adult; Area Under Curve; Atazanavir Sulfate; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Our objective was to identify possible differences in protease inhibitor plasma concentrations between and within three protease inhibitor regimens (indinavir, saquinavir and lopinavir all in combination with low-dose ritonavir) and to relate these differences to safety and efficacy. Data originated from pre-defined pharmacokinetic substudies within two randomized 48-week trials evaluating the safety and efficacy of three protease inhibitor regimens. At weeks 4 and 48, plasma was collected and minimum drug plasma concentrations, C(min), were obtained. Out of 656 randomized patients, 283 patients had available C(min) at week 4. Indinavir, saquinavir and lopinavir C(min) were high when combined with low-dose ritonavir. No significant difference in the proportion of patients experiencing treatment failure could be found according to the C(min) within any treatment arm. A saquinavir C(min) > 2000 ng/ml was associated with an increased risk of gastrointestinal grade 3 or 4 adverse events and higher total cholesterol. Overall, there were no changes in C(min) from week 4 to week 48 in patients who remained on therapy. No association between treatment failure and the C(min) could be demonstrated. Associations between high C(min) and toxicity were identified in the saquinavir arm; therefore, dose reductions may be appropriate in certain patients with C(min) several times above the minimum effective concentration.

Topics: Adult; Double-Blind Method; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Saquinavir; Treatment Failure

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

We assessed the safety and efficacy and evaluated the adherence to lopinavir/ritonavir (LPV/r) dosed QD or BID in antiretroviral-naive, HIV-1-infected subjects through 96 weeks of treatment. A randomized, open-label, multicenter comparative study was conducted. A total of 190 antiretroviral-naive subjects with plasma HIV-1 RNA above 1000 copies/ml and any CD4(+) T cell count were enrolled. Subjects were randomized (3:2) to LPV/r 800/200 mg QD (n = 115) or 400/100 mg BID (n = 75). Subjects received TDF 300 mg and FTC 200 mg QD. Adherence to LPV/r through 96 weeks was measured using MEMS((R)) monitors. Median baseline VL and CD4(+) T cell count were 4.8 log(10) copies/ml and 216 cells/mm(3), respectively. Prior to week 96, 37% (QD) and 39% (BID) of subjects discontinued, primarily due either to adverse events (17% QD, 9% BID) or to loss to follow-up or nonadherence (12% QD, 17% BID). The proportion of subjects with VL <50 copies/ml [57% QD, 53% BID; p = 0.582 (ITT NC = F)], change in CD4 count (244 cells/mm(3) QD, 264 cells/mm(3) BID; p = 0.513), and evolution of resistance did not differ between groups through 96 weeks. Diarrhea (17% QD, 5% BID, p = 0.014) was the most common moderate or severe, study drug-related adverse event. Adherence to LPV/r was higher for the QD group than the BID group and declined over time in both groups. Time to loss of virologic response was significantly associated with adherence to LPV/r in both groups. LPV/r QD resulted in virologic response similar to LPV/r BID through 96 weeks in antiretroviral-naive subjects. Adherence was significantly higher in the QD group.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Patient Compliance; Pyrimidinones; Ritonavir; Viral Load

To identify potential causes and clinical implications of transient increases in plasma viral load (hereafter, "blips").. M99-056 and M02-418 were prospective, randomized trials evaluating the safety and efficacy of lopinavir/ritonavir (LPV/r) capsules administered twice per day or once per day to subjects infected with human immunodeficiency virus-1 (HIV-1). Plasma viral load was measured every 4 weeks (from baseline through week 24, excluding week 12 and week 20 in M02-418), every 8 weeks (from week 24 through week 48), and every 12 weeks (from week 48 through week 96). Blips were defined by 1 plasma viral load measurement of between 50-1000 copies/mL, immediately preceded and immediately followed by a measurement of <50 copies/mL. A medication event monitoring system was used to record the date and time subjects administered a dose of LPV/r.. Of 228 subject enrolled, event monitor data were available for 223 (98%) subjects (92 of whom received twice-daily LPV/r therapy, and 131 of whom received once-daily therapy). Viral load blips (median plasma viral load, 82 copies/mL [range, 51-858 copies/mL]) were identified in 60 (27%) of the subjects (21 in the LPV/r twice-daily group and 39 in the LPV/r once-daily group). Neither the baseline plasma viral load nor the CD4(+) T cell count were associated with blips. During the week prior to a blip, the mean number of days that the subject administered the prescribed number of doses was lower than the number during a matched period for the same subject during which a blip did not occur (5.55 vs. 6.22 days; P = .007). Blips were not associated with virologic failure or the development of drug resistance.. Blips were associated with decreased adherence, but not with virologic failure or development of drug resistance in these studies of LPV/r.. Clinicaltrials.gov identifier: NCT00043966 .

Topics: Adult; Aged; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Refusal; Viral Load; Viremia

To determine the impact of genotypic inhibitory quotient (GIQ) for lopinavir (LPV) in patients failing HAART with limited antiretroviral exposure.. Retrospective analysis of a prospective trial.. Lopinavir GIQ was calculated as the ratio between the mean trough concentration (C(trough)) and the number of protease mutations using eight different HIV drug resistance mutation lists or algorithms. Early (by week 12) and confirmed (up to week 24) virological response (HIV-RNA< 400 copies/mL, ECVR) was used as dependent variable in logistic regression model.. Seventy-one of 109 (65%) patients achieved ECVR. At multivariable logistic regression analysis, each mug/mL increase of GIQ was correlated with increasing probability of ECVR as far as the following mutations were computed: multi-protease inhibitor (PI) associated mutations listed by IAS (OR=1.17; 95% CI=0.99-1.39; P=0.058), mutations associated with LPV resistance by ANRS algorithm (OR=1.21; 95% CI=1.02-1.44; P=0.03), major mutations associated with LPV resistance by Stanford database (OR=1.16; 95% CI=1-1.35; P=0.05), and the whole set of mutations associated with LPV resistance in the same database (OR=1.22; 95% CI=1.02-1.46; P=0.03). Using ROC curve method, a specific threshold GIQ was assessed, above which this parameter could predict ECVR with the highest sensitivity (74.6% with GIQ obtained through Stanford LPV mutations) or specificity (89.5% with GIQ obtained through ANRS LPV mutations).. Our results suggest that increasing GIQ can improve virological outcome even in patients with limited exposure to PIs. Further studies are necessary to understand what HIV protease mutations should be considered and whether such mutations should be weighted differently to improve LPV GIQ predictive value.

Topics: Adult; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Logistic Models; Lopinavir; Male; Predictive Value of Tests; Pyrimidinones; RNA, Viral; Salvage Therapy

Topics: Child; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Salvage Therapy

The effect of hepatic impairment on lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.

Topics: Adult; Area Under Curve; Biological Availability; Drug Combinations; Drug Monitoring; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Male; Middle Aged; Pyrimidinones; Radioligand Assay; Ritonavir

In BMS Study 045, once-daily (QD) atazanavir/ritonavir (ATV/RTV) demonstrated comparable efficacy and safety to twice-daily (BID) lopinavir/ritonavir (LPV/RTV) over 48 weeks in treatment-experienced patients. Results of extended follow-up to 96 weeks are presented.. BMS Study 045 was an open-label, randomized, multi-national trial of HIV-infected patients with virologic failure on two or more prior HAART regimens designed to evaluate the efficacy and safety of ATV/RTV (300/100 mg) QD and LPV/RTV (400/100 mg) BID, each with tenofovir (300 mg) QD and one nucleoside reverse transcriptase inhibitor. The primary efficacy measure was the time-averaged difference (TAD) in reduction in HIV RNA from baseline. Secondary objectives included evaluation of safety and plasma lipid levels through week 96.. Over 96 weeks, the ATV/RTV regimen demonstrated similar virologic efficacy to the LPV/RTV regimen. Mean reductions from baseline in HIV RNA were -2.29 and -2.08 log10 copies/ml, respectively [TAD (97.5% confidence interval): 0.14 log10 copies/ml (-0.13, 0.41)]. The LPV/RTV regimen resulted in significant increases in total cholesterol (+9%) and fasting triglycerides (+30%) in comparison with the ATV/RTV regimen, which demonstrated decreases in these parameters [-7 and -2%, respectively, (P < 0.0001)]. Grade 2-4 diarrhoea occurred less frequently in ATV/RTV patients (3%) in comparison with LPV/RTV patients (13%) (P < 0.01). Grade 3-4 elevations in bilirubin were more common in ATV/RTV patients (53%) than LPV/RTV patients (< 1%) (P < 0.0001), with no resulting discontinuations.. Regimens containing once-daily ATV/RTV demonstrated comparable efficacy and safety, with significant reductions in total cholesterol and fasting triglycerides and improved gastrointestinal-tolerability in comparison with twice-daily regimens containing LPV/RTV over 96 weeks in treatment-experienced patients.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipids; Lopinavir; Male; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Saquinavir; Tenofovir; Time Factors; Treatment Outcome

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

To assess potential pharmacokinetic (PK) interactions between atazanavir (ATV, 300 mg, once daily) and lopinavir (LPV, 400 mg, twice daily), both boosted by ritonavir (RTV, 100 mg).. Two-parallel groups, addition of LPV in patients receiving ATV (n=6), and addition of ATV in patients receiving LPV (n=7), with before/after comparisons.. Each group had two complete PK profiles before and 2 weeks after the addition of the second protease inhibitor (PI). Total plasma concentrations (Ctot) were analysed by HPLC-UV and unbound plasma concentrations (Cu) and cellular concentrations (Ccell) were analysed by LC-MS/MS. Plasma and cellular PK parameters were also calculated. Unbound and cellular fractions were expressed as Cu/Ctot and Ccell/Ctot ratio. Data were analysed by paired Student t-test on log values; correlations between Ccell, Cu and Ctot were explored by log-log linear regression.. Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV was associated with a decrease in LPV concentrations (by 16% for area under the time-concentration curve, maximum concentration and trough concentration, NS; and by 35% for Cmin, P=0.04). The RTV PK parameters remained unmodified. The Ccell/Ctot and Cu/Ctot ratio was unaffected by the addition of the second PI and remained stable throughout dosing interval. Good correlations were observed between Ccell, Cu and Ctot for each drug. No relevant toxicity was observed.. Adding LPV to ATV did not influence the plasma and cellular PK parameters of ATV. Adding ATV to LPV caused a limited decrease in LPV concentrations. The clinical significance of this decrease is unknown and warrants further investigation to determine the need for tailoring LPV dosage in selected cases.

Topics: Adult; Atazanavir Sulfate; Blood Proteins; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Protein Binding; Pyridines; Pyrimidinones; Ritonavir; Treatment Outcome

Lopinavir/ritonavir is approved for treatment of HIV-infected children at a dosage regimen of 230/57.5 mg/m(2) twice daily. However, once daily administration could increase convenience and patient adherence. Our study aimed at evaluating whether inhibitory concentrations are maintained in plasma following administration of lopinavir/ritonavir once daily.. Lopinavir/ritonavir was administered at the standard twice daily regimen to 21 HIV-infected children, as a component of their antiretroviral treatment. Following at least 1 month of administration, seven patients received a dose of 460/115 mg/m(2) once daily for three consecutive days. After the third dose of once daily administration, blood samples were drawn at the following times: 0 (pre-dose), 1, 2 and 4 h following administration. The pre-dose (C(min)) and the peak (C(max)) concentrations were compared with the values obtained following twice daily administration in all the study patients.. Median (interquartile range) C(min) with the once daily regimen was 1.59 (0.77-6.85) mg/L versus 7.90 (5.45-9.77) mg/L with the twice daily regimen (P < 0.05). C(min) was considered inhibitory for wild-type virus (>1.0 mg/L) in four out of seven patients. C(max) did not differ significantly between the once daily and twice daily regimens.. Our small pilot study suggests that lopinavir/ritonavir once daily may be a suitable regimen for antiretroviral-naive children. However, due to the high interindividual variability and low concentrations in some patients, therapeutic drug monitoring may be necessary to ensure that concentrations are adequate to inhibit viral replication. A formal clinical study of lopinavir/ritonavir once daily in treatment-naive children is warranted.

Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Male; Plasma; Pyrimidinones; Ritonavir

The purpose of this study was to determine the pharmacokinetics and tolerability of three different indinavir and lopinavir/ritonavir dosing regimens.. HIV-infected adults receiving lopinavir/ritonavir 400/100 mg twice daily with food had nine plasma samples taken over a 12 h dosing interval at baseline (BL), after adding indinavir 600 mg twice daily for 10 days (R1), indinavir 800 mg twice daily for 5 days (R2) and lopinavir/ritonavir 533/133 mg plus indinavir 600 mg twice daily for 10 days (R3). Plasma samples were assayed using HPLC.. A total of 12 patients completed the BL visit [10 male; mean (SD) age=43.9 (5.8) years] and 9, 7 and 7 completed R1, R2 and R3 visits, respectively. Two subjects discontinued treatment due to hypertriglyceridaemia. Compared with BL, the R3 lopinavir AUC (P<0.05) and Cmin (P=0.0025) were significantly higher and the R2 AUC trended higher (P=0.09). The indinavir AUC (P=0.030) and Cmax (P=0.035) were significantly higher for R2 compared with R1. There was a trend for increased total bilirubin (TB) after the addition of indinavir (P=0.09). Lopinavir and indinavir AUC, Cmax and Cmin were associated with TB during univariate analyses (P<0.01) while only lopinavir AUC (P=0.0004) and indinavir AUC (P=0.0028) were associated with TB during multivariate analysis. Only indinavir AUC was significant when both drugs were included in the model (P=0.0028).. Elevated lopinavir and indinavir concentrations are associated with elevated TB.

Topics: Adolescent; Adult; Anti-HIV Agents; Bilirubin; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; HIV Infections; Humans; Indinavir; Lopinavir; Male; Middle Aged; Multivariate Analysis; Pyrimidinones

Lopinavir is an HIV protease inhibitor that is co-formulated with ritonavir. The approved paediatric dose is 230/57.5 mg/m2 twice daily. Once-daily dosing may offer an advantage to adherence. We studied the pharmacokinetics of lopinavir/ritonavir in a once-daily regimen in HIV-1-infected children.. HIV-1-infected children on stable antiretroviral therapy with a viral load <50 copies/ml for at least 6 months received lopinavir/ritonavir 460/115mg/m2 once daily with zidovudine and lamivudine. Blood samples were collected at 0, 2, 4, 6, 8, 12, 18 and 24 h after observed intake during steady state. Target level for lopinavir Cmin was 1.0 mg/l, based on in vitro IC50 data.. Nineteen HIV-1-infected children with a median (range) age of 4.5 (1.4-12.9) years were enrolled. The median (interquartile range) dose of lopinavir was 456 (444-477) mg/m2. The mean (standard deviation) AUC0-24, Cmax and Cmin of lopinavir were 149.8 +/- 58.8 h*mg/l, 10.77 +/- 2.90 mg/l and 2.88 +/- 3.74 mg/l respectively. These values are comparable to data observed in adults using lopinavir/ritonavir 800/200 mg once daily. In 10/19 (53%) children Cmin was considered to be too low (<1.0 mg/l). Younger children more often experienced subtherapeutic trough levels.. Our findings indicate that 460/115 mg/m2 lopinavir/ritonavir once daily leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children. Further research, especially in young children, is necessary to determine whether a higher dosage of lopinavir/ritonavir once daily must be given to reach the target level for Cmin.

Topics: Anti-HIV Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Lamivudine; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome; Zidovudine

Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients.. This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943.. At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir.. Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Topics: Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

To evaluate the safety and noninferiority and to explore the efficacy of administration of once-daily versus twice-daily lopinavir/ritonavir (LPV/r) in antiretroviral-naive HIV-1-infected subjects.. Randomized, open-label, multicenter, comparative study.. One hundred ninety antiretroviral-naive subjects with plasma HIV-1 RNA level >1000 copies/mL and any CD4 cell count were randomized to lopinavir/ritonavir at a dose of 800/200 mg administered once daily (n = 115) or lopinavir/ritonavir at a dose of 400/100 mg administered twice daily (n = 75). Subjects also received tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg administered once daily.. The median baseline plasma HIV-1 RNA level and CD4 count were 4.8 log10 copies/mL and 216 cells/mm, respectively. Before week 48, 20% (once daily) and 29% (twice daily) subjects discontinued. Virologic responses of the subjects through 48 weeks were comparable; 70% (once daily) and 64% (twice daily) achieved an HIV-1 RNA level <50 copies/mL by intent-to-treat, noncompleter = failure analysis. No subject demonstrated LPV or TDF resistance, but 3 subjects (2 in the once-daily group, 1 in the twice-daily group) demonstrated FTC resistance. Mean increases in CD4 count were similar. Diarrhea (16% in the once-daily group, 5% in the twice-daily group; P = 0.036) was the most common moderate or severe study drug-related adverse event.. Through 48 weeks, a once-daily regimen of lopinavir/ritonavir + TDF + FTC appears to have similar virologic and immunologic responses in antiretroviral-naive subjects as the same regimen with lopinavir/ritonavir administered twice daily. Both regimens were relatively well tolerated, and no LPV or TDF resistance was observed.

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Safety

To evaluate the virological, immunological and clinical responses to the boosted double protease inhibitor (PI) regimen combination of lopinavir/ritonavir and saquinavir ('LOPSAQ') without reverse transcriptase inhibitors (RTI) in HIV-positive patients who have few viable RTI treatment options.. Cohort study of 128 heavily pre-treated patients who were experiencing therapy failure on their current regimen due to RTI resistance and/or systemic toxicities. Patients with PI-resistance mutations or RTI toxicity underwent a structured treatment interruption (STI) (n=76) until virus reverted to wild-type or until resolution of toxicity symptoms. Baseline was defined as the time point when lopinavir/ritonavir plus saquinavir therapy was initiated. Virological response was defined as viral load<400 copies/mL at week 48.. A total of 78 (61%) patients experienced a virological response to therapy (ITT). Median viral load at baseline was 5.06 log10 copies/mL; at week 48 median was 2.16 log10 copies. Median CD4 at week 48 was 280 cells/mm3 compared with 172 cells at baseline. At week 48, 78/128 patients were still on therapy. In univariable analyses, significant predictors of virological response included higher CD4 count (P<0.001), lower viral load (P=0.002), less PI-experience (P=0.006) at baseline and fewer PI-resistance mutations (P=0.043) at end of prior failing regimen; in the multivariable analysis only higher CD4 count at baseline (P=0.009) and fewer number of drugs previously taken (P=0.003) could be specified as independent predictors for response.. The combination of lopinavir/ritonavir and saquinavir without RTIs is a potential option as salvage therapy for patients experiencing therapy failure due to RTI resistance or toxicity. This regimen may not be suitable for patients with very low baseline CD4 cell counts, very broad antiretroviral therapy experience or extensive PI-resistance mutations.

Topics: Adult; Aged; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cohort Studies; Drug Interactions; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Salvage Therapy; Saquinavir; Viral Load

To conduct a cost-efficacy analysis of lopinavir/ritonavir (LPV/r) monotherapy as a maintenance regimen following induction of virological response with triple therapy including LPV/r. The pharmacoeconomic analysis was performed from the perspective of the Spanish public health system.. A cost-efficacy analysis was performed in a phase IV-II, comparative, randomized, multicenter, open-label clinical trial evaluating the efficacy and safety of maintenance therapy with LPV/r monotherapy versus continuation of triple therapy in HIV-infected patients with a persistently undetectable viral load for 6 months. For the pharmacoeconomic analysis, efficacy was defined as the proportion of patients with plasma HIV RNA concentrations < 50 copies/mL at 48 weeks from the start of the study. An intent-to-treat analysis was performed. Only direct costs were considered. Cost, efficacy and the cost-efficacy ratio were calculated for each treatment option.. The cost-efficacy ratio of LPV/r maintenance monotherapy was 5186 euros per unit of achieved effect (patient with plasma HIV RNA concentrations < 50 copies/mL at 48 weeks), whereas maintenance with triple therapy had a cost-efficacy ratio of 8688 euros per unit of achieved effect.. The option of LPV/r monotherapy as maintenance therapy in HIV-infected patients following induction of virological response with triple therapy including LPV/r might be a more efficient alternative than maintaining triple therapy, as evidenced by a more favorable cost-efficacy ratio.

Topics: Adult; Cost-Benefit Analysis; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

Optimal antiretroviral exposure during pregnancy is critical for prevention of mother-to-child HIV transmission and for maternal health. Pregnancy can alter antiretroviral pharmacokinetics. Our objective was to describe lopinavir/ritonavir (LPV/r) pharmacokinetics during pregnancy.. We performed intensive steady-state 12-h pharmacokinetic profiles of lopinavir and ritonavir (three capsules: LPV 400 mg/r 100 mg) at 30-36 weeks gestation and 6-12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured LPV and ritonavir by reverse-phase high-performance liquid chromatography. Target LPV area under concentration versus time curve (AUC) was > or = 52 microg h/ml, the estimated 10th percentile LPV AUC in non-pregnant historical controls (mean AUC = 83 microg h/ml).. Seventeen women completed antepartum evaluations; average gestational age was 35 weeks. Geometric mean antepartum LPV AUC was 44.4 microg h/ml [90% confidence interval (CI), 38.7-50.9] and 12-h post-dose concentration (C12h) was 1.6 microg/ml (90% CI, 1.1-2.5). Twelve women completed postpartum evaluations; geometric mean LPV AUC was 65.2 microg h/ml (90% CI, 49.7-85.4) and C12h was 4.6 microg/ml (90% CI, 3.7-5.7). The geometric mean ratio of antepartum/postpartum LPV AUC was 0.72 (90% CI, 0.54-0.96). Fourteen of 17 (82%) pregnant and three of 12 (25%) postpartum women did not meet our target LPV AUC. The ratio of cord blood/maternal LPV concentration in ten paired detectable samples was 0.2 +/- 0.13.. LPV/r exposure during late pregnancy was lower compared to postpartum and compared to non-pregnant historical controls. Small amounts of lopinavir cross the placenta. The pharmacokinetics, safety, and effectiveness of increased LPV/r dosing during the third trimester of pregnancy should be investigated.

Topics: Adolescent; Adult; Area Under Curve; Case-Control Studies; Chromatography, High Pressure Liquid; Female; Fetal Blood; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Prospective Studies; Puerperal Infection; Pyrimidinones; Ritonavir

Topics: Adenine; Adult; Atazanavir Sulfate; Cohort Studies; Female; HIV Infections; Humans; Kidney; Lopinavir; Male; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Ritonavir; Tenofovir

To compare the efficacy and safety of a nucleoside-sparing approach with a conventional highly active antiretroviral therapy (HAART) regimen in antiretroviral-experienced patients with prolonged viral suppression.. Pilot study including 31 antiretroviral-experienced patients with HIV RNA <80 copies/mL. Subjects were randomly assigned to lopinavir/ritonavir (LPV/rtv) 400/100 mg BID plus nevirapine (NVP) 200 mg BID (NVP group, n = 16) or LPV/rtv plus the 2 previous NRTIs (NRTI group, n = 15). The primary endpoint was the percentage of subjects who maintained viral suppression at week 48. Changes in lipid metabolism, mitochondrial parameters, and LPV trough levels were also assessed.. All patients maintained viral suppression after 48 weeks. No subject discontinued therapy because of adverse events. HDL cholesterol increased by 28% at week 24 (P < 0.0001) and 10% after 48 weeks of follow-up (P = 0.319) in the NVP group. In the NRTI group, LDL cholesterol increased by 14% at week 48 (P = 0.076). Mitochondrial DNA/nuclear DNA ratio and mitochondrial respiratory chain complex IV activity showed a trend toward increasing in the NVP group. Mean (SD) LPV trough levels were 6340 (2129) ng/mL in the NRTI group and 5161 (2703) ng/mL in the NVP group (P = 0.140).. In antiretroviral-experienced subjects with sustained viral suppression, dual therapy with NVP plus LPV/rtv at standard dosage was as potent and safe as standard-of-care HAART at 48 weeks of follow-up. This approach may reduce mitochondrial toxicity and improve LPV/rtv-associated lipid abnormalities. The results of this pilot study support the study of this approach in a larger, randomized trial.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cholesterol, HDL; Cholesterol, LDL; Drug Tolerance; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lipids; Lopinavir; Male; Middle Aged; Mitochondria; Nevirapine; Prospective Studies; Pyrimidinones; Ritonavir; Safety

Tolerability of the combination of zidovudine-lamivudine and lopinavir-ritonavir as postexposure prophylaxis (PEP) for human immunodeficiency virus infection was prospectively assessed. A total of 121 patients were enrolled in the study; 23 patients discontinued PEP prematurely for reasons other than adverse events. Of the other 98 patients, 58 (59%) experienced adverse effects, which led to premature PEP discontinuation in 20 cases (20%).

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Combinations; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; Viral Load; Zidovudine

To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk.. Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects.. A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001).. Amprenavir mean area under the curve over 12 h (AUC0-12 h) and concentration at 12 h (C12 h) (microg/ml) were, respectively, 42.7 microg x h/ml (range, 33.1-55.1) and 2.4 microg/ml (range, 1.4-3.2) in arm B and 17.4 microg x h/ml (range, 4.6-41.3) and 0.9 microg/ml (range, 0.2-2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P < or = 0.0001). Lopinavir AUC0-12 h and C12 h were, respectively, 95.3 microg x h/ml (range, 60.3-119.3) and 6.3 microg/ml (range, 2.2-9.2) in arm A and 54.4 microg x h/ml (range, 23.5-112.2) and 3.0 microg/ml (range, 0.4-7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P < or = 0.0008). Ritonavir exposure was not significantly different between arms.. APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.

Topics: Adult; Carbamates; Drug Interactions; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Ritonavir; Salvage Therapy; Sulfonamides; Treatment Outcome

Topics: Atazanavir Sulfate; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; Humans; Lopinavir; Male; Maximum Tolerated Dose; Oligopeptides; Probability; Pyridines; Pyrimidinones; Risk Assessment; Severity of Illness Index; Treatment Outcome

The selection of in vivo resistance to lopinavir was characterized by analyzing the longitudinal isolates from 54 protease inhibitor-experienced subjects who either experienced incomplete virologic response or viral rebound subsequent to initial response while on treatment with lopinavir-ritonavir in Phase II and III studies. The evolution of incremental resistance to lopinavir (emergence of new mutation[s] and/or at least a twofold increase in phenotypic resistance compared to baseline isolates) was highly dependent on the baseline phenotype and genotype. Among the subjects demonstrating evolution of lopinavir resistance, mutations at positions 82, 54, and 46 in human immunodeficiency virus protease emerged frequently, suggesting that these mutations are important for conferring high-level resistance. Less common mutations, such as L33F, I50V, and V32I together with I47V/A, were also selected; however, new mutations at positions 84, 90, and 71 were not observed. The emergence of incremental resistance contrasts greatly with the low incidence of resistance observed after initiating lopinavir-ritonavir therapy in antiretroviral-naive patients, suggesting that partial resistance accumulated during prior protease inhibitor therapy can compromise the genetic barrier to resistance to lopinavir-ritonavir. The emergence of incremental resistance was uncommon in subjects whose baseline isolates contained eight or more mutations associated with lopinavir resistance and/or displayed >60-fold-reduced susceptibility to lopinavir, providing insight into suitable upper genotypic and phenotypic breakpoints for lopinavir-ritonavir.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Microbial Sensitivity Tests; Mutation; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sequence Analysis

To describe the occurrence of a high early virological failure (VF) rate and development of resistance mutations in antiretroviral-naive patients receiving tenofovir, didanosine and efavirenz.. HIV-infected antiretroviral-naive patients with viral load > or =30 000 copies/ml were enrolled in a pilot randomized trial of tenofovir/didanosine (250 mg)/ efavirenz with (arm A) or without (arm B) lopinavir/r for the first 12 weeks. As six cases of early VF (a drop of <2 log at month 3, or a rebound of >1 log from the nadir) were detected (five in arm B and one in arm A who had previously stopped lopinavir/r) an unplanned interim analysis was performed.. A total of 29 out of 36 enrolled patients completed at least 3 months of follow-up and were included in the interim analysis. An intent-to-treat analysis showed treatment failure in 7/15 (46.7%) patients in arm B (five VF, one lost, one switched) versus 2/14 (14.3%) in arm A (one lost, one switched) (P=0.109). The patient in arm A who interrupted lopinavir/r at day 3 and continued with tenofovir/didanosine/efavirenz later developed VF. At baseline, 6/6 VF patients had VL >100000 copies/ml and an advanced stage of disease (CD4 <200 plus CDC stage C or B3) versus 0/8 non-VF patients taking the triple drug regimen (P<0.001). At failure, G190S/E alone or associated with K103N and K101R mutations was detected in five patients, and K103N/L1001/V108l in the sixth patient. Additionally, L74V/I and K65R were detected in four and two patients, respectively.. A high early virological failure rate and the occurrence of resistance mutations were detected in a group of antiretroviral-naive patients treated with tenofovir/didanosine/efavirenz.

Topics: Adenine; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation; Organophosphonates; Oxazines; Pyrimidinones; RNA, Viral; Tenofovir; Time Factors; Treatment Failure; Viremia

The aim of this study was to evaluate the frequency, characteristics and risk factors of lipid changes associated with lopinavir/ritonavir treatment in antiretroviral-naive patients.. A prospective cohort of 107 antiretroviral-naive HIV-infected patients was followed for 12 months after starting lopinavir/ritonavir-based highly active antiretroviral therapy.. At 12 months, percentages of patients with hypercholesterolaemia and hypertriglyceridaemia were 17.4% and 40%, respectively. Mean increases in total cholesterol and triglycerides were 40.7 and 73.3 mg/dL. There was a significant increase in both low-density and high-density (HDL) cholesterol, and no increase in the total cholesterol/HDL ratio (from 4.16 at baseline to 4.49 after 12 months). Baseline cholesterol > 200 mg/dL and triglycerides > 150 mg/dL were independent risk factors for dyslipidaemia, while hepatitis C coinfection appeared to be protective.. Patients with elevated lipid values at baseline have the greatest risk of developing hypercholesterolaemia and hypertriglyceridaemia after starting lopinavir/ritonavir. Antiretroviral-naive patients coinfected with hepatitis C have a low risk of developing hyperlipidaemia after starting lopinavir/ritonavir.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Cholesterol, HDL; Cholesterol, LDL; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Risk Factors; Ritonavir; Triglycerides

The influence of nevirapine (NVP) on lopinavir (LPV) pharmacokinetics was investigated by a population analysis based on a non-linear mixed-effect modelling method.. In this analysis, 95 HIV-1 infected patients were studied [52 treated with LPV/ritonavir (400/100 mg twice a day) plus nucleoside reverse transcriptase inhibitors (group A), 22 patients treated with LPV/ritonavir (533.3/133.3 mg twice a day) plus NVP (group B) and 21 patients treated with LPV/ritonavir (400/100 mg twice a day) plus NVP (group C)].. The apparent clearance of LPV [mean+/-SD: 4.56+/-3.94 l h(-1) (group A) versus 7.14+/-1.77 l h(-1) (group B) versus 7.74+/-1.45 l h(-1) (group C)] was significantly (P <0.001) increased by the presence of NVP in the antiretroviral regimen and the mean trough plasma concentration of LPV was reduced in group C relative to group A [mean+/-SD: 2.23+/-1.35 mg/l versus 5.29+/-2.19 mg/l (P < 0.001)].. These results suggest an induction of LPV metabolism by NVP.

Topics: Adult; Anti-HIV Agents; Bayes Theorem; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Male; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors

To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening.. This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis.. Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (C(max)) and concentration at the end of the dosing interval (C(24 h)) after am and pm dosing was, respectively, 143 (116-214) mg l(-1) h, 12.8 (10.3-17.2) mg l(-1), 1.34 (0.58-3.25) mg l(-1), and 171 (120-232) mg l(-1) h, 12.9 (8.22-16.3) mg l(-1), 1.15 (0.59-1.98) mg l(-1). The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), C(max), and C(24 h) was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir C(max) after am and pm dosing was 1.05 and 0.90 mg l(-1), respectively. The GMR (95% CI) of the RTV AUC(0,24 h), C(max), and C(24 h) was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated.. No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.

Topics: Adult; Aged; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

Topics: Child; Child, Preschool; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Lopinavir; Nelfinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Salvage Therapy; Viral Load

To evaluate atazanavir/ritonavir (ATV/RTV) (300/100 mg) once daily, atazanavir/saquinavir (ATV/SQV) (400/1200 mg) once daily, and lopinavir/ritonavir (LPV/RTV) (400/100 mg) twice daily, each with tenofovir (300 mg) once daily and a nucleoside reverse transcriptase inhibitor in treatment-experienced HIV-infected patients.. Randomized, open-label, 48-week multicenter trial of 358 randomized adult patients who had failed two or more prior HAART regimens with baseline HIV RNA > or = 1000 copies/ml and CD4 cell count > or = 50 x 10(6) cells/l.. The primary efficacy endpoint [plasma HIV RNA reduction assessed by time-averaged difference (TAD)] was similar for ATV/RTV and LPV/RTV [TAD 0.13; 97.5% confidence interval, -0.12 to 0.39] at 48 weeks. Mean reductions from baseline for ATV/RTV and LPV/RTV were comparable at 1.93 and 1.87 log10 copies/ml, respectively. Mean CD4 cell count increases were 110 and 121 x 10(6) cells/l for ATV/RTV, and LPV/RTV, respectively. The efficacy of ATV/SQV was lower than LPV/RTV by both these parameters. Declines in total cholesterol and fasting triglycerides were greater with ATV/RTV and ATV/SQV than with LPV/RTV (P < or = 0.005). Lipids in the LPV/RTV arm at week 48 generally increased from baseline. Lipid-lowering agents were used more frequently in the LPV/RTV arm than in the ATV arms (P < 0.05 versus ATV/RTV), as were antidiarrheal agents (P < or = 0.04 versus both ATV treatments). No new or unique safety findings emerged.. ATV boosted with RTV is as effective and well tolerated as LPV/RTV in treatment-experienced patients, with a more favorable impact on serum lipids. Pharmacokinetically enhanced ATV provides a suitable choice for therapy of treatment-experienced HIV-infected patients.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; CD4 Lymphocyte Count; Cholesterol; Drug Administration Schedule; Drug Resistance, Multiple, Viral; HIV Infections; HIV-1; Humans; Lipids; Lopinavir; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Tenofovir; Viral Load

The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of -1.50 log(10) copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C(min) concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.

Topics: Adult; Aged; Drug Combinations; Drug Monitoring; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Linear Models; Lopinavir; Male; Middle Aged; Mutation; Predictive Value of Tests; Pyrimidinones; Ritonavir; RNA, Viral

Relationships between adherence to protease inhibitor (PI)-based therapy and resistance development have not been fully characterized.. We conducted a double-blind, randomized, controlled study of lopinavir/ritonavir versus nelfinavir, each administered with stavudine and lamivudine, in 653 antiretroviral-naive, human immunodeficiency virus (HIV)-1-infected patients. Relationships between adherence and probability of resistance development were evaluated by local linear regression or logistic regression.. A higher risk of detectable HIV-1 RNA loads after week 24 was associated with lower adherence (odds ratio [OR], 1.08 per 1% decrease in adherence [95% confidence interval {CI}, 1.05-1.10]; P<.001) and nelfinavir use (OR, 2.4 vs. lopinavir/ritonavir [95% CI, 1.6-3.6]; P<.001). Among all nelfinavir-treated patients, a bell-shaped relationship between adherence and the risk of nelfinavir resistance was observed, with a maximum probability of 20% at 85%-90% adherence. No lopinavir resistance was observed. A bell-shaped relationship was also observed for the probability of lamivudine resistance, with a maximum probability of 50% at 75%-80% adherence to nelfinavir and of 15% at 80%-85% adherence to lopinavir/ritonavir.. Bell-shaped relationships between adherence and resistance were observed. Irrespective of adherence level, the risk of detectable HIV-1 RNA loads or of PI or lamivudine resistance was significantly higher in nelfinavir-treated patients than in lopinavir/ritonavir-treated patients.

Topics: Double-Blind Method; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nelfinavir; Odds Ratio; Patient Compliance; Pyrimidinones; Risk Factors; Ritonavir; RNA, Viral; Viral Load

We evaluated the effect of salvage antiretroviral therapy with lopinavir/ritonavir (LPV/r) on the immune system of heavily antiretroviral pretreated HIV-infected children. We carried out a longitudinal study in 20 antiretroviral experienced HIV-infected children to determine the changes in several immunological parameters (T cell subsets, thymic function) every 3 months during 18 months of follow-up on salvage therapy with LPV/r. Statistical analyses were performed with the Wilcoxon test, taking as a reference the basal value at the entry in the study. HIV-infected children showed an increase of CD4+ T cells, a decrease in CD8+ T cells, and an increase in T cell rearrangement excision circle (TRECs) levels. The percentage of HIV children with undetectable viral load (VL < or = 400 copies/ml) increased significantly (p = 0.007) and the percentage with SI viral phenotype decreased significantly (p = 0.002) at the end of the study. Thus, the viral phenotype changed to NSI/R5 after salvage therapy with LPV/r. Interestingly, we observed a significant decrease of memory (CD4+ CD45RO+) and a moderate decrease of activated (CD4+ HLA-DR+, CD4+ HLA-DR+CD38, CD4+, CD45RO+HLA-DR+) CD4+ T cells during the follow-up. On the other hand, memory (CD8+ CD45RO+ and CD8+ CD45RO+CD38+), activated (CD8+ HLA-DR+CD38+, CD8+ HLA-DR+, CD8+ CD38+), and effector (CD8+ CD57+, CD8+ CD28(-)CD57+) CD8+ T cells had a very significant decrease during follow-up. Our data indicate an immune system reconstitution in heavily pretreated HIV-infected children in response to salvage therapy with LPV/r as a consequence of a decrease in immune system activation and an increase in thymic function.

Topics: Adolescent; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunologic Memory; Infant; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Salvage Therapy; T-Lymphocyte Subsets; Thymus Gland; Treatment Outcome

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

Highly active antiretroviral therapy (HAART) initiation in patients coinfected with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) has been associated with transaminase and HCV viral load flares. Previous studies have included highly variable antiretroviral regimens. We compared effects of 2 protease inhibitor-based regimens on alanine aminotransferase (ALT) levels and HCV loads in HCV-HIV-coinfected patients initiating HAART.. Seventy HIV-infected patients with positive baseline results of HCV enzyme-linked immunosorbant assay from a treatment trial comparing lopinavir-ritonavir with nelfinavir were evaluated during a 48-week period. HCV and HIV titers were analyzed at baseline, at weeks 24 and 48 of treatment, and during flares in the ALT level of >5 times the upper limit of normal.. A total of 57 of 70 patients tested positive for HCV RNA at baseline. HCV titers for patients in lopinavir-ritonavir and nelfinavir groups, respectively, were as follows: baseline, 6.07 and 6.22 log IU/mL; week 24 of treatment, 6.68 and 6.48 log IU/mL; and week 48 of treatment, 6.32 and 6.44 log IU/mL. Of patients with a CD4+ cell count of <100 cells/mm3 at baseline, 5 of 11 in the nelfinavir group and 0 of 10 in the lopinavir-ritonavir group had an increase in the HCV load of >0.5 log IU/mL from baseline to week 48. The mean ALT level increased by 45 U/L at 24 weeks and 18 U/L at 48 weeks in the nelfinavir group but decreased by 18 U/L at 24 weeks and 7 U/L at 48 weeks in the lopinavir-ritonavir group. Eight patients in the nelfinavir group and 2 patients in the lopinavir-ritonavir group had grade 3 or 4 flares in the ALT level.. HAART initiation is associated with increased HCV loads and ALT levels. A low baseline CD4+ cell count is associated with persistent increases in the HCV RNA load in nelfinavir-treated patients. These results warrant careful interpretation of abnormalities in the ALT load after HAART initiation in HCV-HIV-coinfected patients to prevent premature discontinuation of treatment.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver; Lopinavir; Male; Middle Aged; Nelfinavir; Pyrimidinones; Ritonavir; RNA, Viral; Viral Load

To assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r).. Open-label, prospective, randomized (1:1), international multi-centre trial.. Adult HIV-1-infected patients were assigned LPV/r 400/100 mg twice daily or SAQ/r 1000/100 mg twice daily with two or more nucleoside reverse transcriptase inhibitors (NRTIs)/non-NRTIs. All patients, whether on or off the assigned treatment, were followed for 48 weeks.. Of 339 randomized patients, 324 initiated assigned treatment (intention-to-treat/exposed [ITT/e] population). At 48 weeks, treatment failure occurred in 29/163 (18%) and 53/161 (33%) of patients in the LPV/r and SAQ/r arms, respectively (ITT/e, P = 0.002, log rank test). In an analysis that also considered those patients who discontinued treatment as having failed treatment (ITT/e/discontinuation = failure), 40/161 (25%) LPV/r-treated individuals versus 63/161 (39%) SAQ/R-treated individuals failed treatment (P = 0.005, log rank test). Discontinuation of the assigned treatment occurred in 23/163 (14%) patients in the LPV/r-treated group, compared with 48/161 (300%) in the SAQ/r-treated group (ITT/e; P = 0.001). The primary reasons for premature discontinuation were non-fatal adverse events (LPV/r: 12/163; SAQ/r: 21/161) and patients' choice (LPV/r: 7/163; SAQ/r: 8/161). In the on-treatment analysis of time to treatment failure, no difference was observed between the two arms (P = 0.27, log rank test).. LPV/r had better antiretroviral effects compared with SAQ/r at the doses and in the formulations studied. This may have been a result of patients' preferences and ability to adhere to assigned therapy, rather than a result of differences in the intrinsic potency of the study protease inhibitors.

Topics: Adult; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Saquinavir; Treatment Outcome

Many human immunodeficiency virus type 1 (HIV-1)-infected children have already failed treatment with 2 or even 3 classes of antiretrovirals. Coformulation of lopinavir with low dose ritonavir exhibits a potent antiretroviral effect. However, the data in heavily pretreated children are still scarce. This study evaluated the safety and effectiveness of combination therapy including lopinavir/ritonavir in children with prior exposure to all classes of oral antiretrovirals.. This was an open label multicenter observational study, in which data were reviewed according to a standardized protocol. The study population included all HIV-1-infected children with virologic failure (HIV-1 RNA >5000 copies/mL) followed in 12 Spanish hospitals for >12 months, experienced with the 3 classes of oral antiretrovirals, in whom a lopinavir/ritonavir-containing regimen was started.. By March 2003, 45 patients had been treated with lopinavir/ritonavir for a median of 18 months (range, 3-28). The median age at baseline was 9.7 years (range, 4.3-17.1). The median times of prior treatment were 88 months (range, 31-145) with nucleoside reverse transcription inhibitors and 42 months (range, 19-63) with protease inhibitors. Twenty-five patients were classified as Centers for Disease Control and Prevention clinical category C. Median values for absolute and percentage CD4 at baseline were 501 (range, 6-1512) and 19% (range, 0.5-49), respectively, and plasma HIV-RNA was 5.0 log10 copies/mL (range, 4.1-6.1). During follow-up, 11 (24%) children switched from liquid to solid formulation. At 48 weeks, the median values for absolute and percentage CD4 increased by 199 cells/microL and 3%, respectively, and median plasma viral load declined 1.75 log10 copies/mL. Forty-two percent of children achieved a plasma RNA of <400 copies/mL (intent to treat analysis). Baseline genotypic resistance was available in 40 children. Nonresponders had 7.0 +/- 1.6 protease inhibitor-associated mutations at baseline compared with 4.8 +/- 1.7 in children achieving virologic suppression (P = 0.06). Adverse events were described in 18 children. Three children permanently discontinued and 4 transiently withdrew lopinavir/ritonavir. At 12 months, there were mild but not significant increases in plasma cholesterol and triglycerides.. Lopinavir/ritonavir when given as part of salvage regimen is well-tolerated, although switching to pills is frequently required. The regimen has a potent and durable antiretroviral activity in most heavily pretreated children, despite the presence of multiple mutations to all classes of oral antiretrovirals.

Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Salvage Therapy; Treatment Outcome

To assess the pharmacokinetics and 24-week efficacy and safety of dual boosted saquinavir/lopinavir/ritonavir combination in children.. Twenty reverse transcription inhibitor-pretreated children at 2 centers in Thailand were treated with saquinavir/lopinavir/ritonavir in an open label, single arm, 6-month prospective study. The dosage was 50 mg/kg twice daily (bid) for saquinavir and 230/57.5 mg/m bid for lopinavir/ritonavir. Ten children also received lamivudine.. Samples were collected for a 12-hour pharmacokinetic profile in all children. Plasma concentrations of saquinavir, lopinavir and ritonavir were determined using a validated high performance liquid chromatography technique.. At baseline, the median age was 8.5 years, with human immunodeficiency virus (HIV) RNA 4.9 log10 copies/mL, CD4 count 129 cells/microL and CD4%, 6.5%. Median area under the concentration curve at 0-12 hours and Cmin were 39.4 mg/L.h and 1.4 mg/L for saquinavir and 118 mg/L.hr and 5.9 mg/L for lopinavir. After 24 weeks of treatment, HIV RNA was suppressed below 400 copies/mL for 16 of 20 (80%) children (intent-to-treat analysis) and below 50 copies/mL for 12 of 20 children (60%), and CD4% (count) rose by a median of 6% (216 cells/microL). Median changes of triglyceride and total cholesterol were 56 and 36.5 mg/dL, respectively (P = 0.01). Lopinavir Cmin <1 and saquinavir Cmin <0.28 mg/L correlated with HIV RNA >400 copies/mL, and lopinavir Cmax >15 mg/L correlated with rises in cholesterol (P < 0.05).. Plasma drug concentrations of saquinavir, lopinavir and ritonavir were at the higher limits of expected ranges for adult treatment at approved dosages (1000/100 mg bid for saquinavir, 400/100 mg bid for lopinavir/ritonavir). The regimen was well-tolerated and had good efficacy at 24 weeks. This dual boosted protease inhibitor combination should be assessed in larger trials of reverse transcription inhibitor-experienced children.

Topics: Anti-HIV Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Treatment Outcome

To compare change from baseline in HIV RNA and fasting low-density lipoprotein (LDL) cholesterol levels in protease inhibitor (PI)-experienced patients receiving unboosted atazanavir 400 mg once daily versus lopinavir 400 mg boosted with ritonavir 100 mg twice daily, with two nucleoside reverse transcriptase inhibitors (NRTIs). Secondary objectives included virologic response, CD4 cell count changes, other lipid changes, safety, and tolerability.. Randomized, open-label, multinational, 48-week study in patients with one PI-regimen failure, HIV RNA > or = 1000 copies/mL, and CD4 count > or = 50 cells/mm3.. Three hundred patients were randomized; 290 treated (144 atazanavir, 146 lopinavir/ritonavir). Lopinavir/ritonavir resulted in a significantly greater reduction in HIV RNA than unboosted atazanavir (-2.02 vs -1.59 log10 copies/mL, p < 0.001) at week 48. Secondary efficacy endpoints also favored lopinavir/ritonavir; the differences in efficacy between regimens were also observed in secondary analyses comparing those subjects who were susceptible and those subjects who were resistant to their respective PIs at baseline. However, both regimens were equally effective in subjects who had no baseline NRTI mutations. From baseline to week 48, atazanavir resulted in either no change or decreases in fasting LDL cholesterol, total cholesterol, and fasting triglycerides (-6%, -2%, and +1%), whereas lopinavir/ritonavir resulted in increases (+3%, +12%, and +53%) (p < 0.05, all between-treatment comparisons). Fewer patients were administered lipid-lowering therapy in the atazanavir arm (6% vs 20% for lopinavir/ritonavir). Both regimens were safe and well tolerated.. While both treatments demonstrated good antiviral efficacy, relatively greater antiviral suppression was observed with lopinavir/ritonavir. In those patients with no NRTI mutations at baseline, both regimens demonstrated comparable virologic suppression. Atazanavir-treated patients demonstrated a superior lipid profile and required less frequent lipid-lowering treatment.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Cholesterol; Cholesterol, LDL; Female; HIV; HIV Infections; Humans; Lopinavir; Male; Oligopeptides; Protease Inhibitors; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Triglycerides

This study evaluated maintenance with lopinavir/ritonavir monotherapy vs. continuing lopinavir/ritonavir and 2 nucleosides in HIV-infected patients with suppressed HIV replication.. Randomized, controlled, open-label, multicenter, pilot clinical trial.. Adult patients were eligible if they had no history of virologic failure while receiving a protease inhibitor, were receiving 2 nucleosides + lopinavir/ritonavir (400/100 mg b.i.d.) for >1 month and had maintained serum HIV RNA <50 copies/mL for >6 months prior to enrollment.. Forty-two patients were randomly assigned 1:1 to continue or stop the nucleosides. At baseline there were no significant differences between groups in median CD4 cells/muL (baseline or nadir), pre-HAART (highly active antiretroviral therapy) HIV log10 viremia, or time with HIV RNA <50 copies/mL prior to enrollment. After 48 weeks of follow-up, percentage of patients remaining at <50 HIV RNA copies/mL (intention to treat, M = F) was 81% for the monotherapy group (95% CI: 64% to 98%) vs. 95% for the triple-therapy group (95% CI: 86% to 100%); P = 0.34. Patients in whom monotherapy failed had significantly worse adherence than patients who remained virally suppressed on monotherapy. Monotherapy failures did not show primary resistance mutations in the protease gene and were successfully reinduced with prerandomization nucleosides. Mean change in CD4 cells/microL: +70 (monotherapy) and +8 (triple) (P = 0.27). Mean serum fasting lipids remained stable in both groups. No serious adverse events were observed.. Most of the patients maintained with lopinavir/ritonavir monotherapy remain with undetectable viral load after 48 weeks. Failures of lopinavir/ritonavir monotherapy were not associated with the development of primary resistance mutations in the protease gene and could be successfully reinduced adding back prior nucleosides.

Topics: Adult; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pilot Projects; Pyrimidinones; Ritonavir; RNA, Viral; Spain

Six HIV-positive antiretroviral experienced patients initiating therapy with a regimen including lopinavir/ritonavir (400/100 mg twice per day) and indinavir (800 mg twice per day) underwent steady-state pharmacokinetic analysis. The AUC0-12 h of indinavir when combined with lopinavir/ritonavir was comparable with previously published data on indinavir/ritonavir 800/100 mg twice per day in HIV-infected individuals. However, lopinavir AUC0-12 h, Cmax, and C12 h were lower than previously reported in the absence of indinavir. The regimen was well tolerated, although 2 patients developed grade 3 hypertriglyceridemia. No patient discontinued the regimen because of indinavir-related urologic or retinoid-type adverse effects. Further study of the regimen with larger cohorts of patients is necessary.

Topics: Adult; Area Under Curve; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypertriglyceridemia; Indinavir; Lopinavir; Male; Metabolic Clearance Rate; Pyrimidinones

The influence of saquinavir hard-gel capsules on lopinavir pharmacokinetic parameters was investigated using a population approach. Forty-nine patients infected with human immunodeficiency virus type 1 and treated with lopinavir/ritonavir, nucleoside/nucleotide reverse transcriptase inhibitors plus saquinavir (group A), and 118 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (group B) were included in the study. No significant relationship was established between the presence or the daily dosage of saquinavir in the treatment and lopinavir population pharmacokinetic parameters. The values (mean+/-standard deviation) of the individual apparent clearance (5.0+/-1.8 vs. 5.0+/-3.2 L/h), volume of distribution (66.6+/-1.6 vs. 66.8+/-1.9 L), absorption rate constant (0.37+/-0.01 vs. 0.37+/-0.03 hours), and trough plasma concentration (5.5+/-2.3 vs. 5.3+/-1.9 mg/L) of lopinavir are not significantly different between groups A and B. This lack of influence of saquinavir on lopinavir pharmacokinetics makes the use of this combination in salvage therapy easier.

Topics: Administration, Oral; Adult; Bayes Theorem; Capsules; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Female; Gels; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Metabolic Clearance Rate; Pyrimidinones; Regression Analysis; Retrospective Studies; Ritonavir; Saquinavir

Study M98-863 was a double-blind, randomized, phase 3 study that compared lopinavir/ritonavir with nelfinavir, each coadministered with stavudine and lamivudine, in 653 antiretroviral therapy-naive human immunodeficiency virus (HIV) type 1-infected subjects. The incidence of HIV drug resistance was analyzed using baseline and rebound virus isolates from subjects with plasma HIV RNA >400 copies/mL from weeks 24 to 108 of therapy. No evidence of genotypic or phenotypic resistance to lopinavir/ritonavir, defined as any active site or primary mutation in HIV protease, was detected in virus isolates from 51 lopinavir/ritonavir-treated subjects with available genotypes. Primary mutations related to nelfinavir resistance (D30N and/or L90M) were observed in 43 (45%) of 96 nelfinavir-treated subjects. Resistance to lamivudine and stavudine was also significantly higher in nelfinavir-treated versus lopinavir/ritonavir-treated subjects. These differences suggest substantially different genetic and pharmacological barriers to resistance for these 2 protease inhibitors and may have implications for strategies for initiating antiretroviral therapy.

Topics: Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Global Health; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Mutation; Nelfinavir; Patient Compliance; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Stavudine; Time Factors; Viral Load

The safety, pharmacokinetics, and antiviral activity of lopinavir, a human immunodeficiency virus (HIV) protease inhibitor, coformulated with ritonavir as a pharmacokinetic enhancer were evaluated in 38 antiretroviral-naive patients randomized 1:1 to receive open-label lopinavir/ritonavir at a dose of 800/200 mg once daily or 400/100 mg twice daily, each in combination with stavudine and lamivudine twice daily, for 48 weeks. Over the course of 48 weeks, median predose concentrations of lopinavir exceeded the protein-binding corrected concentration required to inhibit replication of wild-type HIV by 50% in vitro by 40- and 84-fold in the once- and twice-daily groups, respectively. Predose concentrations of lopinavir were more variable in the once-daily group (mean +/- SD, 3.62+/-3.38 microg/mL for the once-daily group and 7.13+/-2.93 microg/mL for the twice-daily group). At week 48, in an intent-to-treat (missing = failure) analysis, 74% of patients in the once-daily group and 79% of patients in the twice-daily group had HIV RNA levels of <50 copies/mL (P=.70). Study drug-related discontinuations occurred in 1 patient in each treatment group. Genotypic resistance testing of 4 patients with HIV RNA levels >400 copies/mL between weeks 24 and 48 demonstrated no protease inhibitor-resistance mutations.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Patient Compliance; Pyrimidinones; Ritonavir

Plasma and cervicovaginal secretion (CVS) samples were collected from 19 human immunodeficiency virus type 1-infected women on lopinavir- or indinavir-containing regimens. Lopinavir and indinavir were detectable in 29 and 93% of CVS samples, respectively, a finding that may be ascribed to these drugs' differences in protein binding and pK(a). The relationship between lopinavir and indinavir pharmacodynamics and viral evolution in the female genital tract should be assessed over time.

Topics: Adult; Anti-HIV Agents; Chromatography, High Pressure Liquid; Female; Genitalia, Female; HIV Infections; HIV-1; Humans; Indinavir; Lopinavir; Protein Binding; Pyrimidinones; Vagina

Most protease inhibitors available for the treatment of human immunodeficiency virus (HIV) infection are highly bound to plasma proteins, mainly alpha-1 acid glycoprotein. Therapeutic drug monitoring (TDM) of total protease inhibitor (PI) concentrations has been increasing in the past few years; however, the pharmacological activity of the PIs is dependent on unbound drug entering cells harboring HIV. There is little information available on unbound drug concentrations of these drugs in vivo. The aim of the study was to measure unbound plasma concentrations of lopinavir (LPV) and to relate them to the total plasma concentrations to establish the unbound percentage in vivo during a full dosage interval. A pharmacokinetic study was performed in HIV-infected subjects (n = 23; median CD4 cell count = 290 x 10(6) cells x L(-1); viral load < 50 copies x mL(-1)) treated with a LPV/ritonavir (RTV)-containing regimen. Ultrafiltration was used to separate unbound LPV in all plasma samples (n = 115). Equilibrium dialysis was also used to compare with ultrafiltration measurements in 10/23 patients at baseline and 2 hours after drug intake. Total and unbound LPV concentrations were measured by a fully validated method using high-performance liquid chromatography-mass spectometry (HPLC-MS/MS). Based on a comparison of AUC(unbound)AUC(total), the mean (+/- SD) unbound percentage of LPV from all the samples studied (n = 115) was 0.92% (+/- 0.22) when measured with ultrafiltration and 1.32% (+/- 0.44) when equilibrium dialysis was used (n = 20), showing a higher drug recovery (P = 0.048). The unbound percentage of LPV was found to be significantly higher after 2 h than at baseline (P < 0.05 with both methods), suggesting a concentration-dependent binding of LPV that has not been observed in vitro. However, the clinical significance of such phenomena is still unclear.

Topics: Adult; Area Under Curve; Blood Proteins; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Protein Binding; Pyrimidinones; Ritonavir; Ultrafiltration

Coadministration of amprenavir (APV) with small doses of ritonavir (RTV) results in a significant increase in APV plasma concentrations. Viruses showing resistance to other protease inhibitors (PI) may remain susceptible to APV, supporting a role for this drug in salvage therapy. We enrolled 35 patients who began a rescue intervention based on APV/RTV 600/100 mg twice daily. Their median viral load before beginning APV/RTV was 4.15 logs and their median CD4 count was 247 cells per microliter. The median prior PI exposure was of 43 months. At baseline, the median number of PI resistance mutations was 7. A significant virologic response (VR) (>1 log drop in plasma HIV-RNA and/or to <50 copies per milliliter) was recorded in 21.7% (5/23) of treated patients at week 48 (14.3% in the intent-to-treat analysis). The VR was significantly more frequent among subjects with less than 5 PI resistance mutations (66.6% vs. 5.8%; p = 0.008). Patients with prior exposure to lopinavir showed VR significantly less frequently than those not exposed to that drug (11% versus 60%; p < 0.05). The mean APV plasma trough concentration at week 12 was 1.3 microg/mL, and did not differ significantly comparing subjects having or not having VR. A trend toward a higher VR rate at week 48 was noticed among subjects with high genotypic inhibitory quotients (GIQ). In summary, HIV genotyping but not drug levels might be helpful to predict which patients would benefit from a rescue intervention based on APV/RTV 600/100 twice daily.

Topics: Adult; Antiretroviral Therapy, Highly Active; Area Under Curve; Carbamates; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Resistance, Viral; Female; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Mutation; Patient Selection; Phenotype; Predictive Value of Tests; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Salvage Therapy; Sulfonamides; Treatment Outcome; Viral Load

To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in body fat composition.. A prospective, non-randomized study.. HIV clinic of a University Hospital.. HIV-infected subjects who had virological failure on protease inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19 completed 24 weeks of treatment and 16 completed the full 48-week study period.. Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. LPV trough plasma concentrations were measured at baseline and weeks 4, 8, 12, 24, 36 and 48. Body fat composition was quantified by computerized tomographic scanning at baseline, and weeks 24 and 48.. LPV trough concentrations correlated with absolute and proportional changes in limb fat from baseline to week 48. Significant differences were found in mean LPV trough concentrations between patients losing less than 5% of limb fat, those experiencing a limb fat loss between 5 and 20%, and those losing more than 20% at week 24 [mean (SD), 4.67 (1.67); 8.57 (1.77); 9.49 (2.67) microg/ml, respectively; P=0.013] and week 48 [mean (SD), 4.5 (2.24); 7.04 (1.77); 9.7 (2.8) microg/ml, respectively; P=0.027]. Most patients losing more than 5% of limb fat during LPV/r therapy had mean LPV trough concentrations > or = 8 microg/ml.. In patients receiving salvage therapy with LPV/r there was an association between LPV plasma trough concentrations and limb fat loss. The risk of peripheral limb fat loss may be greater among patients achieving higher LPV trough concentrations.

Topics: Adipose Tissue; Anti-HIV Agents; Area Under Curve; Body Composition; Body Mass Index; Body Weight; CD4 Lymphocyte Count; Follow-Up Studies; HIV Infections; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir; Salvage Therapy; Tomography, X-Ray Computed

Within this open-label, uncontrolled prospective trial we evaluated safety, efficacy and development of genotypic resistance under the new protease inhibitor lopinavir/ritonavir (LPV/r) in antiretroviral (ARV) HIV patients.. 58 patients with virological failure under their current ARV therapy were started on a LPV/r containing regimen. Median baseline HIV RNA and CD4 count were 4.6 log(10) cps/ml (range 2.1-6.4) and 128 x 10(6)/l (0-767), respectively. CD4 count, HIV RNA and metabolic parameters were assessed at weeks 0, 4, 8, 12, 16, 24, 32, 40, 48. Genotypic resistance testing was performed at baseline and again at weeks 12, 24 and 48 in the event of virological failure.. Until week 48, viral load (VL) decreased by a median of 1.9 log(10) cps/ml (-0.8-3.8). A VL below 80 cps/ml was found in 20/58 patients (34.5%) at week 48. In parallel, CD4 cells increased to a median of 332 x 10(6)/l (8-905). Nine patients discontinued study treatment. At 48 weeks, median triglyceride and cholesterol levels increased significantly. While the median number of overall protease mutations at baseline was four in all patients, it was six in patients virologically failing on LPV/r. The average number of mutations increased significantly to eight at week 48. Several mutations were detected considerably more often in the event of failure than in response to treatment, e. g. at amino acid positions 10, 24, 54, 71, 82, 84.. LPV/r is effective in heavily pretreated patients. Discontinuation due to adverse events is infrequent. No individual mutation can be associated with failure on LPV/r. However, a greater number of protease mutations at baseline is associated with poorer treatment outcome and several mutations seem to be related to treatment failure.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Microbial Sensitivity Tests; Middle Aged; Pharmacogenetics; Probability; Prospective Studies; Pyrimidinones; Risk Assessment; Ritonavir; RNA, Viral; Severity of Illness Index; Treatment Outcome; Viral Load

This pharmacokinetic study was designed to characterize interactions between amprenavir and the lopinavir-ritonavir combination in patients infected with human immunodeficiency virus in whom previous antiretroviral therapy had failed.. Twenty-seven patients included in a randomized clinical trial (ANRS [National Agency for AIDS Research] Protocol 104) participated in this study. They were randomized to receive ritonavir at a dose of either 100 mg twice daily or 200 mg twice daily. For the first 2 weeks of therapy, they were randomly assigned to receive lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily), amprenavir (600 mg twice daily) plus ritonavir (100 mg twice daily), lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily) plus additional ritonavir (100 mg twice daily), or amprenavir (600 mg twice daily) plus ritonavir (200 mg twice daily). From week 3 onward, all patients received amprenavir plus lopinavir-ritonavir with or without an additional ritonavir dose (100 mg twice daily). The pharmacokinetics of the 3 drugs was studied in weeks 2 and 6 of therapy.. Median amprenavir concentrations decreased by 54% (P =.004) when lopinavir was added to the amprenavir-ritonavir regimen. Lopinavir weakly displaced amprenavir from plasma proteins: The average unbound fraction of amprenavir was 0.089 in week 2 and 0.114 in week 6 (P =.03), but this did not fully account for the observed interaction. Increasing the ritonavir dose did not affect the amprenavir concentration. The relationship between lopinavir and ritonavir concentrations fitted a maximum effect (E(max)) model;the average concentration of ritonavir that yielded a lopinavir concentration of 8119 ng/mL (50% of E(max)) was 602 ng/mL (coefficient of variation, 22%). There was a significant relationship between the lopinavir inhibitory quotient and the virologic response in week 2 (P =.005).. Lopinavir markedly decreases the amprenavir concentration during amprenavir and lopinavir-ritonavir combination therapy. The inhibitory quotients were more predictive of the short-term virologic response than was the level of drug exposure.

Topics: Administration, Oral; Adult; Antiretroviral Therapy, Highly Active; Biological Availability; Carbamates; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Furans; HIV Infections; Humans; Lopinavir; Male; Maximum Tolerated Dose; Middle Aged; Probability; Pyrimidinones; Risk Assessment; Ritonavir; Salvage Therapy; Severity of Illness Index; Single-Blind Method; Statistics, Nonparametric; Sulfonamides; Survival Rate; Treatment Outcome; Viral Load

Combination antiretroviral therapy with lopinavir/ritonavir (LPV/r) has been highly effective in clinical trials. Results of long-term therapy with LPV/r-based regimens have not been previously reported. This study describes the 4-year (204-week) safety and antiretroviral activity of LPV/r-based treatment in antiretroviral-naive individuals.. Long-term, open-label follow-up of a phase II, prospective, randomized, multicenter trial.. A group of 100 antiretroviral-naive HIV-infected patients were randomized to one of three blinded doses of LPV/r [200/100 mg (n = 16), 400/100 mg (n = 51), or 400/200 mg (n = 33)] with stavudine 40 mg and lamivudine 150 mg every 12 hours. After 48 weeks, LPV/r was dosed open-label at 400/100 mg every 12 hours with stavudine and lamivudine.. : Mean baseline plasma HIV-1 RNA and CD4 cell count were 4.9 log10 copies/ml and 338 x 10 cells/l, respectively. At week 204, 72 patients remained on study, 70 of whom had HIV-1 RNA < 50 copies/ml (70% by intent-to-treat analysis). Twenty-eight patients discontinued therapy prior to week 204 because of adverse events (n = 10), lost to follow-up (n = 9), or other reasons (n = 9). Of 15 patients who met protocol-defined criteria for virologic failure, seven remained on the study regimen and their HIV-1 RNA was re-suppressed to < 50 copies/ml at week 204. Genotypic analysis of rebound viral isolates was available from 10 patients, including all eight patients who discontinued the study prematurely. No isolate demonstrated primary or active site mutations in protease. The most common adverse events were gastrointestinal symptoms and lipid elevations.. LPV/r-based therapy provides durable antiretroviral response and is generally well tolerated through 204 weeks of therapy.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Stavudine; Time Factors

Topics: Adult; Anti-HIV Agents; Drug Administration Schedule; Drug Monitoring; Female; HIV Infections; Humans; Lipids; Lopinavir; Male; Metabolic Diseases; Pyrimidinones; Reproducibility of Results

The safety, efficacy, and mutual interactions of combination amprenavir with lopinavir/ritonavir as deep salvage treatment were investigated in a prospective 24-week pilot study. HIV-infected patients (n = 22) with virologic failure to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, and at least 2 protease inhibitors received 400/100 mg of lopinavir/ritonavir with 600 mg of amprenavir every 12 hours combined with NRTIs. Patients receiving the same doses of lopinavir/ritonavir (n = 10) or amprenavir with ritonavir (n = 8) were chosen as controls for pharmacokinetic analyses. Mean changes from baseline HIV RNA levels and CD4 counts after 24 weeks were -1.13 log10 copies/mL and +88 x 10 cells/L, respectively. The mean plasma trough concentration (Cmin)and peak concentration (Cmax) of amprenavir were 104% and 228% lower and the Cmin of lopinavir was 46% lower in patients in whom the drugs were coadministered than in controls. There were 4 permanent drug discontinuations because of toxicity. An inhibitory quotient (IQ) of amprenavir higher than 0.8 was the best predictor of virologic outcome at 24 weeks, even after adjusting for amprenavir Cmin or phenotypic susceptibility. Deep salvage therapy using lopinavir/ritonavir with amprenavir is sufficiently safe and shows partial efficacy. When these drugs are coadministered, therapeutic drug monitoring should be employed and the IQ can be used to determine target drug levels.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pilot Projects; Pyrimidinones; Ritonavir; RNA, Viral; Salvage Therapy; Sulfonamides

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

Baseline CD4 cell counts and human immunodeficiency virus (HIV)-1 RNA levels have been shown to predict immunologic and virologic responses in HIV-infected patients receiving antiretroviral therapy. In our randomized, double-blind, comparative trial, 653 antiretroviral therapy-naive patients received lopinavir/ritonavir or nelfinavir, plus stavudine and lamivudine, for up to 96 weeks. The risk of loss of virologic response was significantly higher for nelfinavir-treated patients than for lopinavir/ritonavir-treated patients (Cox model hazard ratio, 2.2; 95% confidence interval, 1.7-3.0; P<.001). For nelfinavir-treated patients, but not for lopinavir/ritonavir-treated patients, higher baseline HIV-1 RNA levels and lower baseline CD4 cell counts were associated with a higher risk of loss of virologic response.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Nelfinavir; Predictive Value of Tests; Pyrimidinones; Risk Factors; Ritonavir; RNA, Viral; Sex Characteristics; Stavudine; Viral Load

Lopinavir/ritonavir (LPV/RTV) is a CYP3A4 inhibitor and substrate; it also may induce cytochrome P-450 (CYP) isozymes. Phenytoin (PHT) is a CYP3A4 inducer and CYP2C9/CYP2C19 substrate. This study quantified the pharmacokinetic (PK) drug interaction between LPV/RTV and PHT. Open-label, randomized, multiple-dose, PK study in healthy volunteers. Subjects in arm A (n = 12) received LPV/RTV 400/100 mg twice daily (BID) (days 1-10), followed by LPV/RTV 400/100 mg BID + PHT 300 mg once daily (QD) (days 11-22). Arm B (n = 12) received PHT 300 mg QD (days 1-11), followed by PHT 300 mg QD + LPV/RTV 400/100 mg BID (days 12-23). Plasma samples were collected on day 11 and day 22; PK parameters were compared by geometric mean ratio (GMR, day 22:day 11). P values <0.05 were considered significant. Following PHT addition, LPV area under the concentration-time curve (AUC0-12h) decreased from 70.9 +/-37.0 to 49.6 +/- 25.1 microg.h/mL (GMR 0.67, P = 0.011) and C0h decreased from 6.0 +/- 3.2 to 3.6 +/- 2.3 microg/mL (GMR 0.54, P = 0.001). Following LPV/RTV addition, PHT AUC0-24h decreased from 191.0+/-89.2 to 147.8+/-104.5 microg.h/mL (GMR 0.69, P = 0.009) and C0h decreased from 7.0+/-4.0 to 5.3+/-4.1 microg/mL (GMR 0.66, P = 0.033). Concomitant LPV/RTV and PHT use results in a 2-way drug interaction. Phenytoin appears to increase LPV clearance via CYP3A4 induction, which is not offset by the presence of low-dose RTV. LPV/RTV may increase PHT clearance via CYP2C9 induction. Management should be individualized to each patient; dosage or medication adjustments may be necessary.

Topics: Adult; Anticonvulsants; Cytochrome P-450 Enzyme System; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pharmacogenetics; Phenytoin; Pyrimidinones; Ritonavir; Seizures

To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir.. Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir.. At baseline: lopinavir parameters (n=10) in BP were within expected levels. Median lopinavir trough concentrations (n=5) in CSF and SP were below the limit of detection (BLD) (i.e. <10 ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir C(max), C(min) and AUC(0-12) increased by 9%, 46% and 20%, respectively (P<0.32, P<0.32 and P<0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20-2734). Median indinavir PK parameters were C(max) 3365 ng/mL (range 2130-5194), C(min) 293 ng/mL (14-766), T(max) 2.25 h (1-3), AUC(0-12) 22452 ng/mL.h (11243-33661), and t(1/2) 2.8 h (1.4-3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21-86) and 592 ng/mL (96-983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir.. Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were >80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected.

Topics: Adult; Area Under Curve; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Drug Combinations; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Mass Spectrometry; Middle Aged; Pyrimidinones; RNA, Viral; Semen; Viral Load

To investigate the normalized inhibitory quotient (NIQ) of lopinavir (LPV) as a predictor of 48-week virological responses to a lopinavir/ritonavir (LPV/RTV)-containing regimen in highly treatment-experienced patients.. We calculated the NIQ for 59 patients who completed 48 weeks' treatment and assessed the factors predicting a week-48 virological response.. The NIQ was calculated by dividing each subject's IQ (LPV Ctrough/fold change in LPV susceptibility, as assessed by VirtualPhenotype) by a reference IQ (mean population LPV Ctrough/fold change in LPV IC50, as assessed by VirtualPhenotype). HIV-1 RNA was assessed by NASBA (quantification limit: 80 copies/ml). The general linear model and multiple logistic regression, respectively, were used to estimate the independent predictors of a change in viral load and HIV-1 RNA <80 copies/ml.. The median (interquartile range) baseline levels of CD4+ cells and HIV-1 RNA were 251 (141-385) cells/microl and 4.85 (4.49-5.23) log10 copies/ml, respectively. The median NIQ was 2.2 (0.5-14). At week 48, the median decrease in HIV-1 RNA was 1.4 (0.59-2.79) log10 copies/ml (P<0.0001), with 24 subjects (41%) reaching <80 copies/mi. Baseline HIV-1 RNA (P=0.001), CD4+ cells (P=0.002) and NIQ (P=0.0006) independently predicted the week-48 change in viral load, whereas baseline CD4+ cells (P=0.011) and NIQ (P=0.009) independently predicted a week-48 HIV-1 RNA level of <80 copies/ml.. The LPV NIQ independently predicts virological responses to an LPV/RTV-containing regimen in highly treatment-experienced HIV-1-infected patients.

Topics: Adult; CD4 Lymphocyte Count; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Microbial Sensitivity Tests; Multivariate Analysis; Phenotype; Pyrimidinones; Ritonavir; Viral Load

To compare the antiviral efficacy of a salvage therapy combining lopinavir and amprenavir with 200 mg/d or 400 mg/d ritonavir, together with nucleoside reverse transcriptase inhibitors, over a 26-week period in HIV-infected patients in whom multiple antiretroviral regimens had failed.. Phase IIb, randomized, open-label, multicentre trial. Patients were eligible if they had <500 CD4+ cells/mm3 and >4 log10 copies/ml HIV-RNA after treatment with at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor.. At baseline (n=37), the median CD4+ cell count was 207/mm3 and the median plasma HIV-1 RNA level was 4.7 log10 copies/ml; the median number of PI mutations was seven and the median decrease in phenotypic susceptibility to lopinavir and amprenavir was 9.7 and 2.6, respectively. The mean number of antiretrovirals received prior to randomization was 7.7. The fall in the median HIV-1 RNA level at week 26 was -1.4 log10 copies/ml in the 200 mg/d ritonavir group and -2.5 log10 copies/ml in the 400 mg/d group (P=0.02). Viral load fell below 50 copies/ml in 32% and 61% of patients, respectively (P=0.07). After adjustment for the ritonavir dose, a smaller number of PI mutations was the only baseline characteristic associated with a better virological response at week 26. Amprenavir concentrations were significantly lower in presence of lopinavir. The lopinavir inhibitory quotient at week 6 correlated weakly with the change in the HIV-RNA level at week 26.. Combination of amprenavir, lopinavir and 400 mg/d ritonavir shows significant virological efficacy without increased toxicity in HIV-infected patients in whom multiple antiretroviral regimens have failed.

Topics: Adult; Aged; Carbamates; Drug Administration Schedule; Drug Therapy, Combination; Female; France; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Salvage Therapy; Sulfonamides; Viral Load

Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 85.1 microg/ml . h; maximum concentration of drug in serum (C(max)), 10.0 microg/ml; trough concentration of drug in serum (C(trough)), 7.3 microg/ml; and minimum concentration of drug in serum (C(min)), 5.5 microg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC(0-12), 22.9 microg/ml . h; C(max), 2.9 microg/ml; C(trough), 1.6 microg/ml; and C(min), 1.4 microg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.

Topics: Adult; Area Under Curve; Body Weight; Capsules; Drug Therapy, Combination; Excipients; Female; Gelatin; Hepatitis, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Saquinavir; Sex Characteristics; Treatment Failure; Viral Load

Topics: Adult; CD4 Lymphocyte Count; Cholesterol; Cohort Studies; Drug Therapy, Combination; Dyslipidemias; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Pyrimidinones; Retrospective Studies; Ritonavir; Treatment Outcome; Triglycerides; Viral Load

To study the control of viral replication in human immunodeficiency virus (HIV)-infected children on different salvage therapies.. A retrospective observational study in 120 HIV-infected children was conducted. The children were divided into 3 groups according to their salvage therapies: (1) children receiving first line highly active antiretroviral therapy (HAART); (2) protease inhibitor-experienced children receiving second line HAART; (3) protease inhibitor-experienced children receiving HAART including lopinavir-ritonavir (LPV/r). The outcome variables examined were time to achieve viral load (VL) < or =400 copies/mL, success in achieving VL < or =400 copies/mL and time to virologic failure (VL >400 copies/mL).. VL (HIV-RNA copies/mL) was quantified with reverse transcription-polymerase chain reaction molecular assay. For each protocol, survival analyses were conducted to determine the probability of achieving VL < or =400 copies/mL and rebound of VL.. VL < or =400 copies/mL was achieved by 52.4% of children receiving first line HAART, 48.3% receiving second line HAART and 71.5% receiving HAART including LPV/r. Children receiving HAART including LPV/r reached VL < or =400 copies/mL in a shorter time than children receiving second line HAART (P = 0.017), but quite similar to children receiving first line HAART. In terms of adjusted relative risk, children receiving HAART including LPV/r were 3.36 [95% confidence interval (95% CI), 1.59, 7.07] more likely to achieve VL < or =400 copies/mL than children receiving a different second line HAART. VL rebound occurred in 68.2% children receiving first line HAART, 73.4% receiving second line HAART and 32.4% receiving HAART including LPV/r. Children receiving HAART that includes LPV/r has less incidence of VL rebound (P=0.013) and 3.29 (95% CI 1.04, 10.3) times less risk to achieve a VL rebound than children receiving a different second line HAART.. HAART that includes LPV/r is able to control HIV replication more efficiently than other classic salvage antiretroviral therapies.

Topics: Amino Acid Sequence; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Drug Resistance, Viral; Drug Therapy, Combination; Genes, Viral; Genotype; HIV Infections; HIV-1; Humans; Lopinavir; Mutation; Pyrimidinones; Ritonavir; Salvage Therapy; Viral Load

Increased lopinavir (LPV) exposure obtained in vivo through combination with low-dose ritonavir may overcome a certain grade of resistance but not all. We sought to analyze LPV variability and possible risk factors. LPV trough plasma concentrations were determined by high-performance liquid chromatography after 1, 4, and 12 weeks from salvage regimens and tested in both univariate and multivariate regression analyses with age, gender, weight, risk factors for HIV acquisition, hepatitis C virus reactivity, hepatitis B surface antigen positivity, baseline aspartate transferase (AST) or alanine transferase (ALT) levels, creatinine, non-nucleoside reverse transcriptase inhibitors (NNRTIs) or tenofovir as concomitant drugs, and NNRTIs administered in the previous regimen. Fifty-six patients were included into the study. Among them, 8 of 56 (14.3%) at week 1, 12 of 56 (21.4%) at week 4, and 9 of 56 (16.1%) at week 12 had suboptimal LPV plasma concentrations, defined as trough concentration less than 4 microg/mL. No correlation was found between LPV trough concentrations and assessed variables. In conclusion, pharmacokinetic variability and low LPV concentrations have been found, supporting the use of therapeutic drug monitoring in those starting this drug.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Salvage Therapy; Substance Abuse, Intravenous

Our objective was to study the effect of lopinavir/ritonavir on cerebrospinal fluid (CSF) viral load as part of an antiretroviral combination treatment for HIV-1 infected individuals, and to determine the steady-state concentrations of lopinavir in CSF in relationship to plasma concentrations. Paired CSF and plasma samples from 12 antiretroviral-naïve HIV-1 infected patients starting combination therapy containing lopinavir/ritonavir were collected at baseline, and during treatment at a first follow-up at median 3.0 months (range 2.6-6.0 months), and at a second follow-up at median 12.1 months (range 6.0-16.5 months). Levels of HIV-1 RNA, CD4+ T-cell count, beta2-microglobulin, neopterin, and lopinavir concentration were analysed. In addition, CSF and plasma lopinavir concentrations in 4 patients already on combination therapy including lopinavir/ritonavir were analysed. Nine of 11 patients had undetectable viral load in CSF and 5/11 in plasma at the first follow-up. At the second follow-up 7/7 had undetectable viral load in CSF and 9/9 in plasma. Intrathecal immunoactivation, measured by neopterin and beta2-microglobulin, decreased significantly both in CSF and serum. The total CSF concentrations of lopinavir were of the same order of magnitude as the unbound concentrations in plasma. Lopinavir mean (+/-SD) concentrations were 42.1 (+/-31.5) nM in CSF and 52.7 (+/-25.2) nM unbound in plasma. We found that antiretroviral combination therapy including lopinavir/ritonavir substantially decreases the viral load, both in CSF and plasma, as well as the intrathecal immunoactivation, measured by beta2-microglobulin and neopterin. CSF concentrations of lopinavir were low, but probably sufficient to have a virological effect.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Neopterin; Pyrimidinones; Ritonavir; RNA, Viral; Viral Load

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; Aged; Aged, 80 and over; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Protease Inhibitors; Pyrimidinones; Ritonavir; Treatment Failure

Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected adult.. The objective of this study was to investigate a liquid coformulation of lopinavir/ritonavir, in combination with reverse transcriptase inhibitors, in HIV-infected children.. One hundred antiretroviral (ARV)-naive and ARV-experienced, nonnucleoside reverse transcriptase inhibitor-naive children between 6 months and 12 years of age participated in this Phase I/II, open label, multicenter trial. Subjects initially received either 230/57.5 mg/m(2) or 300/75 mg/m(2) lopinavir/ritonavir twice daily; ARV-naive subjects also received stavudine and lamivudine, whereas ARV-experienced subjects also received nevirapine and one or two nucleoside reverse transcriptase inhibitors. Lopinavir/ritonavir pharmacokinetics, safety and efficacy were evaluated.. All subjects were escalated to the 300/75 mg/m(2) twice daily dose based on results from an interim pharmacokinetic and safety evaluation. The pharmacokinetics of lopinavir did not appear to be dependent on age when dosing was based on body surface area but were decreased on coadministration with nevirapine. Overall 79% of subjects had HIV RNA levels <400 copies/ml at Week 48 (intent-to-treat: missing = failure). Mean increases in absolute and relative (percent) CD4 counts from baseline to Week 48 were observed in both ARV-naive subjects (404 cells/mm(3); 10.3%) and ARV-experienced subjects (284 cells/mm(3); 5.9%). Only one subject prematurely discontinued the study because of a study drug-related adverse event.. The liquid coformulation of lopinavir/ritonavir demonstrated durable antiviral activity and was safe and well-tolerated after 48 weeks of treatment in HIV-infected children.

Topics: Administration, Oral; Biological Availability; Chemistry, Pharmaceutical; Child; Child, Preschool; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Infant; Lopinavir; Male; Maximum Tolerated Dose; Multivariate Analysis; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Severity of Illness Index; Time Factors; Treatment Outcome; Viral Load

Topics: Adult; CD4 Lymphocyte Count; Cholesterol; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Triglycerides; 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

Two hundred and twelve HIV-positive patients who started a new protease inhibitor (PI)-based antiretroviral regimen between January 1998 and December 2000 in our tertiary care centre were prospectively followed-up during a 12-month study period, in order to assess the incidence of hyperlipidaemia and related clinical adverse events. At the end of 1-year follow-up, PI-containing antiretroviral treatment led to a statistically significant increase in serum triglyceride levels (P<0.005) and total and LDL-cholesterol levels (P<0.05). The overall incidence of hypertriglyceridaemia and hypercholesterolaemia was 38.2 and 25%, respectively. The incidence of increased serum triglyceride levels was significantly higher in patients treated with ritonavir (66.6%) or lopinavir/ritonavir (60.7%), compared with other PIs (P<0.04). Clinical adverse events possibly related to the hyperlipidaemia (such as cardiovascular diseases or acute pancreatitis) were not observed during the entire 12 months study period. In conformity with other previously published studies, the very high incidence of hyperlipidaemia during a PI-based therapy recognised in our work raises a big concern about its potential clinico-pathological consequences and the most convenient pharmacological management of these metabolic imbalances.

Topics: Adult; Antiretroviral Therapy, Highly Active; Cholesterol; Cholesterol, LDL; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Triglycerides

To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in lipid levels.. A prospective, nonrandomized study.. HIV-infected subjects with virologic failure on protease inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19 completed 24 weeks of treatment, and 16 completed the full 48-week study period. INTERVENTION Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. Subjects were evaluated at baseline and weeks 4, 8, 12, 24, 36, and 48. LPV trough plasma concentrations and lipid levels were measured.. LPV trough concentrations were higher in patients experiencing grade 3 or higher lipid elevations (mean [SD]: 9.71 microg/mL (5.62) vs. 6.09 microg/mL (3.83); P = 0.002) and in those developing grade 2 or higher hypercholesterolemia (mean [SD]: 8.48 microg/mL [4.64] vs. 5.71 microg/mL [3.94]; P = 0.003). All patients developing grade 2 or higher cholesterol elevation had an LPV trough concentration at week 4 greater than 8 microg/mL. Significant positive correlations were found between LPV trough concentrations and changes in triglyceride and cholesterol levels.. In patients receiving salvage therapy with LPV/r, there is an association between LPV plasma concentrations and lipid changes. Patients achieving higher LPV trough concentrations may be at greater risk of experiencing dyslipidemia. Further investigations are warranted to support a direct cause and effect relationship.

Topics: Adult; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipid Metabolism; Lipids; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Time Factors; Triglycerides

We evaluated the virological outcome of lopinavir/ritonavir (LPV/RTV) in 224 HIV-1-infected and protease inhibitor (PI)-experienced patients showing virological failure to a highly active antiretroviral therapy (HAART) regimen and followed up for at least 3 months. At baseline, the median level of plasma viraemia was 4.61 log10 copies/ml (range 3-6.48) and the median CD4 cell count was 219 cells/mm3 (range 1-836). During a median follow-up of 272 days (range 92-635), we observed an increase in the number of CD4 cells (P=0.02) and a dramatic decrease in plasma viraemia levels (P=0.0001), which became undetectable in 122 patients (54.5%). The closely related predictive factors were baseline plasma viraemia levels and the number of mutations known to reduce susceptibility to LPV/RTV. Thirty-one patients (13.8%) discontinued LPV/RTV during the follow-up, and one AIDS event and three deaths were recorded. Of the 134 patients (59.8%) who underwent a baseline genotype resistance test, 22 (16.4%) had > or = 6 mutations known to reduce LPV/RTV susceptibility; plasma viraemia became undetectable in 76 patients (56.7%), only five of whom harboured > or = 6 mutations at baseline (P=0.0001). The independent predictive factors related to virological success were plasma viraemia levels and the number of mutations reducing susceptibility to LPV/RTV at baseline; each additional log10 copies/ml of HIV RNA reduced the probability of virological success by 34.0% and each extra mutation by 14.5%.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Mutation; Proportional Hazards Models; Pyrimidinones; Ritonavir; Salvage Therapy; Viremia

To examine the relationship between levels of the T-cell regulatory cytokine interleukin-7 (IL-7) and CD4 cell counts during immune reconstitution and to assess its prognostic value in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy.. Thirty-six HIV-1-infected adults who completed 48 weeks of follow-up visits were included in this prospective study. Patients having failed two or more antiretroviral therapy regimens were treated with lopinavir/ritonavir-based therapy. An enzyme-linked immunosorbent assay was used to determine IL-7 plasma levels, flow cytometry was used to analyse cell surface antigens, and polymerase chain reaction was used to quantify plasma HIV-1.. Pretreatment IL-7 levels were elevated in all patients (mean 11.0 pg/mL) and were negatively correlated with CD4 cell counts and age (r=-0.59, P<0.001 and r=-0.57, P<0.001, respectively). During the course of treatment, IL-7 levels decreased by 34% while CD4 cell numbers progressively increased by 88%. Multivariate regression analysis showed that only pretreatment IL-7 levels predicted viral load at 48 weeks when controlling for baseline CD4 cell counts, viral load and patient demographics.. These findings are consistent with regulation of T-cell recovery by IL-7, and suggest that IL-7 measurements might be used to predict virological response.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Interleukin-7; Lopinavir; Lymphocyte Count; Male; Prospective Studies; Pyrimidinones; Ritonavir; T-Lymphocytes; Viral Load

Two industry-sponsored prospective studies provide some clarification regarding the optimal use of the new PI atazanavir in PI-experienced patients.

Topics: Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Viral Load

The response to regimens including lopinavir-ritonavir (LPV/r) in patients who have received multiple protease (PR) inhibitors (PI) can be analyzed in terms of human immunodeficiency virus type 1 (HIV-1) genotypic and pharmacokinetic (pK) determinants. We studied these factors and the evolution of HIV-1 resistance in response to LPV/r in a prospective study of patients receiving LPV/r under a temporary authorization in Bordeaux, France. HIV-1 PR and reverse transcriptase sequences were determined at baseline LPV/r for all the patients and at month 3 (M3) and M6 in the absence of response to treatment. pK measurements were determined at M1 and M3. Virological failure (VF) was defined as a plasma viral load >or=400 copies/ml at M3. A multivariate analysis of the predictors of VF, including clinical and biological characteristics and the treatment history of the patients, was performed. The PR gene sequence at M0, including individual mutations or a previously defined LPV mutation score (D. J. Kempf, J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode, J. Virol. 75:7262-7269, 2001), and the individual exposure to LPV were also included covariates. Sixty-eight patients were enrolled. Thirty-four percent had a virological response at M3. An LPV mutation score of >5 mutations, the presence of the PR I54V mutation at baseline, a high number of previous PIs, prior therapy with ritonavir or indinavir, absence of coprescription of efavirenz, and a lower exposure to LPV or lower LPV trough concentrations were independently associated with VF on LPV/r. Additional PI resistance mutations, including primary mutation I50V, could be selected in patients failing on LPV/r. Genotypic and pK parameters should be used to optimize the virological response to LPV/r in PI-experienced patients and to avoid further viral evolution.

Topics: Adult; Amino Acid Substitution; Anti-HIV Agents; Drug Combinations; Female; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Models, Biological; Pyrimidinones; Ritonavir; RNA, Viral; Salvage Therapy

The virological response of multiple protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was examined with respect to baseline viral phenotype and genotype through 72 weeks of therapy with lopinavir/ritonavir plus efavirenz and nucleoside reverse transcriptase inhibitors (Study M98-957). Using a 'dropouts as censored' analysis, plasma HIV RNA < or = 400 copies/ml was observed in 93% (25/27), 73% (11/15) and 25% (2/8) of subjects with <10-fold, 10- to 40-fold, and >40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virological response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) of subjects with baseline lopinavir mutation score of 0-5, 6-7 and > or = 8, respectively. Through 72 weeks, all subjects experiencing virological failure whose baseline isolates contained six or more protease inhibitor mutations had a common genotypic pattern, with mutations at positions 82, 54 and 10, along with a median of four additional mutations in protease. However, an equal number of subjects with a similar genotypic pattern experienced virological response. Further analysis revealed the baseline phenotypic susceptibility to lopinavir to be an additional covariate predicting response in this subset of subjects. In multivariate analyses, baseline susceptibility to lopinavir was associated with response at each time point examined (weeks 24, 48 and 72). These results provide guidance for clinically relevant interpretation of phenotypic and genotypic resistance tests when applied to lopinavir/ritonavir.

Topics: Drug Resistance, Viral; Drug Therapy, Combination; Genes, Viral; Genotype; HIV; HIV Infections; HIV Protease; HIV Protease Inhibitors; Humans; Inhibitory Concentration 50; Logistic Models; Lopinavir; Mutation; Phenotype; Pyrimidinones; Ritonavir; RNA, Viral; Time Factors; Viral Load

The safety and antiviral activity of lopinavir (Lpv), a protease inhibitor (PI) coformulated with ritonavir (Rtv) to enhance its pharmacokinetic properties, were evaluated in 70 patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 1000-100,000 copies/mL on a first PI-containing regimen. Patients were randomized to substitute only the PI with Lpv/Rtv, 400/100 mg or 400/200 mg twice daily. On day 15, nevirapine (200 mg 2x/day) was added, and nucleoside reverse-transcriptase inhibitors were changed. Despite a >4-fold reduction in phenotypic susceptibility to the preentry PI in 63% of patients, mean plasma HIV-1 RNA levels declined by 1.14 log(10) copies/mL after 2 weeks of Lpv/Rtv. At week 48, 86% of subjects receiving treatment had plasma HIV-1 RNA levels of <400 copies/mL; 76% had levels <50 HIV-1 RNA copies/mL (intent-to-treat: 70% and 60%, respectively). Mean CD4 cell counts increased by 125 cells/muL. Three patients discontinued therapy for drug-related adverse events.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nevirapine; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Outcome

A study was designed to determine the interactions, both clinical and pharmacokinetic, between methadone and lopinavir-ritonavir. Results demonstrated a 36% reduction in the methadone area under the plasma concentration-time curve after the introduction of lopinavir-ritonavir, with no coincident symptoms of opioid withdrawal and no requirement for methadone dose adjustment.

Topics: Adult; Analgesics, Opioid; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Methadone; Opioid-Related Disorders; Pyrimidinones; Ritonavir; RNA, Viral; Substance Withdrawal Syndrome

Lopinavir is a newly developed inhibitor of human immunodeficiency virus (HIV) protease that, when formulated with ritonavir, yields mean trough plasma lopinavir concentrations that are at least 75 times as high as that needed to inhibit replication of wild-type HIV by 50 percent.. We conducted a double-blind trial in which 653 HIV-infected adults who had not received antiretroviral therapy for more than 14 days were randomly assigned to receive either lopinavir-ritonavir (400 mg of lopinavir plus 100 mg of ritonavir twice daily) with nelfinavir placebo or nelfinavir (750 mg three times daily) with lopinavir-ritonavir placebo. All patients also received open-label stavudine and lamivudine. The primary efficacy end points were the presence of fewer than 400 HIV RNA copies per milliliter of plasma at week 24 and the time to the loss of virologic response through week 48.. At week 48, greater proportions of patients treated with lopinavir-ritonavir than of patients treated with nelfinavir had fewer than 400 copies of HIV RNA per milliliter (75 percent vs. 63 percent, P<0.001) and fewer than 50 copies per milliliter (67 percent vs. 52 percent, P<0.001). The time to the loss of virologic response was greater in the lopinavir-ritonavir group than in the nelfinavir group (hazard ratio, 2.0; 95 percent confidence interval, 1.5 to 2.7; P<0.001). The estimated proportion of patients with a persistent virologic response through week 48 was 84 percent for patients receiving lopinavir-ritonavir and 66 percent for those receiving nelfinavir. Both regimens were well tolerated, with the rate of discontinuation related to the study drugs at 3.4 percent among patients receiving lopinavir-ritonavir and 3.7 percent among patients receiving nelfinavir. Among patients with more than 400 copies of HIV RNA per milliliter at some point from week 24 through week 48, resistance mutations in HIV protease were demonstrated in viral isolates from 25 of 76 nelfinavir-treated patients (33 percent) and none of 37 patients treated with lopinavir-ritonavir (P<0.001).. For the initial treatment of HIV-infected adults, a combination regimen that includes lopinavir-ritonavir is well tolerated and has antiviral activity superior to that of a nelfinavir-containing regimen.

Topics: Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Double-Blind Method; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Nelfinavir; Proportional Hazards Models; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Survival Analysis; Viral Load

To evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals.. Prospective, randomized, double-blind, multicenter.. Eligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68).. Mean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 x 10(6)/l and 310 x 10(6)/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50-100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound.. ABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Stavudine; Viral Load

Preliminary results are presented from a dose-comparison trial of the regimen stavudine/lamivudine plus the novel protease inhibitor, ABT-378/ritonavir, given to 101 antiretroviral-naive, human immunodeficiency virus (HIV)-infected subjects for > or = 24 weeks. The HIV-1 RNA had decreased to <400 copies/ml in 94% of patients and CD4 cell count had increased by approximately 160 cells/mm3 at 24 weeks. The regimen was well tolerated and merits further study.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Stavudine; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; Drug Therapy, Combination; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir

The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).

Topics: Antigens, Viral; Cell Proliferation; Cells, Cultured; Dasatinib; Drug Delivery Systems; HIV Infections; HIV-1; Homeostasis; Humans; Imidazoles; Leukocytes, Mononuclear; Protein Kinase Inhibitors; Pyridazines; Pyridones; Pyrimidinones

The RNA genome of the human immunodeficiency virus (HIV) is reverse-transcribed into DNA and integrated into the host genome, resulting in latent infections that are difficult to clear. Here we show an approach to eradicate HIV infections by selective elimination of host cells harboring replication-competent HIV (SECH), which includes viral reactivation, induction of cell death, inhibition of autophagy and the blocking of new infections. Viral reactivation triggers cell death specifically in HIV-1-infected T cells, which is promoted by agents that induce apoptosis and inhibit autophagy. SECH treatments can clear HIV-1 in >50% mice reconstituted with a human immune system, as demonstrated by the lack of viral rebound after withdrawal of treatments, and by adoptive transfer of treated lymphocytes into uninfected humanized mice. Moreover, SECH clears HIV-1 in blood samples from HIV-1-infected patients. Our results suggest a strategy to eradicate HIV infections by selectively eliminating host cells capable of producing HIV.

Topics: Animals; Antigens, CD34; Apoptosis; Autophagy; Azepines; CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Mice; Organophosphates; Piperazines; Pyridines; Pyrimidinones; RNA, Viral; T-Lymphocytes; Triazoles

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not targeted by current drugs. Although a few chemotypes have been reported to inhibit HIV RNase H in biochemical assays, their general lack of significant antiviral activity in cell culture necessitates continued efforts in identifying highly potent RNase H inhibitors to confer antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-arylthio subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays these new analogues inhibited RT RNase H in single-digit nanomolar range without inhibiting RT polymerase (pol) at concentrations up to 10 μM, amounting to exceptional biochemical inhibitory selectivity. Many analogues also inhibited integrase strand transfer (INST) activity in low to sub micromolar range. More importantly, most analogues inhibited HIV in low micromolar range without cytotoxicity. In the end, compound 13j (RNase H IC

Topics: Anti-HIV Agents; Cell Line; Drug Design; HIV Infections; HIV-1; Humans; Models, Molecular; Pyrimidinones; Reverse Transcriptase Inhibitors; Ribonuclease H, Human Immunodeficiency Virus; Structure-Activity Relationship

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM.

Topics: Anti-HIV Agents; Catalytic Domain; Cell Line; Drug Design; HIV Infections; HIV-1; Humans; Methylation; Models, Molecular; Pyrimidinones; Reverse Transcriptase Inhibitors; Ribonuclease H, Human Immunodeficiency Virus; Structure-Activity Relationship

A novel series of substituted N-(2-(2,3-dioxoindolin-1-yl)acetyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide was designed, synthesized and evaluated for in vitro Reverse Transcriptase (RT) inhibitory activity. This series is a combination of peculiar structural features from leading scaffolds of [(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and oxyindole. In vitro screening led to identification of two hybrids (9c and 9d) possessing higher RT inhibitory activity than the standard rilpivirine. Docking study was performed to study the binding orientations of synthesized hybrids towards RT enzyme.

Topics: Anti-HIV Agents; Drug Design; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Isatin; Molecular Docking Simulation; Pyrimidinones; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

3-Hydroxypyrimidine-2,4-dione (HPD) represents a versatile chemical core in the design of inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H and integrase strand transfer (INST). We report herein the design, synthesis and biological evaluation of an HPD subtype (4) featuring a cyclohexylmethyl group at the C-6 position. Antiviral testing showed that most analogues of 4 inhibited HIV-1 in the low nanomolar to submicromolar range, without cytotoxicity at concentrations up to 100 μM. Biochemically, these analogues dually inhibited both the polymerase (pol) and the RNase H functions of RT, but not INST. Co-crystal structure of 4a with RT revealed a nonnucleoside RT inhibitor (NNRTI) binding mode. Interestingly, chemotype 11, the synthetic precursor of 4 lacking the 3-OH group, did not inhibit RNase H while potently inhibiting pol. By virtue of the potent antiviral activity and biochemical RNase H inhibition, HPD subtype 4 could provide a viable platform for eventually achieving potent and selective RNase H inhibition through further medicinal chemistry.

Topics: Anti-HIV Agents; Binding Sites; Crystallization; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Models, Molecular; Molecular Docking Simulation; Polymerase Chain Reaction; Pyrimidinones; Reverse Transcriptase Inhibitors; Ribonuclease H, Human Immunodeficiency Virus; Structure-Activity Relationship; Uracil

For human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n = 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) μg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) μg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than the in vitro 90% inhibitory concentration (IC90) of 0.146 μg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC90, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women.

Topics: Administration, Intravaginal; Animals; Anti-HIV Agents; Female; HIV Infections; HIV-1; Lactic Acid; Macaca nemestrina; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrimidinones; Vagina

JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype (GT) 1b replicon-containing cell line 9 is devoid of any anti-HCV activity, an observation attributable to inefficient prodrug metabolism which was found to be CYP3A4-dependent. In contrast, in vitro incubation of 9 in primary human hepatocytes as well as pharmacokinetic evaluation thereof in different preclinical species reveals the formation of substantial levels of 2'-deoxy-2'-spirooxetane uridine triphosphate (8), a potent inhibitor of the HCV NS5B polymerase. Overall, it was found that 9 displays a superior profile compared to its phosphoramidate prodrug analogues (e.g., 4) described previously. Of particular interest is the in vivo dose dependent reduction of HCV RNA observed in HCV infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days of oral administration of 9.

Topics: Administration, Oral; Animals; Antiviral Agents; Dose-Response Relationship, Drug; Drug Discovery; Hepacivirus; Hepatocytes; HIV Infections; Humans; Mice; Microbial Sensitivity Tests; Prodrugs; Pyrimidinones; Spiro Compounds; Structure-Activity Relationship; Viral Nonstructural Proteins; Virus Replication

Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.

Topics: Cell Line; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Models, Molecular; Oxazines; Piperazines; Pyridones; Pyrimidinones; Raltegravir Potassium; Ribonuclease H

A series of novel β-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of DKA and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase and anti-HIV-1 activity. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, but dihydroxylated aromatic derivatives appear little inhibition to HIV-1 integrase. In addition, the preliminary structure-activity relationship (SAR) of these new derivatives was rationalized by docking studies.

Topics: Cell Line; Drug Design; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Molecular Docking Simulation; Pyrimidinones; Structure-Activity Relationship

To evaluate the pharmacokinetic profiles of lopinavir (LPV) in Chinese HIV-infected patients.. A total of 16 patients were enrolled in the LPV pharmacokinetic study. Blood samples were collected before LPV intake and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0 h after administration. Serum level of LPV was determined by the developed high performance liquid chromatography (HPLC) method. The pharmacokinetic profiles were assessed by WinNonlin software.. The non-compartment model pharmacokinetic (PK) parameters were as follows: the peak time of LPV (T(max)) (3.88 ± 0.23)h, maximum plasma concentration (C(max)) (10.36 ± 3.42) mg/L, minimum plasma concentration (C(min)) (2.18 ± 0.34) mg/L, the 24 h area under plasma-concentration-time curve (AUC0-24) (116.22 ± 15.68) mg · h · L⁻¹, half life (T1/2) (4.5 ± 0.13) h, and clearance rate (CL/F) (3.44 ± 1.34) L/h respectively.. The pharmacokinetic profiles of LPV in Chinese HIV-1 infected patients demonstrate lower C(min) than those of reported studies, while other parameters are similar. Patients should be educated for compliance based on the narrow gap between C(min) and minimum effect concentration.

Topics: China; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir

The DuoGel™ was developed for safe and effective dual chamber administration of antiretroviral drugs to reduce the high incidence of HIV transmission during receptive vaginal and anal intercourse. The DuoGel™s containing IQP-0528, a non-nucleoside reverse transcriptase inhibitor (NNRTI), were formulated from GRAS excipients approved for vaginal and rectal administration. The DuoGel™s were evaluated based upon quantitative physicochemical and biological evaluations defined by a Target Product Profile (TPP) acceptable for vaginal and rectal application. From the two primary TPP characteristics defined to accommodate safe rectal administration three DuoGel™ formulations (IQB3000, IQB3001, and IQB3002) were developed at pH 6.00 and osmolality ⩽400mmol/kg. The DuoGel™s displayed no in vitro cellular or bacterial toxicity and no loss in viability in ectocervical and colorectal tissue. IQB3000 was removed from consideration due to reduced NNRTI delivery (∼65% reduction) and IQB3001 was removed due to increase spread resulting in leakage. IQB3002 containing IQP-0528 was defined as our lead DuoGel™ formulation, possessing potent activity against HIV-1 (EC50=10nM). Over 12month stability evaluations, IQB3002 maintained formulation stability. This study has identified a lead DuoGel™ formulation that will safely deliver IQP-0528 to prevent sexual HIV-1 transmission in the vagina and rectum.

Topics: Administration, Intravaginal; Administration, Rectal; Anti-Infective Agents; Chemistry, Pharmaceutical; Chemoprevention; Drug Stability; Excipients; Female; Gels; HIV Infections; HIV-1; Humans; Pyrimidinones

Nucleocapsid 7 (NCp7) inhibitors have been investigated extensively for their role in impeding the function of HIV-1 replication machinery and their ability to directly inactivate the virus. A class of NCp7 zinc finger inhibitors, S-acyl-2-mercaptobenzamide thioesters (SAMTs), was investigated for topical drug delivery. SAMTs are inherently unstable because of their hydrolytically labile thioester bond, thus requiring formulation approaches that can lend stability. We describe the delivery of N-[2-(3,4,5-trimethoxybenzoylthio)benzoyl]-β-alaninamide (SAMT-10), as a single agent antiretroviral (ARV) therapeutic and in combination with the HIV-1 reverse-transcriptase inhibitor pyrimidinedione IQP-0528, from a hydrophobic polyether urethane (PEU) intravaginal ring (IVR) for a month. The physicochemical stability of the ARV-loaded IVRs was confirmed after 3 months at 40°C/75% relative humidity. In vitro, 25 ± 3 mg/IVR of SAMT-10 and 86 ± 13 mg/IVR of IQP-0528 were released. No degradation of the hydrolytically labile SAMT-10 was observed within the matrix. The combination of ARVs had synergistic antiviral activity when tested in in vitro cell-based assays. Toxicological evaluations performed on an organotypic EpiVaginal(™) tissue model demonstrated a lack of formulation toxicity. Overall, SAMT-10 and IQP-0528 were formulated in a stable PEU IVR for sustained release. Our findings support the need for further preclinical evaluation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3426-3439, 2015.

Topics: Administration, Intravaginal; Anti-HIV Agents; Benzamides; Chemistry, Pharmaceutical; Delayed-Action Preparations; Differential Thermal Analysis; Drug Delivery Systems; Female; HIV Infections; HIV-1; Humans; Organ Culture Techniques; Pyrimidinones; Reverse Transcriptase Inhibitors; Solubility

We evaluated the in vivo pharmacokinetics and used a complementary ex vivo coculture assay to determine the pharmacodynamics of IQB3002 gel containing 1% IQP-0528, a nonnucleoside reverse transcriptase inhibitor (NNRTI), in rhesus macaques (RM). The gel (1.5 ml) was applied vaginally to 6 simian-human immunodeficiency (SHIV)-positive female RM. Blood, vaginal fluids, and rectal fluids were collected at 0, 1, 2, and 4 h. RM were euthanized at 4 h, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-human immunodeficiency virus (HIV) activity was evaluated ex vivo by coculturing fresh or frozen vaginal tissues with activated human peripheral blood mononuclear cells (PBMCs) and measuring the p24 levels for 10 days after an HIV-1Ba-L challenge. The median levels of IQP-0528, determined using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods, were between 10(4) and 10(5) ng/g in vaginal and cervical tissue, between 10(3) and 10(4) ng/g in rectal tissues, and between 10(5) and 10(7) ng/ml in vaginal fluids over the 4-h period. The vaginal tissues protected the cocultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81 to 100% in fresh and frozen tissues that were proximal, medial, and distal relative to the cervix. No viral inhibition was detected in untreated baseline tissues. Collectively, the median drug levels observed were 5 to 7 logs higher than the in vitro 50% effective concentration (EC50) range (0.21 ng/ml to 1.29 ng/ml), suggesting that 1.5 ml of the gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, antiviral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo coculture model for future NNRTI efficacy studies.

Topics: Administration, Intravaginal; Animals; Coculture Techniques; Cryopreservation; Female; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Macaca mulatta; Piperidines; Pyrimidinones; Reverse Transcriptase Inhibitors; Simian Acquired Immunodeficiency Syndrome

A series of new 5-allyl-6-benzylpyrimidin-4(3H)-ones bearing different substituents at the C-2 position of the pyrimidine core have been synthesized and evaluated for their in vitro activities against human immunodeficiency virus type 1 (HIV-1) in the human T-lymphotropic type (MT-4 cell cultures). The majority of the title compounds showed moderate to good activities against HIV-1. Amongst them, 5-allyl-6-benzyl-2-(3-hydroxypropylthio)pyrimidin-4(3H)-one analogue 11c exhibited the most potent anti-HIV-1 activity (IC50 0.32 µM). The biological testing results clearly indicated that the substitution at C-2 position of the pyrimidine ring could increase the anti-HIV-1 reverse transcriptase (RT) activity.

Topics: Cell Line; Drug Design; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Models, Molecular; Pyrimidinones; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

Vaginal pre-exposure prophylaxis has focused heavily on gel formulations. Low adherence linked with frequent dosing and short therapeutic duration has emerged as the major reason for inconsistent efficacy outcomes with gels in clinical trials. Osmotic pumps can achieve versatile drug release profiles however, have not been explored for vaginal delivery. In this report, we describe an osmotic pump tablet (OPT) that can deliver antiretrovirals for several days. We also describe configuring the OPT for pH sensitive delivery where the drug delivery system consistently delivers an antiretroviral at vaginal pH and then gives a burst release triggered by a coitally associated pH increase. We have investigated the vaginal OPT for multiple day delivery of a potent antiretroviral, IQP-0528 in a sheep model. To effectively register spatial drug distribution we also engineered a tool to precisely collect multiple vaginal fluid samples. In a 10-day duration post single application, high micromolar mucosal levels were obtained with peak concentration more than 6 logs higher than the EC50 of IQP-0528. Overall, our results show successful implementation of the osmotic pump technology for vaginal antiretroviral delivery.

Topics: Animals; Anti-HIV Agents; Chemistry, Pharmaceutical; Drug Delivery Systems; Female; HIV Infections; Humans; Hydrogen-Ion Concentration; Infusion Pumps, Implantable; Mucous Membrane; Osmosis; Pyrimidinones; Sheep; Tablets; Vagina

The potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD1(0.5 wt%)], PYD1(1 wt%), PYD2(4 wt%), and PYD2(14 wt%)) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD2(14 wt%) IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 μg/ml to vaginal fluid and 1 μg/g to vaginal tissue, a level over 1,000 times the in vitro 50% effective concentration. The in vitro release of PYD1 and PYD2 under nonsink conditions correlated well with in vivo release, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating release in vitro than typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained after in vitro release. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation.

Topics: Administration, Intravaginal; Animals; Anti-HIV Agents; Cell Line; Contraceptive Devices, Female; Cytokines; Drug Stability; Female; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Macaca nemestrina; Polyurethanes; Pyrimidinones; T-Lymphocytes; Tissue Distribution; Vagina; Virus Replication

3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) were selected and derivatized through a HIV-1 replication assay based on GFP reporter cells. Compounds 14, 25, 31, and 36 exhibited significant inhibition of HIV-1 replication with a good safety profile. Chiral separation of each enantiomer by fractional crystallization showed that only the S enantiomer retained anti-HIV activity. Compound (S)-40, a novel and potent DHPM analog, could serve as an advanced lead for further development and the determination of the mechanism of action.

Topics: Anti-HIV Agents; Drug Design; HIV Infections; HIV-1; Humans; Pyrimidinones; Stereoisomerism; Structure-Activity Relationship; Virus Replication

A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC(50) values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors.

Topics: Anti-HIV Agents; Benzoates; Cell Proliferation; Cells, Cultured; Drug Design; HIV Infections; HIV-1; Humans; Molecular Structure; Oxadiazoles; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Virus Replication

Polymeric quick-dissolving films were developed as a solid dosage topical microbicide formulation for the vaginal delivery of the highly potent and non-toxic, dual-acting HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) pyrimidinedione, IQP-0528.. Formulated from approved excipients, a polyvinyl alcohol (PVA) based film was manufactured via solvent casting methods. The film formulations were evaluated based upon quantitative physicochemical evaluations defined by a Target Product Profile (TPP) RESULTS: Films dosed with 0.1% (w/w) of IQP-0528 disintegrated within 10 min with over 50% of drug released and near 100% total drug released after 30 min. The IQP-0528 films were found to be non-toxic in in vitro CEM-SS and PBMC cell-based assays and biologically active with sub-nanomolar efficacy against HIV-1 infection. In a 12 month stability protocol, the IQP-0528 films demonstrated no significant degradation at International Conference on Harmonization (ICH) recommended standard (25°C/65% relative humidity (R.H.)) and accelerated (40°C/75% R.H.) environmental conditions.. Based on the above evaluations, a vaginal film formulation has been identified as a potential solid dosage form for the vaginal delivery of the topical microbicide candidate IQP-0528.

Topics: Administration, Intravaginal; Anti-HIV Agents; Cell Line; Cell Survival; Drug Delivery Systems; Female; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Pyrimidinones; Vagina

Tenofovir (TFV) is a nucleotide reverse transcriptase inhibitor and IQP-0528 is a non-nucleoside reverse transcriptase inhibitor that also blocks virus entry. TFV and IQP-0528 alone have shown antiviral activity as microbicide gels. Because combination therapy will likely be more potent than mono-therapy, these drugs have been chosen to make a combination microbicide gel containing 2.5% TFV/1% IQP-0528. Safety and efficacy testing was done to evaluate five prototype combination gels. The gels retained TZM-bl cell and ectocervical and colorectal tissue viability. Further, the epithelium of the ectocervical and colorectal tissue remained intact after a 24h exposure. The ED(50) calculated from the formulations for IQP-0528 was ~32nM and for TFV was ~59nM and their inhibitory activity was not affected by semen. The ED(50) of TFV in the combination gels was ~100-fold lower than when calculated for the drug substance alone reflecting the activity of the more potent IQP-0528. When ectocervical and colorectal tissue were treated with the combination gels, HIV-1 p24 release was reduced by ≥1log(10) and ≥2log(10), respectively. Immunohistochemistry for the ectocervical tissues treated with combination gels showed no HIV-1 infected cells at study end. With the increased realization of receptive anal intercourse among heterosexual couples often in conjunction with vaginal intercourse, having a safe and effective microbicide for both mucosal sites is critical. The safety and efficacy profiles of the gels were similar for ectocervical and colorectal tissues suggesting these gels have the potential for dual compartment use.

Topics: Adenine; Administration, Mucosal; Anti-Infective Agents; Cell Line; Cell Survival; Chemoprevention; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Organophosphonates; Pyrimidinones; Tenofovir; Tissue Culture Techniques; Vaginal Creams, Foams, and Jellies

The durability of combination antiretroviral therapy (cART) regimens can be measured as time to discontinuation because of toxicity or treatment failure, development of clinical disease or serious long-term adverse events. The aim of this analysis was to compare the durability of nevirapine, efavirenz and lopinavir regimens based on these measures.. Patients starting a nevirapine, efavirenz or lopinavir-based cART regimen for the first time after 1 January 2000 were included in the analysis. Follow-up started ≥ 3 months after initiation of treatment if viral load was <500 HIV-1 RNA copies/mL. Durability was measured as discontinuation rate or development/worsening of clinical markers.. A total of 603 patients (21%) started nevirapine-based cART, 1465 (51%) efavirenz, and 818 (28%) lopinavir. After adjustment there was no significant difference in the risk of discontinuation for any reason between the groups on nevirapine and efavirenz (P=0.43) or lopinavir (P=0.13). Compared with the nevirapine group, those on efavirenz had a 48% (P=0.0002) and those on lopinavir a 63% (P<0.0001) lower risk of discontinuation because of treatment failure and a 31% (P=0.01) and 66% (P<.0001) higher risk, respectively, of discontinuation because of toxicities or patient/physician choice. There were no significant differences in the incidence of non-AIDS-related events, worsening anaemia, severe weight loss, increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels or increased total cholesterol. Compared with patients on nevirapine, those on lopinavir had an 80% higher incidence of high-density lipoprotein (HDL) cholesterol decreasing below 0.9 mmol/L (P=0.003), but there was no significant difference in this variable between those on nevirapine and those on efavirenz (P=0.39).. The long-term durability of nevirapine-based cART, based on risk of all-cause discontinuation and development of long-term adverse events, was comparable to that of efavirenz or lopinavir, in patients in routine clinical practice across Europe who initially tolerated and virologically responded to their regimen.

Topics: Alkynes; Argentina; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Europe; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Israel; Lopinavir; Male; Nevirapine; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Treatment Outcome; 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

We characterized lipid and lipoprotein changes associated with a lopinavir/ritonavir-containing regimen. We enrolled previously antiretroviral-naive patients participating in the Swiss HIV Cohort Study. Fasting blood samples (baseline) were retrieved retrospectively from stored frozen plasma and posttreatment (follow-up) samples were collected prospectively at two separate visits. Lipids and lipoproteins were analyzed at a single reference laboratory. Sixty-five patients had two posttreatment lipid profile measurements and nine had only one. Most of the measured lipids and lipoprotein plasma concentrations increased on lopinavir/ritonavir-based treatment. The percentage of patients with hypertriglyceridemia (TG >150 mg/dl) increased from 28/74 (38%) at baseline to 37/65 (57%) at the second follow-up. We did not find any correlation between lopinavir plasma levels and the concentration of triglycerides. There was weak evidence of an increase in small dense LDL-apoB during the first year of treatment but not beyond 1 year (odds ratio 4.5, 90% CI 0.7 to 29 and 0.9, 90% CI 0.5 to 1.5, respectively). However, 69% of our patients still had undetectable small dense LDL-apoB levels while on treatment. LDL-cholesterol increased by a mean of 17 mg/dl (90% CI -3 to 37) during the first year of treatment, but mean values remained below the cut-off for therapeutic intervention. Despite an increase in the majority of measured lipids and lipoproteins particularly in the first year after initiation, we could not detect an obvious increase of cardiovascular risk resulting from the observed lipid changes.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; Female; HIV Infections; Humans; Lipids; Lipoproteins; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Risk Assessment; Ritonavir

Chronic hepatitis C is an emerging issue in the management of human immunodeficiency virus (HIV) disease because both diseases have the same route of transmission, leading to a very high prevalence of hepatitis C virus (HCV)-coinfection in the HIV-positive patient population. Lopinavir is extensively metabolized by the hepatic cytochrome P450 3A4, and the pharmacokinetics of this protease inhibitor (PI) could be influenced by liver impairment. However, data currently available on the impact of HCV-coinfection on lopinavir plasma concentrations are both limited and conflicting.. This was an observational, open-label study in which adult HIV-infected outpatients on stable antiretroviral treatment that included two nucleoside reverse transcriptase inhibitors (NRTIs) plus lopinavir/ritonavir for at least 4 weeks were asked to participate. The trough plasma concentration (C (trough)) of lopinavir and ritonavir was assessed at steady state by a validated high-performance liquid chromatography-tandem mass spectrometry method.. A total of 65 HIV-positive patients were enrolled in the study. These patients were stratified into two groups based on the absence/presence of HCV-coinfection: 45 were monoinfected (HIV+/HCV-) and 20 were coinfected (HIV+/HCV+). The lopinavir C (trough) in plasma was comparable between HIV+/HCV+ and HIV+/HCV- patients, without any statistically significant difference (geometric mean ratio 0.89, 95% confidence interval 0.61-1.42; p = 0.581). The mean ritonavir C (trough) was also comparable in the two groups. Almost all samples were found to be within the therapeutic plasma level range (97% in HIV+/HCV- group and 100% in HIV+/HCV+ group). No correlation was found between lopinavir plasma levels and adverse events (such as diarrhoea and hypertriglyceridaemia) or immune-virological parameters of HIV disease.. Among the HIV-positive patients participating in this study, the pharmacokinetics of lopinavir/ritonavir did not significantly change in those HIV-positive patients coinfected with HCV and in the absence of liver cirrhosis.

Topics: Adult; Female; Hepacivirus; Hepatitis C, Chronic; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Liver Cirrhosis; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Viral Load

Monoboosted protease inhibitor is being evaluated as a strategy to simplify therapy in virologically suppressed patients who are on complex regimens.. Children with two consecutive HIV-RNA below 50 copies/ml at least 3 months apart while on double boosted protease inhibitor (dPI) were switched to monoboosted lopinavir/r (mLPV/r). The previous dPI regimen was resumed within 4 weeks in children who experienced virological failure defined as two HIV-RNA at least 500 or three HIV-RNA at least 50 copies/ml. Primary endpoint was the proportion of children still on mLPV/r and having HIV-RNA less than 50 copies/ml at week 48.. Forty children on LPV/r + saquinavir (90%) or LPV/r + indinavir (10%) were enrolled, 50% were female, median [interquartile range (IQR)] age was 11.7 (10.2-13.5) years, and body weight was 29.4 (24.1-40.2 kg). The median (IQR) CD4% was 27 (23.5-29.5%). At 48 weeks, none had died or had HIV disease progression. Thirty-one children were on mLPV/r and 29 (72.5%) had HIV-RNA less than 50 copies/ml. Nine resumed dPI due to mLPV/r failure with four achieving undetectable HIV-RNA. Overall, 31 children (82.5%) had HIV-RNA suppression. Predicting factor for failing mLPV/r was baseline HIV-RNA at least 50 copies/ml. No major protease mutations were found.. By simplifying second-line treatment from dPI to mLPV/r, the majority of children had sustained viral suppression at 48 weeks. Randomized study of simplified mono protease inhibitor therapy in children is warranted.

Topics: Adolescent; Antiretroviral Therapy, Highly Active; Child; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; Thailand

Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005.. From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM.. The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM.. The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Guideline Adherence; HIV Infections; Humans; Lopinavir; Netherlands; Nevirapine; Pregnancy; Pyrimidinones; Randomized Controlled Trials as Topic

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

The aim of this study was to estimate the cost-effectiveness of atazanavir/ritonavir (atazanavir/r) versus lopinavir/ritonavir (lopinavir/r) in treatment-naïve human immunodeficiency virus-1 (HIV-1) patients in Sweden for whom efavirenz is not suitable.. A Markov model was developed to predict the lifetime outcomes of atazanavir/r and lopinavir/r in terms of quality-adjusted life years (QALYs) and total costs. The model was structured to focus on treatment lines--how patients progress from first- to second-, and then to third-line treatment. Model inputs were derived directly from clinical trials, such as the CASTLE study (a 96-week head-to-head trial in first-line therapy), and from the Framingham risk-equation. The analysis was conducted from a payer perspective and included extensive scenario and probabilistic sensitivity analyses.. The model predicted atazanavir/r to save 0.16 (95% confidence interval (CI) 0.00 to 0.33) QALYs and reduce total costs by -202,896 SEK (95% CI -332,156 to -81,644 SEK) over a lifetime horizon. Probabilistic sensitivity analyses showed that atazanavir/r had a 100% probability to be cost-effective at a willingness to pay of 200,000 SEK per QALY.. The results indicate that atazanavir/r is cost-saving and more effective compared to lopinavir/r for patients who have previously not been exposed to antiretroviral drugs in Sweden.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Clinical Trials as Topic; Cost-Benefit Analysis; HIV Infections; HIV-1; Humans; Lopinavir; Models, Statistical; Oligopeptides; Pyridines; Pyrimidinones; Quality-Adjusted Life Years; Ritonavir; Sweden

Topics: Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure.. We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study.. Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 µg/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair.. Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing.

Topics: Adult; Anti-HIV Agents; Case-Control Studies; Cross-Sectional Studies; Drug Resistance, Viral; Female; Hair; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Plasma; Pyrimidinones; RNA, Viral; South Africa; Treatment Failure; Viral Load

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

Topics: Anti-HIV Agents; Chemistry, Pharmaceutical; HIV Infections; Humans; India; Lopinavir; Patents as Topic; Pyrimidinones

To evaluate lifetime cost effectiveness of atazanavir-ritonavir (ATV + r) versus lopinavir-ritonavir (LPV/r), both with tenofovir-emtricitabine, in US HIV-infected patients initiating first-line antiretroviral therapy.. A Markov microsimulation model was developed to calculate quality-adjusted life-years (QALYs) based on CD4 and HIV RNA levels, coronary heart disease (CHD), AIDS, opportunistic infections (OIs), diarrhea, and hyperbilirubinemia. A million-member cohort of HIV-1-infected, treatment-naïve adults progressed at 3-month intervals through eight health states. Baseline characteristics, virologic suppression, cholesterol changes, and diarrhea and hyperbilirubinemia rates were based on 96-week CASTLE trial results. HIV mortality, OI rates, adherence, costs, utilities, and CHD risk were from literature and experts.. The incremental cost-effectiveness ratio (ICER) may be overestimated because the ATV + r treatment effect was based on an intention-to-treat analysis. The QALY weights used for diarrhea, hyperbilirubinemia, and CHD events are uncertain; however, the ICER remained < $50,000/QALY when these values were varied in sensitivity analyses.. ATV + r patients received first-line therapy longer than LPV/r patients (97.3 vs. 70.7 months), had longer quality-adjusted survival (11.02 vs. 10.76 years), similar overall survival (18.52 vs. 18.51 years), and higher costs ($275,986 vs. 269,160). ATV+r [corrected] patients had lower rates of AIDS (19.08 vs. 20.05 cases/1000 patient-years), OIs (0.44 vs.0.52), diarrhea (1.27 vs. 6.26), and CHD events(5.44 vs. 5.51), but higher hyperbilirubinemia rates (6.99 vs. 0.25. ATV + r added 0.26 QALYs at a cost of $6826, for $26,421/QALY.. By more effectively reducing viral load with less gastrointestinal toxicity and a better lipid profile, ATV + r lowered rates of AIDS and CHD, increased quality-adjusted survival, and was cost effective (< $50,000/QALY) compared with LPV/r.

Topics: Adenine; Adult; Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Cost-Benefit Analysis; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Markov Chains; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Quality-Adjusted Life Years; Reverse Transcriptase Inhibitors; Risk Assessment; Ritonavir; Tenofovir; United States

The OCTANE trial reports superior outcomes of lopinavir/ritonavir vs. nevirapine-based antiretroviral therapy (ART) among women previously exposed to single-dose nevirapine to prevent mother-to-child HIV transmission. However, lopinavir/ritonavir is 12 times costlier than nevirapine.. We used a computer model, with OCTANE and local data, to simulate HIV-infected, single-dose nevirapine-exposed women in South Africa. Outcomes of three alternative ART sequences were projected: no ART (for comparison), first-line nevirapine, and first-line lopinavir/ritonavir. OCTANE data included mean age (31 years) and CD4 cell count (135/μl); median time since single-dose nevirapine (17 months); and 24-week viral suppression efficacy for first-line ART (nevirapine: 85%, lopinavir/ritonavir: 97%). Outcomes included life expectancy, per-person costs (2008 US$), and incremental cost-effectiveness ratios.. With no ART, projected life expectancy was 1.6 years and per-person cost was $2980. First-line nevirapine increased life expectancy (15.2 years) and cost ($13 990; cost-effectiveness ratio: $810/year of life saved versus no ART). First-line lopinavir/ritonavir further increased life expectancy to 16.3 years and cost to $15 630 (cost-effectiveness ratio: $1520/year of life saved versus first-line nevirapine). First-line lopinavir/ritonavir cost-effectiveness was sensitive to prevalence of nevirapine-resistant virus at ART initiation, time from single-dose nevirapine exposure to ART initiation (6-12, 12-24, or >24 months), second-line ART efficacies, and outcomes after 24 weeks on ART.. First-line lopinavir/ritonavir-based ART is very cost-effective in single-dose nevirapine-exposed, South African women similar to OCTANE participants. Lopinavir/ritonavir should be initiated in women with known nevirapine resistance or single-dose nevirapine exposure less than 12 months prior, or in whom such information is unknown.

Topics: Adult; Anti-HIV Agents; Cost-Benefit Analysis; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Life Expectancy; Lopinavir; Male; Nevirapine; Pregnancy; Pyrimidinones; Ritonavir; South Africa; Treatment Outcome

Topics: Adolescent; Anti-HIV Agents; Child Behavior Disorders; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; Humans; Kidney Calculi; Lopinavir; Male; Mutation, Missense; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

The pharmacokinetics of antiretroviral drugs in pregnancy is poorly understood. We reviewed the use of therapeutic drug monitoring (TDM) in clinical settings to document plasma concentrations of lopinavir during pregnancy and investigated how clinicians acted upon TDM results. A retrospective review was carried out of all HIV-infected pregnant women taking boosted lopinavir-based highly active antiretroviral therapy (HAART) at five National Health Service (NHS) centres in the UK between May 2004 and March 2007. Seventy-three women in receipt of lopinavir were identified, of whom 89% had plasma lopinavir concentrations above the suggested minimum recommended for wild-type HIV. Initial TDM results prompted dosage change in 10% and assessment of adherence and/or pharmacist review in 11%. TDM was repeated in 29%. TDM can play an important role in the clinical management of HIV-positive pregnant women, allowing informed dose modification and an alternative measure of adherence.

Topics: Adolescent; Adult; Anti-HIV Agents; Drug Monitoring; Female; HIV Infections; Humans; Lopinavir; Plasma; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Retrospective Studies; Treatment Outcome; United Kingdom; Young Adult

Topics: Female; Genitalia, Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Virus Shedding

Topics: Bradycardia; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Post-Exposure Prophylaxis; Pyrimidinones; Ritonavir

Lopinavir/ritonavir (LPV/r) is now the protease inhibitor regimen of choice in the first-line antiretroviral therapy for children <6 years of age.. We included all the human immunodeficiency virus (HIV) type 1-infected highly active antiretroviral therapy (HAART)-naive children who started an LPV/r-based regimen between 2000 and 2009 at the Necker Hospital (Paris, France). Virologic failure (VF) was defined as an HIV-RNA ≥50 copies/mL. Resistance genotypic test was performed in case of VF.. A total of 43 children were included at a median age of 4.8 years (1.8-8.0). Median level of HIV RNA and percentage of CD4 cell count was 5.5 log₁₀ copies/mL (4.6-6) and 15% (8-27.5), respectively. HAART included LPV/r and 2 nucleoside reverse-transcriptase inhibitors, mainly lamivudine (3TC), zidovudine, and/or abacavir. The median follow-up period was 36 months (18-72). Less than 50 copies/mL of HIV RNA was observed in 46%, 67%, and 70% of the children at months 6, 9, and 12, respectively. In all, 20 children (46.5%) experienced a VF. The risk factors of primary VF were a young age and a low socioeconomic status. The genotypic resistance test, performed for 18 of 20 children with VF, revealed 1 LPV/r-resistant virus and protease inhibitor-related major mutations without LPV/r resistance in 2 other children. Of the 18 children with VF, 15 received a 3TC-based HAART: 12 of 15 (80%) harbored a 3TC-resistant virus. No virus resistant to zidovudine or abacavir was found.. In all, 70% of HAART-naive children had virologic success at month 12. The selection of LPV-resistant strains was a rare event. A high rate of selection of 3TC-mutations strengthens the recommendation to prefer a first-line 3TC-sparing regimen, particularly for children with risk factors of poor adherence.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Deoxycytidine; Drug Resistance, Viral; Emtricitabine; Female; HIV Infections; HIV Protease; HIV-1; Humans; Infant; Lamivudine; Lopinavir; Male; Mutation; Paris; Pyrimidinones; Ritonavir; Treatment Failure

Topics: Anti-HIV Agents; Clinical Trials as Topic; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lopinavir; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Reverse Transcriptase Inhibitors

To investigate whether Thai HIV-1-infected pregnant women require a dose increase of lopinavir/ritonavir (LPV/r) and to assess the safety and efficacy of the generic tablets during pregnancy.. Prospective, single-center pharmacokinetic study.. HIV-infected pregnant, antiretroviral therapy-naive or experienced women started HAART containing generic LPV/r 400/100 mg tablets twice daily. The 12-h pharmacokinetic curves were recorded at gestational age 20 weeks (GA20, optional), 33 weeks (GA33) and 12 weeks postpartum (12PP, optional).. Twenty women were included. Median [interquartile range (IQR)] age was 28 (25-33) years and mean (SD) weight at GA33 was 59.9 (4.2) kg. Mean (SD) values for LPV area under the curve(0-12 h), C(max), C(min), and T(half) were 72.9 (19.2) mg/l h, 9.3 (2.2) mg/l, 3.2 (1.3) mg/l and 4.8 (2.4) h, respectively, on GA33 and 98.0 (24.1) mg/l h, 11.7 (2.2) mg/l, 4.7 (2.2) mg/l and 5.9 (2.7) h, respectively on 12PP. Twelve women recorded both GA33 and 12PP curves; mean LPV AUC(0-12) was significantly lower at GA33 [-24.1 (95% confidence interval -44.4 to -3.7) mg/l h]. At GA33, 19 of 20 women had sufficient LPV trough concentrations (>1.0 mg/l) and at 12PP, all had sufficient LPV trough concentrations. None of the women stopped LPV/r before planned discontinuation due to side-effects. At delivery, 19 of 20 women had a viral load below 50 copies/ml. One woman had a viral load of 60 copies/ml, but was undetectable at 12PP.. Standard dose generic LPV/r (400/100 mg twice daily) in Thai HIV-1-infected pregnant women leads to adequate plasma concentrations during the third trimester. The generic LPV/r tablet is well tolerated and effective for use during pregnancy.

Topics: Adult; Antiretroviral Therapy, Highly Active; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pregnancy Trimester, Third; Pyrimidinones; Ritonavir; RNA, Viral; Viral Load

Coadministration of rifampicin dramatically reduces the concentrations of protease inhibitors. A pharmacokinetic study in healthy adults showed that doubling the dose of coformulated lopinavir/ritonavir was able to overcome the inducing effect of rifampicin. We evaluated this strategy in children treated with rifampicin-based antituberculosis therapy attending antiretroviral clinics in South Africa.. Plasma concentrations of lopinavir were measured in children (aged 0.64-2.43 years) established on antituberculosis treatment who commenced antiretroviral therapy comprising double the usual recommended dose of lopinavir/ritonavir oral solution (460/115 mg/m(2) twice daily) plus two nucleoside reverse transcriptase inhibitors. Control children (0.57-4.23 years old) without tuberculosis received standard doses of lopinavir/ritonavir (230/57.5 mg/m(2) twice daily).. Pre-dose lopinavir concentrations were reduced by >80% in children with tuberculosis (median 0.7 mg/l, IQR 0.1-2.0) compared with controls (4.2 mg/l, IQR 3.4-8.1; P<0.001) and were below the minimum recommended concentration of 1 mg/l in 12 of 20 (60%) children with tuberculosis versus 2 of 24 (8%) controls (P<0.001).. Double doses of coformulated lopinavir/ritonavir results in inadequate lopinavir concentrations in young children treated concurrently with rifampicin. Suitable regimens are urgently needed for treating young children with HIV-associated tuberculosis.

Topics: Anti-HIV Agents; Antitubercular Agents; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infant; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; South Africa; Treatment Outcome; Tuberculosis

The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Dyslipidemias; Fluorobenzenes; HIV Infections; HIV-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lopinavir; Male; Middle Aged; Pyrimidines; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Ritonavir; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome

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

Topics: Adult; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Viral Load

Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France.. To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir.. Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine.. Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency.. Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (>23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P < .001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P < .001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P < .001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment.. Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Insufficiency; Case-Control Studies; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Female; France; HIV Infections; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lopinavir; Male; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Retrospective Studies; Ritonavir; Zidovudine

Topics: Adenine; Adult; Anti-HIV Agents; Antiviral Agents; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Esophageal Diseases; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; RNA, Viral; Syndrome; Tenofovir; Ulcer

Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance (MDR) in a fully transformed KS cell line (SLK) was explored.. The KS cells were exposed to both acute and chronic treatments of physiological concentrations of different HIV-PIs (indinavir, nelfinavir, atazanavir, ritonavir, or lopinavir), alone or together with doxorubicin. The ABCB1 mRNA and protein expression levels were then assessed by qRT-PCR and western blotting, flow cytometry, and immunofluorescence.. Chronic treatment of SLK cells with one of the five HIV-PIs alone or together resulted in increased resistance to doxorubicin. Co-treatment with one of the HIV-PIs in combination with doxorubicin resulted in a synergistic increase in resistance to doxorubicin, and the degree of resistance was found to correlate with the expression of ABCB1. The SLK cells were also revealed to be cross-resistant to the structurally unrelated drug paclitaxel.. These studies suggest that ABCB1 is primarily responsible for mediating MDR in SLK cells selected with either HIV-PIs alone or in combination with doxorubicin. Therefore, the roles that ABCB1 and drug cocktails play in mediating MDR in KS in vivo should be evaluated.

Topics: Antibiotics, Antineoplastic; Atazanavir Sulfate; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings.

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Developing Countries; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Health Planning; Health Services; HIV Infections; Humans; Lamivudine; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Treatment Outcome

Since the discovery of raltegravir, the first FDA-approved integrase inhibitor, Merck and other pharmaceutical companies have continued their research programs in order to introduce novel molecules as second generation integrase inhibitors. Elvitegravir (Japan Tobacco/Gilead) and dolutegravir (Shionogi/GlaxoSmithKline) are in advanced stages of clinical development. Bristol-Myers Squibb has developed molecules leading to BMS-707035, which was stopped at the Phase II clinical trial stage. Herein is presented the last patent from this company where, in particular, new 3-hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones are synthesized and their biological properties given.

Topics: Drug Design; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Patents as Topic; Pyrimidinones

HIV-HBV-coinfected individuals who need to be treated only for their HBV infection have limited therapeutic options, since most approved anti-HBV agents have a risk of selecting for drug-resistant HIV mutants. In vivo data are inconclusive as to whether telbivudine (LdT) may exert antiviral effects against HIV. Thus, we investigated in further detail the antiviral activity and the biochemical properties of LdT against HIV-1.. To investigate the activity of LdT against HIV-1 in humans we analysed viral dynamics and genotypic and phenotypic resistance development in two HIV-HBV-coinfected individuals with no prior antiviral exposure. To investigate the activity of LdT against HIV-1 in vitro, LdT susceptibility for HIV-1 wild-type strains as well as drug-resistant strains was determined. Furthermore, we studied whether the 5'-triphosphate form of LdT (LdT-TP) can act as a substrate for wild-type HIV-1 RT.. In the two patients studied, LdT treatment did not result in a significant decline of HIV-1 RNA load nor in selection of genotypic or phenotypic resistance in HIV-1 RT. In vitro virological analyses demonstrated that LdT had no activity (50% effective concentration >100 μM) against wild type HIV and drug-resistant variants. Biochemical analyses demonstrated that LdT-TP is not incorporated by wild-type HIV-1 RT.. Based on the in vivo and in vitro evidence obtained in this study, we conclude that LdT has no anti-HIV-1 activity and is currently the only selective anti-HBV agent among the five FDA-approved nucleoside/nucleotide analogues for treatment of HBV infections in HIV-infected individuals.

Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Cell Line; Coinfection; DNA, Viral; Drug Resistance, Viral; Genotype; HEK293 Cells; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nucleosides; Phenotype; Pyrimidinones; RNA, Viral; Telbivudine; Thymidine; Viral Load

Evaluation of: Decloedt E, McIlleron H, Smith P, Merry C, Orrell C, Maartens G. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Antimicrob. Agents Chemother. 55(7), 3195-3200 (2011). HIV and TB coinfection is a widespread problem, especially in resource-limited settings. Interactions between drugs metabolized through cytochrome P450 enzymes and p-glycoprotein efflux pump, such as rifampin and HIV protease inhibitors, complicate the management of both pathologies when they coexist. The article by Decloedt et al. elegantly assesses the pharmacokinetics of three twice-daily escalating doses of lopinavir/ritonavir (400/100 mg, 600/150 mg and 800/200 mg), together with 600 mg daily of rifampin in 21 black African HIV-infected patients without TB. The article also reports safety, tolerability and virological outcomes after 3 weeks. Doubling lopinavir/ritonavir dose overcomes rifampin induction effect with good tolerability. However, concerns arise regarding the real interactions, tolerability and virological efficacy in HIV-TB-coinfected patients, which may differ from healthy volunteers or HIV-infected patients without TB.

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Male; Pyrimidinones; Rifampin; Ritonavir; Tablets

Europe is currently observing a significant rise in non-B subtypes. Consequently, the effect of genetic variability on therapy response or genotypic resistance interpretation algorithms is an emerging concern. The purpose of this study is to investigate the amino acid substitutions selected under drug pressure in the protease of human immunodeficiency virus type 1 (HIV-1) subtypes B and G, and determine if there are any significant differences. We investigated therapy-related and subtype-related substitutions in the protease, considering subtype, overall protease inhibitor treatment and individual drug exposure. Many mutations were significantly related to protease inhibitor (PI) therapy, with mutations exclusive to subtype B or subtype G. Some mutations are at positions related to resistance in both subtypes, but the amino acid substitution is different. Other mutations were significantly associated with subtype and PI selective pressure (p<0.05), pointing towards a differential selective pressure in both subtypes. We confirmed previous reports on the subtype-dependent selection of D30N and 89I, and identified a new mutation with such differential selective pressure: 37D was preferentially selected by lopinavir in subtype B. Other novel mutations found under therapy pressure were 13A, 35N, K55R, I66F, I72L/T, T74S, 82M and 89I/V. Our study indicates that even though in general, drug selective pressure and resistance pathways are relatively similar between subtypes B and G, some differences do occur, leading to subtype-dependent substitutions.

Topics: Amino Acid Substitution; Drug Resistance, Viral; Genetic Variation; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Phylogeny; Pyrimidinones; Selection, Genetic; Sequence Analysis, Protein

Topics: Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biological Availability; Chemistry, Pharmaceutical; Dogs; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Solubility; Tablets; Therapeutic Equivalency

Human immunodeficiency virus (HIV) protease inhibitor (PI)-induced adverse effects have become a serious clinical problem. In addition to their metabolic and cardiovascular complications, these drugs also frequently cause severe gastrointestinal disorders, including mucosal erosions, epithelial barrier dysfunction, and diarrhea. However, the exact mechanisms underlying gastrointestinal adverse effects of HIV PIs remain unknown. This study investigated whether HIV PIs disrupt intestinal epithelial barrier integrity by activating endoplasmic reticulum (ER) stress.. The most commonly used HIV PIs (lopinavir, ritonavir, and amprenavir) were used; their effects on ER stress activation and epithelial paracellular permeability were examined in vitro as well as in vivo using wild-type and CHOP(-)/(-) mice.. Treatment with lopinavir and ritonavir, but not amprenavir, induced ER stress, as indicated by a decrease in secreted alkaline phosphatase activities and an increase in the unfolded protein response. This activated ER stress partially impaired the epithelial barrier integrity by promoting intestinal epithelial cell apoptosis. CHOP silencing by specific small hairpin RNA prevented lopinavir- and ritonavir-induced barrier dysfunction in cultured intestinal epithelial cells, whereas CHOP(-)/(-) mice exhibited decreased mucosal injury after exposure to lopinavir and ritonavir.. HIV PIs induce ER stress and activate the unfolded protein response in intestinal epithelial cells, thus resulting in disruption of the epithelial barrier integrity.

Topics: Animals; Apoptosis; Carbamates; Cell Line; Cell Membrane Permeability; Endoplasmic Reticulum; Furans; HIV Infections; HIV Protease Inhibitors; Intestinal Mucosa; Lopinavir; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pyrimidinones; Ritonavir; Stress, Physiological; Sulfonamides; Transcription Factor CHOP

Topics: Animals; Anti-HIV Agents; Biological Availability; Chemistry, Pharmaceutical; Data Interpretation, Statistical; Dogs; Drug Combinations; Drug Evaluation, Preclinical; Food-Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Models, Biological; Pyrimidinones; Ritonavir; Tablets; Therapeutic Equivalency

To determine rates of survival, viral suppression, and immunologic change after 1 year on second-line antiretroviral therapy, we conducted a cohort study among 328 patients initiated on zidovudine, didanosine, and lopinavir/ritonavir. All patients who switched to standard second-line therapy at a large urban public-sector clinic in Johannesburg, South Africa, were included. A year after initiating second-line therapy 243/313 [78%; 95% confidence interval (CI) 73%-82%], subjects were alive and in care. Further, 203/262 (77%; 95% CI: 72%-82%) had a suppressed viral load by 1 year. Mean CD4 gain by 12 months was 133 cells/microL (95% CI: 106-160). Patients on second-line therapy had a small decreased likelihood of being alive and in care by 1 year [hazard ratio (HR) 0.84; 95% CI: 0.73-0.97] as time-matched comparisons on first-line antiretroviral therapy (ART). Patients switched before 2 viral loads >1000 (HR 1.68; 95% CI: 1.08-2.61), and those switched for reasons not related to noncompliance with first-line (HR 1.83; 95% CI: 1.14-2.93) were more likely to achieve virologic suppression by 1 year on second-line ART. As rates of treatment failure over the first year on second-line therapy were low, provision of second-line treatment to patients who fail their first-line ART should be considered a high priority in resource-poor settings.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Female; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; South Africa; Survival Analysis; Treatment Outcome; Viral Load; Zidovudine

Thirty-three persons became victims of a serial knife stabbing incident. One of the first victims one day later disclosed that he was HIV-infected. Thereafter thirty-one victims initiated HIV post-exposure prophylaxis (PEP), one exposed patient declined. None of the victims evaluated had seroconverted six months later. In most such incidents HIV exposure will be difficult to rule out as reliable information on the HIV serostatus of all serial victims will be lacking. It appears prudent, however, to inform serial stab victims about the potential risk of HIV transmission and to at least consider PEP in such scenarios.

Topics: Anti-HIV Agents; Crime Victims; Disease Transmission, Infectious; Drug Combinations; Hepatitis B; Hepatitis C; HIV Infections; Humans; Lamivudine; Lopinavir; Post-Exposure Prophylaxis; Pyrimidinones; Viral Load; Wounds, Stab; Zidovudine

Because of the lack of a lopinavir/ritonavir (LPV/r) pediatric formulation, 54 HIV-infected children were given generic LPV/r adult tablets. Of 54 children, 21 took cut pills to get the appropriate dose. The median (interquartile range) LPV trough serum concentration (C trough) was 6.7 (5.0-9.9) mg/L. All the children had C trough >1.0 mg/L and 96% had values >4.0 mg/L. LPV/r adult tablets can be used in children when it is necessary.

Topics: Adolescent; Child; Drug Monitoring; HIV Infections; Humans; Lopinavir; Pyrimidinones; Serum; Tablets

The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration.. Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake.. Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54).. This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.

Topics: Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Body Weight; Cyclopropanes; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Plasma; Pyridines; Pyrimidinones; Rifabutin; United Kingdom

It is debated whether a risk of protease inhibitor mutation selection in proviral DNA exists during intermittent HIV-1 viraemia thereby impacting long-term virological control.. Virologically controlled patients treated with lopinavir/ritonavir were included in a 48 week pilot trial during which lopinavir/ritonavir dosage was reduced if lopinavir concentration was >5000 ng/mL at inclusion. Serum lipids were longitudinally assessed and proviral DNA was quantified and sequenced in patients experiencing transient viraemia.. Thirty-three virologically suppressed patients while on a lopinavir/ritonavir-containing regimen were included, of whom 28 [20 males, mean age 44.6 years (SD 10.9)] completed the 48 week follow-up as scheduled. A significant decrease in lopinavir level was noted [mean C(min), 7363 ng/mL (min, 5118; max, 12 415) at baseline versus 4319 ng/mL (min, 1427; max, 8683) at week 48, P < 0.03]. A significant decrease in triglycerides was also observed [1.73 mmol/L (SD 1.08) at baseline versus 1.34 mmol/L (SD 0.91) at week 48, P = 0.03], whereas no significant change occurred for total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. In the 15 patients with transient viraemia, analysis of proviral DNA for antiretroviral resistance showed that mutations had occurred when compared with baseline genotypes in three patients: I47M (n = 2) and M46I (n = 1). Selection of these mutations was not associated with virological failure as all three patients had a sustained virological response without treatment modification after a 3 year follow-up.. This pilot study evaluating the biochemical and virological impact of a reduced dosing of lopinavir/ritonavir suggests that lower exposure to lopinavir/ritonavir could be associated with a significant decrease in triglycerides during treatment, without occurrence of resistance mutations that might impact the virological response to treatment.

Topics: Adult; Anti-HIV Agents; DNA, Viral; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lipids; Lopinavir; Male; Middle Aged; Proviruses; Pyrimidinones; Ritonavir; Viral Load; Young Adult

HIV infected patients often take at least three anti-HIV drugs together in Highly Active Antiretroviral Therapy (HAART) and/or Ritonavir-Boosted Protease Inhibitor Therapy (PI/r) to suppress the viral replications. The potential drug-drug interactions affect efficacy of anti-HIV treatment and major source of such interaction is competition for the drug metabolizing enzyme, cytochrome P450 (CYP). CYP3A4 isoform is the enzyme responsible for metabolism of currently available HIV-1 protease drugs. Hence administration of these drugs in HARRT or PI/r leads to increased toxicity and reduced efficacy in HIV treatment. We used computational molecular docking method to predict such interactions by which to compare experimentally measured metabolism of each HIV-1 protease drug. AutoDock 4.0 was used to carry out molecular docking of 10 HIV-protease drugs into CYP3A4 to explore sites of reaction and interaction energies (i.e., binding affinity) of the complexes. Arg105, Arg106, Ser119, Arg212, Ala370, Arg372, and Glu374 are identified as major drug binding residues, and consistent with previous data of site-directed mutagenesis, crystallography structure, modeling, and docking studies. In addition, our docking results suggested that phenylalanine clusters and heme are also participated in the binding to mediate drug oxidative metabolism. We have shown that HIV-1 protease drugs such as tipranavir, nelfinavir, lopinavir, and atazanavir differ in their binding modes on each other for metabolic clearance in CYP3A4, whereas ritonavir, amprenavir, indinavir, saquinavir, fosamprenavir, and darunavir share the same binding mode.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Computational Biology; Cytochrome P-450 CYP3A; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

Topics: Antiretroviral Therapy, Highly Active; Black People; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Drug Interactions; Female; Genotype; HIV Infections; Humans; Infant; Lopinavir; Pharmacogenetics; Polymorphism, Genetic; Pyrimidinones; Ritonavir; Treatment Failure

Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and alpha-1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to > or =1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously.. P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP.. AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96+/-0.16% AP vs. 0.82+/-0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG.. LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.

Topics: Acute-Phase Proteins; Adolescent; Adult; Antiretroviral Therapy, Highly Active; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Prospective Studies; Protein Binding; Pyrimidinones; Ritonavir; Young Adult

Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence.. We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008.. The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/microL increase; P < .001), and HIV-RNA of more than 5.0 log(10) copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56).. Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.

Topics: Adenine; Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Oligopeptides; Organophosphonates; Proportional Hazards Models; Prospective Studies; Pyridines; Pyrimidinones; Risk Factors; Switzerland; Tenofovir; Zidovudine

Topics: Adenine; Administration, Oral; Adolescent; Adult; Aged; Anti-HIV Agents; Deoxycytidine; Dose-Response Relationship, Drug; Drug Resistance, Viral; Emtricitabine; Female; Genotype; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Organophosphonates; Patient Compliance; Pyrimidinones; Randomized Controlled Trials as Topic; RNA, Viral; Stavudine; Tenofovir; Treatment Outcome; Young Adult

* There is large interindividual variability in the pharmacokinetics of protease inhibitors (PIs) among human immunodeficiency virus (HIV)-infected individuals under highly active antiretroviral therapy. * Protease inhibitor have been recently reported to be substrates of the SLCO1B1/OATP1 drug transporter. * A single nucleotide polymorphism (SNP) in the SLCO1B1 gene (521T-->C) was associated with plasma levels of lopinavir in HIV-infected individuals.. * Data on the impact of three SLCO1B1 SNPs (521T-->C, 388A-->G, 463C-->A) on the trough plasma concentration of lopinavir and ritonavir in a cohort of 99 adult HIV-infected Brazilian men under stable highly active antiretroviral therapy. * Evidence that carriers of the 521C allele display significantly higher lopinavir, but not ritonavir plasma concentrations relative to the wild-type TT genotype. * No effect of either 388A-->G or 463C-->A SNPs on lopinavir or ritonavir plasma concentrations. * Further studies are required to confirm the clinical significance of the association between the SLCO1B1521T-->C polymorphism and lopinavir pharmacokinetics.. To investigate possible associations between three SLCO1B1 single nucleotide polymorphisms (388A-->G, 463C-->A, 521T-->C) and lopinavir/ritonavir plasma concentrations.. The study included 99 human immunodeficiency virus-infected men on stable highly active antiretroviral therapy containing lopinavir/ritonavir. Trough concentrations of lopinavir and ritonavir in plasma were quantified using liquid chromatography-tandem mass spectrometry. Genotyping of SLCO1B1388A-->G, 463C-->A and 521T-->C polymorphisms was performed by allelic discrimination using real-time polymerase chain reaction.. The trough concentration of lopinavir in plasma is significantly associated with SLCO1B1521T-->C genotypes (P= 0.03). There is a significant trend for increasing concentrations of lopinavir from TT to TC to CC genotypes (P= 0.02). Carriers of the 521C allele display significantly higher lopinavir plasma concentrations relative to the wild-type TT genotype (P= 0.03).. Reduced uptake of lopinavir by hepatocytes in carriers of the 521C allele may account for these results, but further studies to confirm the clinical importance of SLCO1B1 polymorphisms in lopinavir pharmacokinetics are warranted.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chromatography, Liquid; Gene Frequency; Genotype; HIV Infections; Humans; Liver-Specific Organic Anion Transporter 1; Lopinavir; Male; Organic Anion Transporters; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Pyrimidinones; Ritonavir; Tandem Mass Spectrometry

Topics: Anti-HIV Agents; Child; Child, Preschool; HIV Infections; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome

The relationship between plasma protease inhibitor (PI) trough concentrations and hyperlipidemic effects were evaluated retrospectively using data from 2 pilot clinical trials of a double-boosted PI regimen (saquinavir/lopinavir/ritonavir) in 25 HIV patients. The patients' median age was 39 years (range, 25-60). At baseline, PI-naive patients had a median viral load of 53 500 copies/mL and median CD4 of 296 cells/mm(3), while PI-experienced patients had 37 750 copies/mL and 214 cells/mm(3). Plasma PI trough concentrations of saquinavir, lopinavir, and ritonavir at week 12 were 520, 4482, and 153 ng/mL, respectively. At week 12, median fasting lipids increased significantly from baseline: total cholesterol increased from 165 to 189 mg/dL (P = .0005) and the triglyceride increased from 113 to 159 mg/dL (P = .001). There were no associations between PI trough concentrations at week 12 and the percent total cholesterol change at week 12. No associations were found between PI trough concentrations and lipid changes in HIV patients on a double-boosted PI regimen (saquinavir/lopinavir/ritonavir). Factors other than systemic exposure to PIs (such as host or genetic factors) may modulate the hyperlipidemic effect of PIs.

Topics: Adult; Clinical Trials as Topic; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Lopinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrimidinones; Retrospective Studies; Ritonavir; Saquinavir

Recently, first-line lopinavir failure was observed due to protease mutation 76V. In the present study, we found 76V associated with protease mutation 46I and gag cleavage-site mutation 431V. Longitudinal analysis of patients failing protease inhibitor therapies demonstrated that 76V strictly occurs either together with 46I and/or 431V or in HIV isolates already harbouring one of both mutations. Therefore, all three mutations seem to cooperate in terms of protease inhibitor resistance.

Topics: Drug Resistance, Viral; Evolution, Molecular; Female; gag Gene Products, Human Immunodeficiency Virus; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Molecular Sequence Data; Mutation; pol Gene Products, Human Immunodeficiency Virus; Pyrimidinones; Sequence Analysis, DNA

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Omeprazole; Proton Pump Inhibitors; Pyrimidinones; Ritonavir; Young Adult

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

Most approved drugs with activity against hepatitis B virus (HBV) have activity against human immunodeficiency virus type 1 (HIV-1), which precludes their use in patients who are coinfected with HBV and HIV-1 and who are not receiving antiretroviral therapy due to the risk of inducing resistance. The activity of telbivudine, a highly selective HBV inhibitor, against temporally and geographically distinct wild-type and multidrug-resistant HIV-1 clinical isolates was evaluated in vitro. No inhibition was observed with up to 600 muM drug, which supports further exploration of telbivudine as a therapeutic option for the treatment of HBV infections in patients coinfected with HIV-1.

Topics: Anti-HIV Agents; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Highly active antiretroviral therapy might lead to the development of dyslipidemia and lipodystrophy (LD) syndrome. We carried out a multicenter prospective study of 22 human immunodeficiency virus (HIV)-1-infected children treated during 48 months with lopinavir/ritonavir-based highly active antiretroviral therapy to evaluate the trend of serum lipids and adipokines. Increase in plasma leptin levels and leptin/adiponectin ratio was associated with LD. These adipokines may be surrogate markers of LD.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; Child; Child, Preschool; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Leptin; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir

Accurate calculation of important thermodynamic properties, such as macromolecular binding free energies, is one of the principal goals of molecular dynamics simulations. However, single long simulation frequently produces incorrectly converged quantitative results due to inadequate sampling of conformational space in a feasible wall-clock time. Multiple short (ensemble) simulations have been shown to explore conformational space more effectively than single long simulations, but the two methods have not yet been thermodynamically compared. Here we show that, for end-state binding free energy determination methods, ensemble simulations exhibit significantly enhanced thermodynamic sampling over single long simulations and result in accurate and converged relative binding free energies that are reproducible to within 0.5 kcal/mol. Completely correct ranking is obtained for six HIV-1 protease variants bound to lopinavir with a correlation coefficient of 0.89 and a mean relative deviation from experiment of 0.9 kcal/mol. Multidrug resistance to lopinavir is enthalpically driven and increases through a decrease in the protein-ligand van der Waals interaction, principally due to the V82A/I84V mutation, and an increase in net electrostatic repulsion due to water-mediated disruption of protein-ligand interactions in the catalytic region. Furthermore, we correctly rank, to within 1 kcal/mol of experiment, the substantially increased chemical potency of lopinavir binding to the wild-type protease compared to saquinavir and show that lopinavir takes advantage of a decreased net electrostatic repulsion to confer enhanced binding. Our approach is dependent on the combined use of petascale computing resources and on an automated simulation workflow to attain the required level of sampling and turn around time to obtain the results, which can be as little as three days. This level of performance promotes integration of such methodology with clinical decision support systems for the optimization of patient-specific therapy.

Topics: Anti-HIV Agents; Drug Resistance, Multiple; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Molecular Dynamics Simulation; Pyrimidinones; Thermodynamics

The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Cell Line; Cells, Cultured; Codon; Genotype; HIV Infections; HIV Protease; HIV-1; Humans; Lopinavir; Nelfinavir; Oligopeptides; Polymorphism, Genetic; Pyridines; Pyrimidinones

Topics: HIV Infections; HIV-1; Humans; Lopinavir; Meningitis, Viral; Pyrimidinones; Ritonavir

We report a case of the syndrome of inappropriate antidiuretic hormone associated with use of lopinavir in an HIV-infected child. This rare phenomenon has not previously been reported in children. Clinicians should be alert to the possibility of the syndrome of inappropriate antidiuretic hormone when prescribing lopinavir in children.

Topics: Adolescent; Anti-HIV Agents; HIV Infections; Humans; Inappropriate ADH Syndrome; Lopinavir; Male; Pyrimidinones

Topics: Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Delayed-Action Preparations; HIV Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Lopinavir; Male; Middle Aged; Pyrimidinones; Tacrolimus

The population pharmacokinetics (PK) of lopinavir in tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected South African children taking super-boosted lopinavir (lopinavir/ritonavir ratio 1:1) as part of antiretroviral treatment in the presence of rifampicin were compared with the population PK of lopinavir in HIV-infected South African children taking standard doses of lopinavir/ritonavir (ratio 4:1).. Lopinavir concentrations were measured in 15 TB/HIV-co-infected paediatric patients who were sampled during and after rifampicin-based TB treatment and in 15 HIV-infected children without TB. During TB therapy, the dose of ritonavir was increased to lopinavir/ritonavir 1:1 in order to compensate for the induction of rifampicin. The children received median (interquartile range=IQR) doses of lopinavir 292 mg/m(2) (274, 309) and ritonavir 301 mg/m(2) (286, 309) twice daily. After TB treatment completion the children received standard doses of lopinavir/ritonavir 4:1 (median [IQR] lopinavir dose 289 mg/m(2) [286, 303] twice daily) as did those without TB (median [IQR] lopinavir dose 265 mg/m(2) [249, 289] twice daily).. Lopinavir oral clearance (CL/F) was about 30% lower in children without TB than in co-infected children treated with super-boosted lopinavir. However, the predicted lopinavir C(min) was above the recommended minimum therapeutic concentration during TB/HIV co-treatment in the 15 children. Lopinavir CL/F increased linearly during the dosing interval.. Increasing the ritonavir dose to achieve a lopinavir/ritonavir ratio of 1:1 when given in combination with rifampicin-based TB treatment did not completely compensate for the enhancement of lopinavir CL/F caused by rifampicin. The time-dependent lopinavir CL/F might be due to a time-dependent recovery from ritonavir inhibition of lopinavir metabolism during the dosing interval.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; South Africa; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

The advent of highly active antiretroviral therapy in the treatment of HIV disease has substantially extended the lifespan of individuals infected with HIV resulting in a growing population of older HIV-infected individuals. The efficacy and safety of antiretroviral agents in the population are important concerns. There have been relatively few studies assessing antiretroviral pharmacokinetics in older patients. Thirty-seven subjects aged 18-30 years and 40 subjects aged 45-79 years, naive to antiretroviral therapy, received lopinavir/ritonavir (400/100) bid, emtricitibine 200 mg qd, and stavudine 40 mg bid. Trough lopinavir concentrations were available for 44 subjects, collected at 24, 36, and 96 weeks. At week 24, older age was associated with higher lopinavir trough concentrations, and a trend was observed toward older age being associated with higher lopinavir trough concentrations when all time points were evaluated. In the young cohort, among subjects with two or more measurements, there was a trend toward increasing intrasubject trough lopinavir concentrations over time. Using a nonlinear, mixed-effects population pharmacokinetic model, age was negatively associated with lopinavir clearance after adjusting for adherence. Adherence was assessed by patient self-reports; older patients missed fewer doses than younger patients (p = 0.02). No difference in grade 3-4 toxicities was observed between the two age group. Older patients have higher trough lopinavir concentrations and likely decreased lopinavir clearance. Age-related changes in the pharmacokinetics of antiretroviral drugs may be of increasing importance as the HIV-infected population ages and as older individuals comprise an increasing proportion of new diagnoses.

Topics: Adolescent; Adult; Age Factors; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Plasma; Pyrimidinones; Young Adult

Topics: Anti-HIV Agents; Drug Approval; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

Topics: Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

HIV protease inhibitors must penetrate into cells to exert their action. Differences in the intracellular pharmacokinetics of these drugs may explain why some patients fail on therapy or suffer from drug toxicity. Yet, there is no information available on the intracellular levels of HIV protease inhibitors in HIV infected children, which is in part due to the large amount of sample that is normally required to measure the intracellular concentrations of these drugs. Therefore, we developed an ultra-fast and sensitive assay to measure the intracellular concentrations of HIV protease inhibitors in small amounts of peripheral blood mononuclear cells (PBMCs), and determined the intracellular concentrations of lopinavir and ritonavir in HIV infected children. An assay based on matrix-assisted laser desorption/ionization (MALDI)-triple quadrupole mass spectrometry was developed to determine the concentrations of HIV protease inhibitors in 10 microL plasma and 1x10(6) PBMCs. Precisions and accuracies were within the values set by the FDA for bioanalytical method validation. Lopinavir and ritonavir did not accumulate in PBMCs of HIV infected children. In addition, the intracellular concentrations of lopinavir and ritonavir correlated poorly to the plasma concentrations of these drugs. MALDI-triple quadrupole mass spectrometry is a new tool for ultra-fast and sensitive determination of drug concentrations which can be used, for example, to assess the intracellular pharmacokinetics of HIV protease inhibitors in HIV infected children.

Topics: Adolescent; Child; Chromatography, High Pressure Liquid; HIV Infections; HIV Protease Inhibitors; Humans; Leukocytes, Mononuclear; Lopinavir; Pyrimidinones; Ritonavir; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Topics: Drug Interactions; Drug Labeling; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

Kaletra (Abott Laboratories) is a co-formulated medication used in the treatment of HIV-1-infected children, and it contains the two antiretroviral protease inhibitor drugs lopinavir and ritonavir. We validated two new ultrafast and high-throughput mass spectrometric assays to be used for therapeutic drug monitoring of lopinavir and ritonavir concentrations in whole blood and in plasma from HIV-1-infected children. Whole blood was blotted onto dried blood spot (DBS) collecting cards, and plasma was collected simultaneously. DBS collecting cards were extracted by an acetonitrile/water mixture while plasma samples were deproteinized with acetone. Drug concentrations were determined by matrix-assisted laser desorption/ionization-triple quadrupole tandem mass spectrometry (MALDI-QqQ-MS/MS). The application of DBS made it possible to measure lopinavir and ritonavir in whole blood in therapeutically relevant concentrations. The MALDI-QqQ-MS/MS plasma assay was successfully cross-validated with a commonly used high-performance liquid chromatography (HPLC)-ultraviolet (UV) assay for the therapeutic drug monitoring (TDM) of HIV-1-infected patients, and it showed comparable performance characteristics. Observed DBS concentrations showed as well, a good correlation between plasma concentrations obtained by MALDI-QqQ-MS/MS and those obtained by the HPLC-UV assay. Application of DBS for TDM proved to be a good alternative to the normally used plasma screening. Moreover, collection of DBS requires small amounts of whole blood which can be easily performed especially in (very) young children where collection of large whole blood amounts is often not possible. DBS is perfectly suited for TDM of HIV-1-infected children; but nevertheless, DBS can also easily be applied for TDM of patients in areas with limited or no laboratory facilities.

Topics: Blood Specimen Collection; Case-Control Studies; Child; Chromatography, High Pressure Liquid; Drug Monitoring; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Reduced lopinavir concentrations have been demonstrated with use of the capsule formulation during the third trimester of pregnancy. This study determined lopinavir exposure with an increased dose of the new tablet formulation during the third trimester.. International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is a prospective nonblinded pharmacokinetic study in HIV-infected pregnant women, including a cohort receiving 2 lopinavir/ritonavir tablets (400 mg/100 mg) twice daily during the second trimester, 3 tablets (600 mg/150 mg) twice daily during the third trimester, and 2 tablets (400 mg/100 mg) twice daily post delivery through 2 weeks postpartum.. Steady-state 12-hour pharmacokinetic profiles were performed during pregnancy and at 2 weeks postpartum. Lopinavir and ritonavir were measured by reverse-phase high-performance liquid chromatography (detection limit, 0.09 mcg/mL).. Thirty-three women were studied. Median lopinavir AUC for the second trimester (n = 11), third trimester (n = 33), and postpartum (n = 27) were 72, 96, and 133 mcg x hr/mL, respectively. Median minimum lopinavir concentrations were 3.4, 4.9, and 6.9 mcg/mL.. The higher lopinavir/ritonavir tablet dose (600 mg/150 mg) provided exposure during the third trimester similar to the average AUC (98 mcg x hr x mL(-1) in nonpregnant adults taking 400 mg/100 mg twice daily. The higher dose should be used during the second and third trimesters of pregnancy. Postpartum dosing can be reduced to standard dosing before 2 weeks postpartum.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Body Weight; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethnicity; Female; Gestational Age; HIV Infections; Humans; Lopinavir; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Pyrimidinones; Racial Groups; Zidovudine

This study was conducted to examine the pharmacokinetic interactions between buprenorphine/naloxone (BUP/NLX) and lopinavir/ritonavir (LPV/r) in HIV-seronegative subjects chronically maintained on BUP/NLX.. This study was an open labeled pharmacokinetic study in twelve HIV-seronegative subjects stabilized on at least 3 weeks of BUP/NLX therapy. Subjects sequentially underwent baseline and steady-state pharmacokinetic evaluation of once-daily LPV/r (800/200 mg).. Compared to baseline values, BUP AUC0-24h (46.8 vs. 46.2 ng*hr/mL) and Cmax (6.54 vs. 5.88 ng/mL) did not differ significantly after achieving steady-state LPV/r. Similar analyses of norBUP, the primary metabolite of BUP, demonstrated no significant difference in norBUP AUC0-24 hours (73.7 vs. 52.7 ng x h/mL); however, Cmax (5.29 vs. 3.11 ng/mL) levels were statistically different (P < 0.05) after LPV/r administration. Naloxone concentrations were similarly unchanged for AUC0-24 hours (0.421 vs. 0.374 ng x hr/mL) and Cmax (0.186 vs. 0.186 ng/mL). Using standardized measures, no objective opioid withdrawal was observed. The AUC0-24 hours and Cmin of LPV in this study did not significantly differ from historical controls (159.6 vs. 171.3 microg x hr/mL) and (2.3 vs. 1.3 microg/mL).. The addition of LPV/r to stabilized patients receiving BUP/NLX did not affect buprenorphine pharmacokinetics but did increase the clearance of norbuprenorphine. Pharmacodynamic responses indicate that the altered norbuprenorphine clearance did not lead to opioid withdrawal. Buprenorphine/naloxone and LPV/r can be safely coadministered without need for dosage modification.

Topics: Adult; Analgesics, Opioid; Anti-HIV Agents; Buprenorphine; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Male; Metabolic Clearance Rate; Middle Aged; Naloxone; Pyrimidinones; Ritonavir

To evaluate the tolerability of HIV postexposure prophylaxis (PEP) with tenofovir/emtricitabine and lopinavir/ritonavir tablet formulation (TDF/FTC+LPV/r).. Multicentric observational prospective study.. Adults with an HIV transmission risk in the past 48 h were eligible. Baseline sociodemographic characteristics, description of exposure event, and HIV serostatus of the source patient were collected. Laboratory monitoring for toxicity and a clinical evaluation were performed; adherence and side effects were recorded using a standardized form on day 0, 15, and 28.. Between November 2006 and June 2008, 249 participants were included in 10 French hospitals. Mean age was 31.5 +/- years. Sex ratio male/female was 1.96. Exposure events are as follows: occupational exposure, 40 (16%); sexual intercourse, 204 (82%); and other, 5 (2%). Tolerability could be evaluated in 188 cases. In 22 cases, PEP was discontinued for adverse effects before day 28, including two cases of skin rash related to TDF/FTC prescription, one renal lithiasis related to LPV/r prescription, and one rhabdomyolysis. One hundred and sixty-six persons completed the 28 days of PEP with tolerability judged as good in 96 (58%) individuals. Among everyone who experienced at least one side effect, 78% reported diarrhea, 78% asthenia, and 59% nausea and/or vomiting.. Considering data of previous studies performed using similar methodology, the dropout rate due to adverse events appeared significantly lower in TDF/FTC+LPV/r tablet formulation than those in zidovudine/lamivudine (ZDV/3TC)+nelfinavir (P < 0.0001), ZDV/3TC+lopinavir/ritonavir soft gel capsules (P < 0.01), and 3TC+TDF+atazanavir boosted by ritonavir (P < 0.05) and should be considered as standard of care concerning HIV PEP.

Topics: Adenine; Adolescent; Adult; Antiviral Agents; CD4 Lymphocyte Count; Deoxycytidine; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Organophosphonates; Post-Exposure Prophylaxis; Practice Guidelines as Topic; Pyrimidinones; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome; Young Adult

To compare plasma antiretroviral concentrations in HIV-HCV co-infected and in matched HIV mono-infected patients.. This was a cross-sectional, observational study. Antiretroviral trough concentrations (C(min)) in plasma were measured in HIV-HCV co-infected patients with liver disease documented by liver biopsy, matched with HIV mono-infected patients according to gender and antiretroviral treatment. C(min) values in serum were measured using an HPLC method. Statistical analysis was performed using the Wilcoxon test.. Seventy-three HIV-HCV co-infected patients and 66 HIV-infected patients were enrolled; 70% of patients were receiving a protease inhibitor (PI)- and 30% a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Among the 73 co-infected patients, 27 had a fibrosis score (Fibrotest(®)) of F4. Abacavir was the only nucleoside reverse transcriptase inhibitor whose trough concentrations differed between the co-infected and mono-infected groups. PI median plasma C(min) values were not different in the two groups, except for lopinavir, with a lower C(min) in the co-infected group than in the HIV-infected group (median 3673 versus 5990 ng/mL, P=0.04), and nelfinavir, with significantly higher concentrations in the co-infected group. Seventy-five percent of co-infected patients scoring F4, 33% of those scoring F0-F3 and 12% of HIV-infected patients were underdosed (P=0.02). Co-infected patients receiving an NNRTI had a higher plasma C(min) than HIV-infected patients; median C(min) was 3583 versus 1494 ng/mL (P=0.025) and 5331 versus 3954 ng/mL (P=0.10) for efavirenz and nevirapine, respectively. Overall, there was a greater proportion of co-infected patients with high concentrations of both NNRTIs (15/23) compared with HIV mono-infected patients (5/21) (P=0.008), especially in co-infected patients with an advanced liver fibrosis stage.. Median plasma C(min) values differed significantly between HIV and HIV-HCV co-infected patients for abacavir, lopinavir and efavirenz. NNRTIs were strongly overdosed in HIV-HCV co-infected patients.

Topics: Adult; Aged; Alkynes; Anti-Retroviral Agents; Benzoxazines; Case-Control Studies; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Cyclopropanes; Dideoxynucleosides; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Lopinavir; Male; Middle Aged; Plasma; Pyrimidinones

Topics: HIV Infections; HIV-1; Humans; Lopinavir; Meningitis, Viral; Pyrimidinones; Ritonavir

To determine whether and how protease inhibitors (PIs) could affect vascular aging.. HIV therapy with PIs is associated with an increased risk of premature cardiovascular disease. The effect of ritonavir and a combination of lopinavir and ritonavir (for 30 days) on senescence, oxidative stress, and inflammation was evaluated in human coronary artery endothelial cells (HCAECs). These HCAECs were either cotreated or not cotreated with pravastatin or farnesyl transferase inhibitor (FTI)-277 or with 2 antioxidants (manganese [III] tetrakis [4-benzoic acid] porphyrin [MnTBAP] and N-acetyl cysteine). Senescence markers were evaluated in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients under PI treatment. PIs induced senescence markers, prelamin A accumulation, oxidative stress, and inflammation in HCAECs. Senescence markers and prelamin A were also observed in PBMCs from HIV-infected patients under ritonavir-boosted PIs. Pravastatin, FTI-277, and antioxidants improved PI adverse effects in HCAECs. Senescence markers were lower in PBMCs from PI-treated patients cotreated with statins.. PIs triggered premature senescence in endothelial cells by a mechanism involving prelamin A accumulation. Accordingly, circulating cells from HIV-infected patients receiving PI therapy expressed senescence markers and prelamin A. Statin was associated with improved senescence in endothelial cells and patient PBMCs. Thus, PIs might promote vascular senescence in HIV-infected patients; and statins might exert beneficial effects in these patients.

Topics: Acetylcysteine; Adult; Antioxidants; Case-Control Studies; Cell Proliferation; Cells, Cultured; Cellular Senescence; Coronary Vessels; Cyclin-Dependent Kinase Inhibitor p21; Drug Therapy, Combination; Endothelial Cells; Farnesyltranstransferase; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lamin Type A; Lopinavir; Metalloporphyrins; Methionine; Middle Aged; Nuclear Proteins; Oxidative Stress; Paris; Pravastatin; Protein Precursors; Pyrimidinones; Ritonavir; Time Factors; Tumor Suppressor Protein p53

It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function revealed that even the lowest dose of lopinavir/ritonavir caused significant cognitive impairment assessed in multi-unit T-maze, but did not affect motor functions assessed as rotarod performance. Collectively, our results indicate that repeated lopinavir/ritonavir administration produces cognitive as well as metabolic impairments, and suggest that the development of selective aspects of metabolic syndrome in HIV patients could contribute to HIV-associated neurocognitive disorders.

Topics: Animals; Cognition; Drug Administration Schedule; Drug Combinations; HIV; HIV Infections; HIV Protease Inhibitors; Lopinavir; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Motor Activity; Pyrimidinones; Ritonavir; Weight Loss

Protease inhibitor (PI)-resistant HIV-1 has hardly ever been detected at failed boosted PI-based first-line antiretroviral regimens in clinical trials. However, this phenomenon has not been investigated in clinical practice. To address this gap, data from patients starting a first-line lopinavir/ritonavir (LPV/rtv)-based therapy with available baseline HIV-1 RNA load, a viral genotype and follow-up viral load after 3 and 6 months of treatment were extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) observational database. Based on survival analysis, 39 (7.1%) and 43 (7.8%) of the 548 examined patient cases had an HIV-1 RNA >500 and >50 copies/ml, respectively, after 6 months of treatment. Cox proportional hazard models detected baseline HIV-1 RNA (RH 1.79, 95%CI 1.10-2.92 per 1-log(10) increase, P=0.02) and resistance to the nucleoside backbone (RH 1.04, 95%CI 1.02-1.06 per 10-point increase using the Stanford HIVdb algorithm, P<0.001) as independent predictors of HIV-1 RNA at >500 copies/ml, but not at the >50 copies/ml cutoff criteria. Higher baseline viral load, older patient age, heterosexual route of infection and use of tenofovir/emtricitabine were predictors of failure at month 3 using the 50-copy and/or 500-copy threshold. Resistance to LPV/rtv did not occur or increase in any of the available 36 follow-up HIV-1 genotypes. Resistance to the nucleoside backbone (M184V) developed in four cases. Despite the likely differences in patient population and adherence, both the low rate of virological failure and the lack of development of LPV/rtv resistance documented in clinical trials are thus confirmed in clinical practice.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cohort Studies; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Survival Analysis; Treatment Failure; Treatment Outcome; Viral Load

In inflammation and infection, cytochrome P450 (CYP) enzyme activities are down-regulated. Information on possible discrepancies in activities of CYP enzymes and drug transporters between HIV-infected patients and healthy people is limited.. We used midazolam, dextromethorphan and digoxin as in vivo phenotyping probes for CYP3A (CYP3A4/5), CYP2D6 and P-glycoprotein activities, respectively, and compared these activities between 12 healthy Caucasian volunteers and 30 treatment-naive HIV-infected patients.. Among the HIV-infected patients, the overall CYP3A activity (apparent oral midazolam clearance) was approximately 50% of the activity observed in healthy volunteers (point estimate 0.490, 90% confidence interval [CI] 0.377-0.638). The CYP2D6 activity (plasma ratio area under the curve [AUC]; AUC(dextromethorphan)/AUC(dextrorphan)) was essentially unchanged (point estimate 1.289, 90% CI 0.778-2.136). P-glycoprotein activity was slightly lower in patients (digoxin maximum concentration point estimate 1.304, 90% CI 1.034-1.644).. The overall CYP3A activity was approximately 50% lower in HIV-infected patients than in healthy volunteers. The CYP2D6 activity was highly variable, but, on average was not different between groups, whereas a marginally lower P-glycoprotein activity was observed in treatment-naive HIV-infected patients.

Topics: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Dextromethorphan; Digoxin; Down-Regulation; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Midazolam; Middle Aged; Pyrimidinones; Ritonavir; Young Adult

As human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are acquired through the same routes of contamination, the prevalence of HBV serological markers found in the HIV-infected population is approximately 7%. Liver-related mortality and morbidity is higher in HIV/HBV co-infected patients than in HBV mono-infected patients. Both viruses must be considered before a treatment decision is made. According to the European consensus conference on the treatment of chronic hepatitis B and C in HIV coinfected patients, treatment is based on whether there is an existing indication of anti- HIV therapy or not. In patients with no indication of anti-HIV therapy, drugs with dual anti-viral activity (lamivudine, entecavir, tenofovir disoproxil fumarate) should not be used due to the risk of developing HIV-resistance. Interferon or adefovir in combination with telbivudine are recommended. In patients with an indication of anti-HIV therapy, a backbone of highly active anti-retroviral therapy should include tenofovir in combination with lamivudine or emtricitabine. The same regimen is recommended in patients who develop lamivudine resistance.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Antiviral Agents; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine

Using data from the phase IIb POWER trials, darunavir boosted with low-dose ritonavir (DRV/r; 600/100 mg twice daily; bid)-based highly active antiretroviral therapy (HAART) was shown to be significantly more efficacious and cost effective than other protease inhibitor (PI)-based therapy in highly treatment-experienced, HIV-1-infected adults. Furthermore, in the phase III TITAN trial (TMC114-C214), DRV/r 600/100 mg bid-based HAART generated a superior 48-week virological response rate compared with standard-of-care lopinavir/ritonavir (LPV/r; 400/100 mg bid)-based therapy in treatment-experienced, lopinavir-naive patients, and in particular those with one or more International AIDS Society - USA (IAS-USA) primary PI resistance-associated mutations at baseline. These patients had a broader degree of previous PI use/failure (0 - ≥ 2) than the POWER patients.. To determine whether DRV/r 600/100 mg bid-based HAART is cost effective compared with LPV/r-based therapy, from the perspective of Belgian, Italian, Swedish and UK reimbursement authorities, when used in treatment-experienced patients similar to TITAN patients with one or more IAS-USA primary PI mutations at baseline.. An existing Markov model containing health states defined by CD4 cell count ranges (>500, 351-500, 201-350, 101-200, 51-100 and 0-50 cells/mm³) and an absorbing state of death was adapted for use in the above-mentioned healthcare settings. Baseline demographics, CD4 cell count distribution, antiretroviral drug usage, virological/immunological response rates and matching transition probabilities were based on data collected during the first 48 weeks of therapy in the modelled subgroup of TITAN patients and the published literature. After treatment failure, patients were assumed to switch to a follow-on combination regimen. For each health state, utility values and mortality rates were obtained from the published literature. Data from local observational studies (Belgium, Sweden and Italy) or the published literature (UK) were used to determine resource-use patterns and costs associated with each CD4 cell count range. Unit costs were derived from official local sources; a lifetime horizon was taken and discount rates were chosen based on local guidelines.. The base-case analysis predicted quality-adjusted life year (QALY) gains of 0.785 in Belgium, 0.608 in Italy, 0.584 in Sweden and 0.550 in the UK when DRV/r-based therapy was used instead of LPV/r-based treatment. The estimated base-case incremental cost-effectiveness ratios (ICERs) were €6964/QALY gained in Belgium, €9277/QALY gained in Italy, €6868 (SEK69,687)/QALY gained in Sweden and €14,778 (£12 612)/QALY gained in the UK. Assuming a threshold of €30,000/QALY gained, DRV/r-based therapy remained cost effective over most parameter ranges tested in extensive one-way sensitivity analyses. The variation of immunological response rates and the time horizon were identified as important drivers of cost effectiveness. Probabilistic sensitivity analysis revealed a greater than 70% probability of achieving an ICER below this threshold in all four healthcare settings.. From the perspective of Belgian, Italian, Swedish and UK payers, DRV/r 600/100 mg bid-based HAART is predicted to be cost effective compared with LPV/r 400/100 mg bid-based therapy, when used to manage treatment experienced, lopinavir-naive, PI-resistant, HIV-infected adults with a broad range of previous PI use/failure.

Topics: Adult; Antiretroviral Therapy, Highly Active; Belgium; CD4 Lymphocyte Count; Clinical Trials, Phase II as Topic; Cost-Benefit Analysis; Darunavir; Drug Resistance, Viral; Female; Health Care Costs; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Italy; Lopinavir; Male; Markov Chains; Multicenter Studies as Topic; Pyrimidinones; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Ritonavir; RNA, Viral; Sulfonamides; Sweden; United Kingdom; Viral Load

Researchers in clinical science and bioinformatics frequently aim to learn which of a set of candidate biomarkers is important in determining a given outcome, and to rank the contributions of the candidates accordingly. This article introduces a new approach to research questions of this type, based on targeted maximum-likelihood estimation of variable importance measures.The methodology is illustrated using an example drawn from the treatment of HIV infection. Specifically, given a list of candidate mutations in the protease enzyme of HIV, we aim to discover mutations that reduce clinical virologic response to antiretroviral regimens containing the protease inhibitor lopinavir. In the context of this data example, the article reviews the motivation for covariate adjustment in the biomarker discovery process. A standard maximum-likelihood approach to this adjustment is compared with the targeted approach introduced here. Implementation of targeted maximum-likelihood estimation in the context of biomarker discovery is discussed, and the advantages of this approach are highlighted. Results of applying targeted maximum-likelihood estimation to identify lopinavir resistance mutations are presented and compared with results based on unadjusted mutation-outcome associations as well as results of a standard maximum-likelihood approach to adjustment.The subset of mutations identified by targeted maximum likelihood as significant contributors to lopinavir resistance is found to be in better agreement with the current understanding of HIV antiretroviral resistance than the corresponding subsets identified by the other two approaches. This finding suggests that targeted estimation of variable importance represents a promising approach to biomarker discovery.

Topics: Anti-HIV Agents; Biomarkers; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; Likelihood Functions; Lopinavir; Pyrimidinones

The purpose of this study was to describe the plasma pharmacokinetics (PK) of elvucitabine at different doses when administered daily or every other day for 21 days with lopinavir-ritonavir (Kaletra) in human immunodeficiency virus (HIV)-infected subjects. Three different dosing regimens of elvucitabine were administered with lopinavir-ritonavir to 24 subjects with moderate levels of HIV. Plasma samples were collected over 35 days. Elvucitabine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK of elvucitabine was determined using both noncompartmental and compartmental analyses. Models were developed and tested using ADAPT II, while a population analysis was performed using IT2S. The PK behavior of elvucitabine was best described by a two-compartment linear model using two absorption rates and an increase in the bioavailability after day 1. The augmentation in the bioavailability after day 1 was variable, with some subjects demonstrating a major increase while others had little or no increase. Elvucitabine has a long half-life of approximately 100 h. The increase in elvucitabine bioavailability may be due to ritonavir inhibiting an efflux gut transporter with activity present in various levels between subjects. The proposed PK model may be utilized and improved further by linking the PK behavior of elvucitabine to various markers of efficacy.

Topics: Anti-HIV Agents; Area Under Curve; Biological Availability; Cohort Studies; Drug Combinations; Half-Life; HIV Infections; HIV-1; Humans; Lopinavir; Models, Statistical; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Zalcitabine

Recent studies have demonstrated that human immunodeficiency virus (HIV) protease inhibitors (PIs) exert inhibitory effects on erythrocytic stages of the human-malaria parasite Plasmodium falciparum in vitro and on erythrocytic stages of the rodent-malaria parasite Plasmodium chabaudi in vivo. Although it remains unclear how HIV PIs inhibit the parasite, the effect seen on parasite development in the erythrocytic stages is potent. The effect on preerythrocytic stages has not yet been investigated. Using the rodent parasite Plasmodium berghei, we screened a panel of HIV PIs in vitro for effects on the preerythrocytic stages. Our data indicated that the HIV PIs lopinavir and saquinavir affect preerythrocytic-stage parasite development in vitro. We then evaluated the effect of HIV PIs on preerythrocytic stages in vivo using the rodent parasite Plasmodium yoelii. We found that lopinavir/ritonavir had a dose-dependent effect on liver-stage parasite development. Given that sub-Saharan Africa is where the HIV/AIDS pandemic intersects with malaria, these results merit analysis in clinical settings.

Topics: Animals; Anopheles; Female; HIV Infections; HIV Protease Inhibitors; Lopinavir; Malaria; Mice; Plasmodium; Plasmodium berghei; Plasmodium yoelii; Pyrimidinones; Ritonavir

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome

Antiretroviral (ARV) therapies fail when behavioral or biologic factors lead to inadequate medication exposure. The currently available methods to assess ARV exposure are limited. Levels of ARVs in hair reflect plasma concentrations over weeks to months, and may provide a novel method for predicting therapeutic responses.. The Women's Interagency HIV Study, a prospective cohort of HIV-infected women, provided the basis for developing and assessing methods to measure commonly prescribed protease inhibitors (lopinavir/ritonavir and atazanavir) in small hair samples. We examined the association between hair protease inhibitor levels and initial virologic responses to therapy in multivariate logistic regression models.. ARV concentrations in hair were strongly and independently associated with treatment response for 224 women starting a new protease inhibitor-based regimen. For participants initiating lopinavir/ritonavir, the odds ratio (OR) for virologic suppression was 39.8 [95% confidence interval (CI) = 2.8-564] for those with lopinavir hair levels in the top tertile (>1.9 ng/mg) compared to the bottom (3.4 ng/mg) compared to the lowest (

Topics: Adult; Atazanavir Sulfate; CD4 Lymphocyte Count; Drug Monitoring; Epidemiologic Methods; Female; Hair; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Middle Aged; Oligopeptides; Patient Compliance; Pyridines; Pyrimidinones; Ritonavir; Specimen Handling; Treatment Outcome; Viral Load

Lopinavir and ritonavir are frequently included in highly active antiretroviral therapy (HAART) regimens for HIV infection. These drugs are substrates, and may also inhibit and/or induce the P-glycoprotein (ABCB1) transporter, encoded by the polymorphic ABCB1 gene. We investigated the impact of three common exonic ABCB1 polymorphisms on the concentrations of lopinavir and ritonavir in blood, semen and saliva of HIV-infected men under stable HAART containing ritonavir-boosted lopinavir.. Blood, semen and saliva samples were collected from 113 subjects, 30-35 minutes before the scheduled morning dose of lopinavir/ritonavir, and trough drug concentrations were measured using LC/MS/MS. The 1236C>T, 2677G>T/A and 3435C>T polymorphisms were genotyped using the single base extension-termination method and ABCB1 haplotypes were statistically inferred.. Median (25th-75th percentile) trough concentrations (ng/ml) of lopinavir in plasma, semen and saliva were 6326 (4070-8617), 286.0 (128.4-475.5) and 72.7 (38.0-119.6), respectively. The corresponding concentrations (ng/ml) for ritonavir were 261.8 (172.2-398.6), 17.7 (9.2-27.6) and 5.3 (3.2-9.0), respectively. Univariate and multivariate regression analysis revealed no influence of ABCB1 genotypes or haplotypes on the concentrations of lopinavir and ritonavir in plasma, semen and saliva of HIV-infected men under stable HAART treatment.. The ABCB1 1236C>T, 2667G>T/A and 3435C>T genotypes and haplotypes are not predictors of lopinavir and ritonavir concentrations in blood plasma, semen or saliva of HIV-infected men under stable HAART treatment. The concentrations of lopinavir and ritonavir in saliva are not reliable predictors of the concentration of these drugs in semen.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Genotype; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Pyrimidinones; Ritonavir; Saliva; Semen

The purpose of the study was to conduct a cost-effectiveness analysis and budget impact analysis comparing lopinavir with ritonavir (LPV/r) and atazanavir plus ritonavir (ATV+RTV) for antiretroviral-naïve patients with a baseline CD4+ T-cell distribution and total cholesterol (TC) profile as reported in the CASTLE study.. This decision analysis study used a previously published Markov model of HIV disease, incorporating coronary heart disease (CHD) events to compare the short- and long-term budget impacts and CHD consequences expected for the two regimens.. Patients were assumed to have a baseline CHD risk of 4.6% (based on demographic data) and it was also assumed that 50% of the population in the CASTLE study were smokers. The CHD risk differences (based on percent of patients with TC >240 mg/dL) in favor of ATV+RTV resulted in an average improvement in life expectancy of 0.031 quality-adjusted life years (QALYs) (11 days), and an incremental cost-effectiveness ratio of $1,409,734/QALY. Use of the LPV/r regimen saved $24,518 and $36,651 at 5 and 10 years, respectively, with lifetime cost savings estimated at $38,490. A sensitivity analysis using a cohort of all smokers on antihypertensive medication estimated an average improvement in life expectancy of 31 quality-adjusted days in favor of ATV+RTV, and a cost-effectiveness ratio of $520,861/QALY: a ratio that is still above the acceptable limit within the US.. The use of an LPV/r-based regimen in antiretroviral-naïve patients with a baseline CHD risk similar to patients in the CASTLE study appears to be a more cost-effective use of resources compared with an ATV+RTV-based regimen. The very small added CHD risk predicted by LPV/r treatment is more than offset by the substantial short- and long-term cost savings expected with the use of LPV/r in antiretroviral-naïve individuals with average to moderately elevated CHD risk.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Budgets; CD4 Lymphocyte Count; Coronary Disease; Cost Savings; Cost-Benefit Analysis; Decision Support Techniques; Drug Costs; Drug Therapy, Combination; HIV Infections; Humans; Life Expectancy; Lopinavir; Markov Chains; Models, Econometric; Oligopeptides; Pyridines; Pyrimidinones; Quality-Adjusted Life Years; Ritonavir; Smoking; United States

Lopinavir (LPV) exposure is reduced during the third trimester of pregnancy. We report the pharmacokinetics of standard LPV-ritonavir dosing (400/100 mg twice daily) in the immediate and early postpartum period when initiated during labor. In 16 human immunodeficiency virus-infected Thai women, the median (range) LPV area under the concentration-time curve and maximum and minimum concentrations in plasma were 99.7 (66.1 to 180.5) microg x h/ml, 11.2 (8.0 to 17.5) microg/ml, and 4.6 (1.7 to 12.5) microg/ml, respectively, at 41 (12 to 74) h after delivery. All of the women attained adequate LPV levels through 30 days postpartum. No serious adverse events were reported.

Topics: Adolescent; Adult; Area Under Curve; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Pyrimidinones; Ritonavir; Thailand; Treatment Outcome; Young Adult

Topics: Anti-HIV Agents; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

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

Markov models have been the standard framework for predicting long-term clinical and economic outcomes using the surrogate marker endpoints from clinical trials. However, they are complex, have intensive data requirements and are often difficult for decision makers to understand. Recent developments in modelling software have made it possible to use discrete-event simulation (DES) to model outcomes in HIV. Using published results from 48-week trial data as model inputs, Markov model and DES modelling approaches were compared in terms of clinical outcomes at 5 years and lifetime cost-effectiveness estimates.. A randomly selected cohort of 100 antiretroviral-naive patients with a mean baseline CD4+ T-cell count of 175 cells/mm3 treated with lopinavir/ritonavir was selected from Abbott study M97-720. Parameter estimates from this cohort were used to populate both a Markov and a DES model, and the long-term estimates for these cohorts were compared. The models were then modified using the relative risk of undetectable viral load as reported for atazanavir and lopinavir/ritonavir in the published BMS 008 study. This allowed us to compare the mean cost effectiveness of the models. The clinical outcomes included mean change in CD4+ T-cell count, and proportion of subjects with plasma HIV-1 RNA (viral load [VL]) <50 copies/mL, VL 50-400 copies/mL and VL >400 copies/mL. US wholesale acquisition costs (year 2007 values) were used in the mean cost-effectiveness analysis, and the cost and QALY data were discounted at 3%.. The results show a slight predictive advantage of the DES model for clinical outcomes. The DES model could capture direct input of CD4+ T-cell count, and proportion of subjects with plasma HIV-1 RNA VL <50 copies/mL, VL 50-400 copies/mL and VL >400 copies/mL over a 48-week period, which the Markov model could not. The DES and Markov model estimates were similar to the actual clinical trial estimates for 1-year clinical results; however, the DES model predicted more detailed outcomes and had slightly better long-term (5-year) predictive validity than the Markov model. Similar cost estimates were derived from the Markov model and the DES. Both models predict cost savings at 5 and 10 years, and over a lifetime for the lopinavir/ritonavir treatment regimen as compared with an atazanavir regimen.. The DES model predicts the course of a disease naturally, with few restrictions. This may give the model superior face validity with decision makers. Furthermore, this model automatically provides a probabilistic sensitivity analysis, which is cumbersome to perform with a Markov model. DES models allow inclusion of more variables without aggregation, which may improve model precision. The capacity of DES for additional data capture helps explain why this model consistently predicts better survival and thus greater savings than the Markov model. The DES model is better than the Markov model in isolating long-term implications of small but important differences in crucial input data.

Topics: Computer Simulation; Cost-Benefit Analysis; Drug Combinations; Economics, Pharmaceutical; Health Care Costs; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Markov Chains; Models, Econometric; Models, Statistical; Pyrimidinones; Ritonavir

In adult protease inhibitor (PI)-experienced patients, a lopinavir (LPV) phenotypic inhibitory quotient (PIQ) of >15 has been associated with a higher likelihood of viral suppression. The aims of this study were to develop a population pharmacokinetic (PK) model of LPV in children and to estimate the probability of achieving a PIQ of >15. HIV-infected, PI-experienced children receiving LPV were intensively sampled for 12 h to measure plasma LPV. The data were fitted to candidate PK models (using MM-USCPACK software), and the final model was used to simulate 1,000 children to determine the probability of achieving an LPV PIQ of >15. In 50 patients (4 to 18 years old), the median LPV plasma 12-hour-postdose concentration was 5.9 mg/liter (range, 0.03 to 16.2 mg/liter) lower than that reported in adults. After a delay, LPV was absorbed linearly into a central compartment whose size was dependent on the weight and age of the patient. Elimination was dependent on weight. The regression line of observed versus predicted LPV had an R(2) of 0.99 and a slope of 1.0. Visual predictive checks against all available measured concentrations showed good predictive ability of the model. The probability of achieving an LPV PIQ of >15 was >90% for wild-type virus but <10% for even moderately resistant virus. The currently recommended dose of LPV/ritonavir appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant human immunodeficiency virus (HIV). PI-experienced HIV-infected children will likely benefit from longitudinal, repeated LPV measurement in plasma to ensure that drug exposure is most often near the maximal end of the observed safe range.

Topics: Adolescent; Child; Child, Preschool; Female; HIV Infections; HIV Protease Inhibitors; Humans; Linear Models; Lopinavir; Male; Models, Biological; Monte Carlo Method; Probability; Prospective Studies; Pyrimidinones

HIV-associated lipoatrophy has been associated with mitochondrial dysfunction induced by nucleoside reverse transcriptase inhibitor therapy. We hypothesize that lipid profiles and markers of mitochondrial function will improve in HIV-lipoatrophic patients switched to the nucleotide analogue tenofovir.. Ten patients receiving stavudine, lamivudine and lopinavir/ritonavir (Kaletra(R)) for over 6 years were switched from stavudine to tenofovir for 48 weeks. Subcutaneous fat tissue biopsies, fasting metabolic tests, HIV RNA, CD4 cell count and whole body dual energy X-ray absorptiometry (DEXA) scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) copies/cell and mitochondrial morphology were assessed in adipose tissue biopsies, mtDNA 8-oxo-deoxyguanine in peripheral blood mononuclear cells, and glutathione (GSH) and F2-isoprostane in plasma.. There was no change in limb fat mass by DEXA; however, trunk fat mass increased by 18.9% (P = 0.01). Fasting total cholesterol decreased by 33 mg/dL (P = 0.005) and serum glucose decreased by 4 mg/dL (P = 0.039). mtDNA copies/cell increased from 386 to 1537 (P < 0.001). Transmission electron microscopy showed that mitochondrial cristae were lacking or poorly defined at study entry, whereas mitochondrial inner structures were more well defined and outer membranes were intact at 48 weeks. Oxidative damage decreased in 8/10 patients, GSH increased and F2-isoprostane decreased.. The results from this study demonstrate that systemic and peripheral fat mitochondria improve in patients switched to tenofovir following long-term exposure to stavudine, while continuing protease inhibitor therapy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenine; Adipose Tissue; Adult; Anti-HIV Agents; Body Fat Distribution; CD4 Lymphocyte Count; Deoxyguanosine; F2-Isoprostanes; Glutathione; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Lopinavir; Male; Mitochondria; Organophosphonates; Pyrimidinones; Ritonavir; Stavudine; Tenofovir; Treatment Outcome; Viral Load

In 29 antiretroviral-naive HIV-2-infected patients starting lopinavir/ritonavir-containing regimen, the median CD4 cell count change from baseline (142 cells/microl) was +71 cells/microl at week 24 and +132 cells/microl at week 96. Seventeen (59%) patients had a CD4 cell count increase of at least 50 cells/microl and undetectable HIV-2 RNA at week 24 and were considered as responders to treatment. This sustained elevation of CD4 cell count in the first 2 years of combination antiretroviral therapy shows the potential for lopinavir/ritonavir regimens as first-line therapy in HIV-2 infection.

Topics: Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-2; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Treatment Outcome

Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse events. Combined use of lopinavir/ritonavir and rifampicin is challenging as it implies balancing between suboptimal efficacy and toxicity.

Topics: Adult; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; Viral Load

Topics: Adenine; Anti-HIV Agents; Drug Approval; Drugs, Generic; HIV Infections; Humans; Lamivudine; Lopinavir; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; United States; United States Food and Drug Administration

To investigate the possible necessity of an increase in lopinavir dose during pregnancy in order to achieve the concentrations previously defined as predictive of virological efficacy.. Lopinavir pharmacokinetics were investigated by a population approach performed on 145 HIV-infected women, including 74 pregnant women. The final model was used to determine the probability of achievement of the target trough concentrations by Monte Carlo simulations.. The typical population estimates (inter-individual variability %) of apparent clearance (CL/F) and volume of distribution were 4.38 L/h (24%) and 58.4 L (59%), respectively. Pregnancy associated with a gestational age >15 weeks and delivery were found to increase lopinavir CL/F by 39% and 58%, respectively. With the standard 400 mg twice-a-day regimen, the probability of reaching the 1 mg/L target trough concentration for protease inhibitor (PI)-naive patients was 99% and 96% for non-pregnant and pregnant women, respectively. An important decrease in the probability of achieving the 5.7 mg/L target trough concentration for salvage therapy was observed for non-pregnant women (55%), this decrease being even greater for pregnant women (21%). Raising the lopinavir dose to 600 mg twice daily increased these probabilities to 87% and 53% for non-pregnant and pregnant women, respectively.. Modification of the lopinavir dose is unlikely to be required for PI-naive pregnant women; however, in pregnant women who have previously received a PI, therapeutic drug monitoring and/or empirical increasing of the dose should be considered.

Topics: Anti-HIV Agents; Chromatography, High Pressure Liquid; Female; HIV Infections; Humans; Lopinavir; Metabolic Clearance Rate; Monte Carlo Method; Plasma; Pregnancy; Pyrimidinones; Tissue Distribution

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Female; HIV Infections; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Risk Factors; Survival Rate; Viral Load; Young Adult

Drug design, antiretroviral therapy (ART), and drug resistance studies have focused almost exclusively on human immunodeficiency virus type 1 (HIV-1), resulting in limited information for patients infected with HIV-2 and for those dually infected with HIV-1 and HIV-2. In this study, 20 patients, 12 infected with HIV-2 and 8 dually infected with HIV-1 and HIV-2, all treated with zidovudine (ZDV), lamivudine (3TC), and lopinavir-ritonavir (LPV/r), were followed up longitudinally for about 3 years. For 19/20 patients, viral loads were reduced to undetectable levels; the patient whose viral load remained detectable reported adverse effects associated with LPV/r that had caused him to stop taking all the drugs. HIV-2 strains containing mutations in both the protease and the reverse transcriptase gene that may confer drug resistance were observed in two patients with viral rebound, as early as 130 days (4.3 months) after the initiation of therapy. We conclude that the combination of ZDV, 3TC, and LPV/r is able to provide efficient and durable suppression of HIV-1 and HIV-2 for as long as 3 years in HIV-2-infected and dually infected patients. However, the emergence of HIV-1 and HIV-2 strains containing drug-resistant mutations can compromise the efficacy of this highly active ART.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; Gambia; HIV Infections; HIV Protease; HIV Reverse Transcriptase; HIV-1; HIV-2; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Pyrimidinones; Ritonavir; Sequence Analysis, DNA; Treatment Outcome; Viral Load; Zidovudine

Risk factors for loss of virological response in patients receiving lopinavir/ritonavir (LPV/r) monotherapy as maintenance treatment have not been determined.. In 121 patients enrolled in the OK and OK04 clinical trials assigned to receive monotherapy with LPV/r, we attempted to identify factors associated with loss of virological suppression at 48 weeks, defined as confirmed serum HIV type-1 RNA>50 copies/ml, with missing data or changes caused by toxicity censored. Univariate and multivariate Cox proportional hazard models were used to calculate hazard ratios for the risk of loss of virological suppression.. At week 48, 15 patients experienced loss of virological suppression. Probability of loss of virological suppression was 12.7%. Less than 9 months of maintenance of virological suppression prior to monotherapy, a lower baseline haemoglobin and low adherence measured by self-reported total missed doses in the week prior to study visit were associated with loss of virological suppression in the univariate analyses. Independent factors associated with loss of virological suppression by multivariate analyses were > or =2 visits with self-reported missed doses in the week prior to the study visit, a lower baseline haemoglobin and a nadir CD4(+) T-cell count <100 cells/microl.. Suboptimal adherence, lower baseline haemoglobin and a nadir CD4(+) T-cell count <100 cells/microl were the main risk factors for losing virological suppression in patients randomized to monotherapy with LPV/r.

Topics: Adult; CD4 Lymphocyte Count; Female; Hemoglobins; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Medication Adherence; Middle Aged; Pyrimidinones; Risk Factors; Ritonavir; RNA, Viral

This study aimed to assess the long-term efficacy, safety and use of therapeutic drug monitoring (TDM) of a double-boosted protease inhibitor (PI) combination, saquinavir (SQV) and lopinavir/ritonavir (LPV/r), in Thai HIV type-1 (HIV-1)-infected children who had failed on reverse transcriptase inhibitors.. In total, 50 children from two sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4(+) T-cell count and percentage, viral load (VL; HIV-1 RNA), minimum plasma drug concentrations (C(min)) and drug safety laboratory evaluations were monitored. Virological failure was defined as having two consecutive VL measures >400 copies/ml after week 12. An intention-to-treat analysis was performed.. Baseline data were a median age of 9.3 years (interquartile range [IQR] 7.1-11.2), VL 4.8 log(10) copies/ml (IQR 4.5-5.1) and CD4(+) T-cell percentage 7% (IQR 3.0-9.5). CDC classifications were N=4%, A=14%, B=68% and C=14% of participants. Median CD4(+) T-cell percentage and CD4(+) T-cell count increase were 14% (IQR 7-19) and 558 cells/mm(3) (IQR 308-782), respectively (both P<0.001). Overall, 37 (74%) children achieved VL<50 copies/ml with significant differences between sites (90% versus 63%). Over 96 weeks, 10 patients had virological failure. Total cholesterol and high-density lipoprotein increased significantly over time, whereas the triglycerides and low-density lipoprotein did not. Approximately 50% of participants reported no change in body shape, and 33%, 43% and 39% reported fatter arms, face and abdomen, respectively. LPV and SQV C(min) were high and stable over time.. Double-boosted SQV+LPV/r was an effective and safe alternative for a second-line regimen in children. Hypercholesterolaemia needs close follow-up. On the basis of the TDM results, PI dose reduction in this population should be considered.

Topics: Adolescent; Child; Drug Administration Schedule; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypercholesterolemia; Lopinavir; Male; Pyrimidinones; Ritonavir; Saquinavir; Thailand; Treatment Outcome

The pregnancy-related adverse effects of antiretroviral therapy (ART) have yielded discordant results, which could be explained in part by the heterogeneity of ART protocols. The objective of our study was to explore whether lopinavir/ritonavir (LPV/r) exposure during pregnancy is associated with adverse outcomes.. Data on 100 consecutive HIV type-1 (HIV-1)-infected women receiving LPV/r during pregnancy and who delivered after 15 weeks gestational age (GA) between January 2003 and June 2007 in a single centre were analysed. For each HIV-1-infected woman, two uninfected women matched by age, parity and geographical origin were selected among patients delivering during the same period. Preterm delivery (PTD), vasculoplacental complications, gestational glucose intolerance and post-partum complication rates were compared between cases and controls. Factors associated with PTD and post-partum complications were assessed in HIV-1-infected women by a logistic regression model.. Rates of vasculoplacental complication and gestational glucose intolerance were not higher among HIV-1-infected women than in controls. PTD was higher in HIV-1-infected women (21%) than in controls (10%; P<0.01). In HIV-1-infected women, PTD was associated with HIV-1 RNA level > or =50 copies/ml at delivery (adjusted odds ratio 6.15, 95% confidence interval 1.83-20.63; P=0.003). No association was found between occurrence of PTD and LPV/r exposure before 14 weeks GA.. In this population of HIV-1-infected pregnant women receiving LPV/r, the risk of PTD was higher than in HIV-1-uninfected controls. As PTD risk was not associated with early exposure to LPV/r, these data support current guidelines to initiate ART earlier in pregnancy.

Topics: Adult; Cohort Studies; Drug Therapy, Combination; Female; France; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Pyrimidinones; Ritonavir

Topics: CD4 Lymphocyte Count; HIV; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Viral Load

Topics: Adult; CD4 Lymphocyte Count; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Sulfonamides; Viral Load

Lopinavir, an antiretroviral drug against human immunodeficiency virus (HIV), was administered through various routes to an HIV-infected patient with duodenal malignant lymphoma. Antiretroviral drugs were first administered through a jejunal tube, and then through bypass route between the stomach and jejunum that was 20 cm distal from the ligament of Treitz after surgery. Oral administration through the bypass achieved sufficient serum concentrations of lopinavir, whereas administration through the jejunal tube did not.

Topics: Administration, Oral; Adult; Anti-Retroviral Agents; Duodenal Neoplasms; Gastric Bypass; HIV Infections; Humans; Intestinal Absorption; Jejunum; Lopinavir; Lymphoma; Male; Pyrimidinones

Topics: Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors

Changes in lipids and lopinavir plasma concentrations were examined in 40 HIV-patients exposed to lopinavir/ritonavir 400/100 mg BID, formulated as tablets and as capsules. Triglycerides and total/HDL-cholesterol ratio were significantly lower with tablets than with capsules. Lopinavir concentrations were higher with tablets than with capsules.

Topics: Adult; Capsules; Cholesterol; Cholesterol, HDL; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Ritonavir; Tablets; Triglycerides

Virological failure of first-line antiretroviral therapy based on lopinavir boosted with ritonavir (lopinavir/r) has rarely been associated with resistance in protease. We identified a new genotypic resistance pathway in 3 patients who experienced failure of first-line lopinavir/r treatment.. Viral protease and the C-term part of Gag were sequenced. The observed mutations were introduced in a reference strain to investigate impact on protease inhibitor susceptibility and replication capacity.. A detailed longitudinal analysis demonstrated the selection of the M46I+L76V protease mutations in all 3 patients. The L76V conferred a solitary 3.5-fold increase in one-half the maximal inhibitory concentration to lopinavir but severely hampered viral replication. Addition of M46I, which did not confer any lopinavir resistance on its own, had a dual effect. It partly compensated for the loss in replication capacity and increased the one-half maximal inhibitory concentration to above the lower clinical cutoff (11-fold). Analysis of a large clinical database (>180,000 human immunodeficiency virus [HIV] sequences) demonstrated a significant association (Spearman rho, 0.93) between the increased presence of L76V in clinical samples (0.5% in 2000 to 3.4% in 2006) and lopinavir prescription over time.. The HIV protease substitution L76V, in combination with M46I, confers clinically relevant levels of lopinavir resistance and represents a novel resistance pathway to first-line lopinavir/r therapy.

Topics: Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; DNA Mutational Analysis; Drug Resistance, Viral; gag Gene Products, Human Immunodeficiency Virus; HIV; HIV Infections; HIV Protease; Humans; Longitudinal Studies; Lopinavir; Molecular Sequence Data; Mutation, Missense; Phylogeny; Pyrimidinones; Ritonavir; Sequence Analysis, DNA; Sequence Homology; Treatment Failure; Virus Replication

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Female; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Rifabutin; Ritonavir; Serum; Tuberculosis; Young Adult

On the basis of a single clinical trial in first-line treatment, the atazanavir and ritonavir combination appears to be no more effective than the fixed-dose combination of lopinavir and ritonavir. The adverse effect profiles were slightly different, but atazanavir carries a troubling risk of torsades de pointes.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Atazanavir Sulfate; Drug Approval; Drug Therapy, Combination; Europe; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Jaundice; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Torsades de Pointes; Viral Load

A 42-year-old Thai man was administered the combination drugs liponavir/ritonavir and abacavir/lamivudine. On day 3 he was admitted and his electrocardiogram demonstrated sinus arrest with junctional escape rhythm with a rate of 42 min(-1). Three days after stopping the medication he reverted to normal sinus rhythm. A 55-year-old Caucasian man was admitted to hospital with triple vessel disease. He had a permanent pacemaker inserted 4 years previously for Mobitz type II AV block detected on stress electrocardiogram, which developed 1 month after initiation of lopinavir/ritonavir. These two cases highlight the importance of considering lopinavir/ritonavir induced arrhythmias when dealing with HIV-positive individuals.

Topics: Adult; Anti-HIV Agents; Arrhythmias, Cardiac; Electrocardiography; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

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

Chronic hepatitis B affects 5-10% of HIV patients in Western countries. Lamivudine should no longer be used as a single anti-HBV agent in HIV-HBV co-infected patients, given its limited antiviral potency and high risk of selection of resistance, which further results in wide cross-resistance to all other nucleoside analogues. Recent reports of transmission of lamivudine-resistant HBV in HIV patients are of especial concern, and large surveillance studies suggest that it may occur in up to 10% of new HBV infections in Western countries. Another worrisome aspect of the selection of lamivudine-resistant HBV is the potential for selection of vaccine escape mutants. Currently, tenofovir must be viewed as the drug of choice in HIV-HBV co-infected patients in whom antiretroviral therapy is advised. Its co-formulation with emtricitabine (Truvada) is particularly convenient for treating both HIV and HBV in co-infected individuals. While pegIFN-alpha monotherapy for 1 year may be considered for HIV-HBV coinfected individuals with good spontaneous HIV control (elevated CD4 cell count, low plasma HIV-RNA), and certain HBV features (genotype A, HBeAg+, low serum HBV-DNA and elevated ALT), it is clear that very few coinfected patients fulfill these criteria. In HBeAg-negative HIV patients, adefovir may be an option but the relatively low antiviral potency of this drug discourages its wide use. Given its potential anti-HIV activity, both entecavir and telbivudine must only be prescribed with antiretroviral agents. Lack of information about potential pharmacodynamic interactions between entecavir and abacavir (both are guanosine analogues) or between telbivudine and zidovudine or stavudine (all are thymidine analogues) further discourages their concomitant use. At this time, most experts agree that early introduction of anti-HBV active HAART is the best strategy for the treatment of chronic hepatitis B in HIV patients, and Truvada must be part of the triple regimen.

Topics: Adenine; Antiviral Agents; Deoxycytidine; DNA, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine; Transaminases

Tipranavir (TPV) is a recently approved nonpeptidic protease inhibitor (PI) of HIV-1 and has been indicated for those infected with PIs-resistant HIV-1. However, in clinical practice, whether the HIV-1 from the patients with virological failure to the regimens containing first-line PIs remains susceptible to TPV/r may be questionable.. To assess the resistance levels to TPV of HIV-1 from patients with treatment failure to first-line PIs, patients who experienced virological failure were tested for genotypic resistance of HIV-1 since August 2006 in National Taiwan University Hospital. Patients were enrolled for this analysis if their failed regimens contained > 12 weeks of atazanavir or lopinavir/ritonavir (defined as ATV group and LPV/r group, respectively), but were excluded if they experienced both or other PIs. The levels of genotypic resistance to TPV/r were determined by TPV mutation score.. Till May 2008, 21 subjects in ATV group and 20 subjects in LPV/r group were enrolled. The TPV mutation scores in subjects in LPV/r group were significantly higher than these in ATV group (median, 3 vs 1, P = 0.007). 95.2% subjects in ATV group and only 45% subjects in LPV/r group had an estimated maximal virological response to TPV/r (P < 0.001). The resistance levels to TPV/r correlated with the duration of exposure to first-line PIs, whether in ATV or LPV/r group.. Cross-resistance from first-line PIs may impede the effectiveness of TPV/r-containing salvage therapy. TPV/r should be used cautiously for patients with virological failure to LPV/r especially long duration of exposure.

Topics: Adult; Atazanavir Sulfate; DNA Mutational Analysis; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Pyrones; Ritonavir; RNA, Viral; Sulfonamides; Treatment Failure; Young Adult

A French Caucasian man aged 39 with HIV infection was treated with abacavir/lamivudine and ritonavir/lopinavir. The patient (normal renal and liver functions) was diagnosed with a Burkitt lymphoma for which he was treated with cyclophosphamide day 1 to 5; doxorubicin day 1; methotrexate day 10; and vincristine day 1 and 8. At day 12, he suffered from abdominal pain associated with constipation. Paralytic ileus was diagnosed by study imaging. Ileus lasted 10 days necessitating parenteral feeding. Later on, a further cycle of chemotherapy with etoposide replacing vincristine was given and was well tolerated.. We speculate that an interaction between ritonavir/lopinavir and vincristine was responsible for this severe toxicity. Vincristine is transported by P-gp and is metabolized via CYP3A5. Ritonavir is a potent CYP3A5 isoenzyme and P-gp inhibitor. Lopinavir is also a P-gp inhibitor. Ritonavir and lopinavir might have delayed vincristine elimination. Clinicians should be aware of this possible interaction.

Topics: Abdominal Pain; Adult; Antineoplastic Agents, Phytogenic; Burkitt Lymphoma; Constipation; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Intestinal Pseudo-Obstruction; Lopinavir; Male; Pyrimidinones; Ritonavir; Vincristine

A large number of patients are switched to second-line antiretroviral therapy, especially in resource limited settings. Lopinavir/Ritonavir is the main drug used in second-line treatment regimens. We describe a patient attending an HIV treatment centre in Kampala, Uganda, who presented with bilateral non-tender pitting inflammatory edema two weeks after switching to a Lopinavir/Ritonavir-containing second-line treatment regimen. The lack of an alternate explanation led us to suspect that Lopinavir/Ritonavir was potentially responsible for the edema.

Topics: Anti-HIV Agents; Edema; HIV Infections; Humans; Leg; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Uganda

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Deoxycytidine; Drug Combinations; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; HIV-1; Humans; Long-Term Care; Lopinavir; Oligopeptides; Organophosphonates; Oxazines; Pyridines; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic

Telbivudine is a potent inhibitor of hepatitis B virus (HBV) replication without anti-HIV type-1 (HIV-1) activity demonstrated in vitro; however, very few clinical data on HIV-1-infected patients are available at present. Because it represents a therapeutic option in HIV-1-HBV-coinfected patients who do not require antiretroviral therapy, we strictly monitored three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy for chronic hepatitis B.. We performed molecular analysis of HBV DNA and of HIV-1 reverse transcriptase and protease RNA and DNA sequences in three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy.. Despite a transient and deep reduction of HIV-1 RNA, observed in two of the three patients studied, no genotypic resistance mutations were detected on both HIV-1 and HBV viruses.. Telbivudine therapy for 24 weeks showed a potent anti-HBV activity in HIV-1-positive, hepatitis B e antigen-positive patients with high HBV viraemia. No direct anti-HIV-1 activity of telbivudine was demonstrated and no genotypic resistance mutations to anti-HIV-1 drugs was found; however, the transient but deep reduction of HIV RNA, after telbivudine introduction, deserves further investigation and a strict monitoring of HIV-1 viraemia in HIV-1-infected patients on treatment with this drug.

Topics: Adult; Anti-HIV Agents; Antiviral Agents; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Lopinavir (LPV) is a potent protease inhibitor used in combination with low doses of ritonavir in the treatment of HIV-infected patients. LPV pharmacokinetics is characterized by a large interindividual variability requiring the use of therapeutic drug monitoring in different clinical situations. While the sources of this variability are still unknown, several genetic polymorphisms in biotransformation enzymes or transporter proteins involved in the metabolism and/or the distribution of LPV appear as good candidates. Therefore, the aim of the present study was to investigate the influence of selected genetic polymorphisms on LPV trough plasma concentrations ([LPV](Cmin)), LPV concentrations in peripheral blood mononuclear cells ([LPV](CC)) and the LPV accumulation ratio ([LPV](CC):[LPV](Cmin)).. A total of 53 patients receiving Kaletra((R)) (Abbott Laboratories, IL, USA) (LPV+ritonavir) were genotyped for 14 different polymorphisms in biotransformation enzymes and transporter proteins. [LPV](Cmin), [LPV](CC) and [LPV](CC):[LPV](Cmin) were compared according to the patient's genotypes.. The 4544G>A (rs8187710)polymorphism in ABCC2 was associated with a higher accumulation of LPV in peripheral blood mononuclear cells of HIV-treated patients. As already observed in previous studies, ABCB1 or CYP3A5 polymorphisms had no impact on [LPV](Cmin) and we did not detect any influence of these polymorphisms on [LPV](CC) and its accumulation in mononuclear cells. In conclusion, this pilot study suggests, for the first time, that the 4544G>A polymorphism in ABCC2 could explain a significant part of the interindividual variability in LPV pharmacokinetics. Further investigations are needed to confirm this association and to explore its real pharmacodynamic impact.

Topics: Adult; Alleles; Black People; Female; Gene Frequency; Genotype; HIV Infections; HIV Protease Inhibitors; Humans; Leukocytes, Mononuclear; Lopinavir; Male; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Pilot Projects; Polymorphism, Genetic; Pyrimidinones; White People

Lopinavir is a potent protease inhibitor (PI) used for the treatment of HIV infection. Different lopinavir target trough concentrations (C(troughs)) were previously determined according to patient treatment histories: 1 mg/l for PI-naive patients, and 4 and 5.7 mg/l for PI-experienced patients. However, the probability to achieve these target C(troughs) with the current 400 mg twice-daily or 800 mg once-daily doses of the new tablet form, and the influence of body weight on this probability are unknown.. A population pharmacokinetic model for lopinavir was developed using data from 424 HIV type-1-infected patients, and the final model was used to estimate the probability to achieve target C(troughs) via Monte Carlo simulations.. A one-compartment model adequately described the data. Mean population estimates (percentage interindividual variability) were 4.61 l/h (36%) for apparent clearance (CL/F) and 63.2 l (70%) for apparent distribution volume. Body weight was found to explain the interindividual variability of lopinavir CL/F. Probability to achieve the 1 mg/l target C(trough) was >96% for the twice-daily dose and comprised between 80% and 90% for the once-daily dose. The probability to achieve the 4 and 5.7 mg/l target C(troughs) with the twice-daily dose significantly decreased when body weight increased (from 76% to 61% and from 56% to 37% respectively, for body weights increasing from 50 to 90 kg).. These results support lopinavir therapeutic drug monitoring and the use of higher lopinavir doses for PI-pretreated patients.

Topics: Adolescent; Adult; Aged; Body Weight; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Models, Statistical; Population Surveillance; Pyrimidinones; Tablets

Although it is well known that antiretroviral drugs (ARVs) across the placenta in different extents, few data are available concerning the impact of the transplacental passage of ARVs on newborn outcome. The aim of this study is to evaluate the transplacental diffusion of ARVs and the clinical assessment of the newborn. Mother and cord lopinavir, nelfinavir, atazanavir and nevirapine plasma levels were determined by high-performance liquid chromatography. Newborn gestational age, weight, and Apgar score were recorded. Cord-to-mother ratio (C:M) was calculated to estimate the placental passage of ARVs. Preterm birth was defined as delivery at <37 weeks of gestation and low birth weight was defined as a birth weight of <2500g. Twenty-six HIV-infected pregnant women were enrolled. Nevirapine presented the highest C:M ratio (0.60 +/- 0.19), the C:M ratio of nelfinavir and atazanavir was 0.37 +/- 0.38 and 0.20 +/- 0.14, respectively. The lopinavir level in the cord was undetectable. The observed prevalence rate of neonatal low birth weight and preterm delivery was 19,2% (n = 5) and 15.4% (n = 4), respectively. A significant linear regression analysis was reported between the C:M ratio and newborn birth weight (p = 0.01). Although the role of highly active antiretroviral therapy (HAART) in preventing mother-to-child transmission is indisputable, these data indicate a pharmacological rationale to the association between birth weight and highly active antiretroviral therapy during pregnancy.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Apgar Score; Atazanavir Sulfate; Birth Weight; Female; Gestational Age; HIV Infections; Humans; Infant, Newborn; Lopinavir; Maternal-Fetal Exchange; Nelfinavir; Nevirapine; Oligopeptides; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyridines; Pyrimidinones

To report the results of therapeutic drug monitoring of lopinavir/ritonavir and itraconazole concentrations in an HIV-infected male who was treated for histoplasmosis.. A 34-year-old HIV-infected man who had recently initiated efavirenz-based antiretroviral therapy was diagnosed with disseminated Histoplasma capsulatum infection. In the hospital, lopinavir/ritonavir 400 mg/100 mg twice daily replaced efavirenz to avoid efavirenz-itraconazole interactions. After 14 days of liposomal amphotericin B therapy, itraconazole solution was initiated at 150 mg twice daily for 3 days, followed by 200 mg daily. Prior to itraconazole initiation, lopinavir trough concentration was 7.4 mg/L. The lopinavir trough concentration 15 days later, after 14 days of itraconazole, was 6.8 mg/L. An itraconazole concentration measured 2 hours post-dose on day 15 of oral therapy was 1.9 microg/mL. After 2 weeks of liposomal amphotericin, urine Histoplasma antigen was 27.23 ng/mL; after 5 months of oral itraconazole therapy, it decreased to 5.24 ng/mL. Plasma HIV RNA decreased 4.26 log(10) in 5 months to less than 40 copies/mL. The patient has demonstrated marked clinical improvement.. In this case, dosing recommendations of itraconazole 200 mg daily with lopinavir/ritonavir were appropriate. Lopinavir trough concentrations were not significantly different following the addition of itraconazole and were above the minimum target of 1 mg/L in treatment-naïve patients. The itraconazole concentration was above the recommended concentration of at least 1 microg/mL.. The dose of itraconazole was reduced to 200 mg daily as recommended by current guidelines, and therapeutic drug monitoring of both itraconazole and lopinavir concentrations confirmed that no further dosage adjustments were necessary.

Topics: Adult; Antifungal Agents; Drug Combinations; Drug Interactions; Drug Monitoring; Histoplasmosis; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Lopinavir; Male; Pyrimidinones; Ritonavir

Protease inhibitors potently suppress HIV viral load but are often associated with metabolic disturbances such as dyslipidemias and lipodystrophy. In addition to exercise, diet modification and anti-lipid therapies, one potential management strategy for HIV-positive patients with dyslipidemia is to switch any antiretrovirals that may be exacerbating the condition to more lipid-neutral drugs. The SWITCHMRK studies examined the effects of substituting lopinavir/ritonavir, a protease inhibitor known to cause dyslipidemias, with the integrase inhibitor raltegravir. Participants who switched from lopinavir/ritonavir to raltegravir experienced an improvement in cholesterol and triglycerides at 12 weeks; however, a large proportion of patients in the raltegravir arms did not maintain HIV virologic suppression at less than 50 copies/ml at week 24. Further analyses are underway to determine why more patients in the raltegravir arms experienced increased virologic failure and to determine whether switching lopinavir/ritonavir with raltegravir may be appropriate for specific subgroups of patients.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load

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

Topics: Anti-HIV Agents; Child; Child, Preschool; Drug Approval; Drug Therapy, Combination; Europe; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Tablets

Topics: Diarrhea; Drug-Related Side Effects and Adverse Reactions; Herb-Drug Interactions; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones

Topics: Adult; Cerebrospinal Fluid; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Meningoencephalitis; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

In the absence of a fully effective human immunodeficiency virus (HIV) vaccine, topical microbicides represent an important strategy for preventing the transmission of HIV through sexual intercourse, the predominant mode of HIV transmission worldwide. Although a comprehensive understanding of HIV transmission has not yet emerged in the microbicide field, it is likely the result of rapid infection of monocyte-derived cells in the vaginal mucosa by CCR5-tropic viruses. Inhibition of HIV transmission requires agents that prevent entry, fusion, reverse transcription, or other preintegrative replication events or agents which directly inactivate HIV or modulate the target cells to render them uninfectible. In vitro assays typically used to evaluate the ability of a microbicide to prevent virus transmission use epithelial or human osteosarcoma-derived cells or immune cells more relevant to the development of anti-HIV therapeutic agents and quantify virus production at short time intervals following infection. We have developed a microbicide transmission and sterilization assay (MTSA) to more sensitively and quantitatively evaluate virus transmission in cell culture in the presence of microbicidal compounds. Results obtained with the MTSA demonstrate that the inhibitory capacity of microbicides is often overestimated in short-term transmission inhibition assays, while some compounds yield equivalent inhibitory results, indicating a biological relevance for the MTSA-based evaluations to identify superior potent microbicides. The MTSA defines the concentration of the microbicide required to totally suppress the transmission of virus in cell culture and may thus help define the effective concentration of the microbicide required in a formulated microbicide product.

Topics: Anti-HIV Agents; Anti-Infective Agents; Cell Line; Cell Line, Tumor; Drug Evaluation, Preclinical; HIV; HIV Infections; Humans; Pyrimidinones

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

Topics: Adenine; Creatinine; Drug Interactions; Drug Therapy, Combination; Female; Glomerular Filtration Rate; HIV Infections; HIV Protease Inhibitors; Humans; Kidney Tubules; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; Sensitivity and Specificity; Tenofovir

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: Chemistry, Pharmaceutical; Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; Lipids; Lopinavir; Pyrimidinones; Ritonavir; Tablets

A retrospective electronic database study was conducted to determine any differences in time to virological failure and percent of virological failure among HIV-infected patients concurrently receiving H2-blockers versus patients not receiving these agents while receiving atazanavir (ATV)/ritonavir (r) or lopinavir (LPV)/r-containing antiretroviral treatment regimens. Data were culled from October 2003 (when ATV became commercially available) through February 2006. Virological failure was defined as (1) two plasma HIV-1 RNA levels >400 copies/mL after at least one HIV-1 RNA level below the level of detection or (2) failure to achieve an HIV-1 RNA <400 copies/mL within 24 weeks. Data from 267 ATV/r-treated patients who met the case definition were compared with data from 670 LPV/r-treated patients. Approximately 10% of the ATV/r group received concurrent H2-blockers when compared with 20% of the LPV/r group. Multivariate analysis showed no statistically significant differences regarding time to virological failure between or among the four subgroups, adjusting for differences in baseline characteristics (P = 0.79, log-rank test). At 750 days following treatment initiation, the proportion of patients not experiencing virological failure was 56% in the ATV/r-blocker subgroup, 48% in the ATV/r-alone subgroup, 45% in the LPV/r-alone subgroup and 42% in the LPV/r-blocker subgroup.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Databases, Factual; Drug Interactions; Drug Therapy, Combination; Female; Histamine H2 Antagonists; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Medical Audit; Multivariate Analysis; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Time Factors; Treatment Failure; Treatment Outcome; Viral Load

Topics: Clinical Trials as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome

Several genotypic interpretation scores have been proposed for the evaluation of susceptibility to lopinavir/ritonavir (LPV/r) but have not been compared using an independent data set. This study was a retrospective multicenter cohort of patients initiating LPV/r-based therapy. The virologic response (VR) was defined as a viral load of <500 copies/ml at week 24. The genotypic interpretation scores surveyed were the LPV mutation score, the ViroLogic score, the ATU score, the Stanford database score, and the International AIDS Society-USA mutation list. Of the 103 patients included in the analysis, 76% achieved VR at 24 weeks. For scores with clinical breakpoints defined (LPV mutation, ATU, ViroLogic, and Stanford), over 80% of the patients below the breakpoints achieved VR, while 50% or less above the breakpoints responded. Protease mutations at positions 10, 54, and 82 and at positions 54, 84, and 90 were associated with a lack of VR in the univariate and multivariate analyses, respectively. The area under the receiver-operator characteristic curves for the five genotypic interpretation scores studied ranged from 0.73 to 0.76. The study confirms that the currently available genotypic interpretation scores which are widely used by clinicians performed similarly well and can be effectively used to predict the virologic activity of LPV/r in treatment-experienced patients.

Topics: Adolescent; Adult; Aged; Cohort Studies; Drug Resistance, Viral; Female; Genes, Viral; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Mutation; Pyrimidinones; Retrospective Studies; Ritonavir; Young Adult

Topics: Adolescent; Child; Drug Labeling; HIV Infections; Humans; Infant; Infant, Newborn; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

The objective of this study was to evaluate the plasma drug concentrations in human immunodeficiency virus (HIV)-infected pregnant women receiving highly active antiretroviral therapy (HAART) and to define the rate of occurrence of subtherapeutic concentrations for some commonly used antiretroviral drugs during pregnancy. We evaluated HIV-infected women (n = 68) in the third trimester of pregnancy in steady-state treatment with an HAART regimen administrated on a twice a day basis, which included 2 nucleoside reverse transcriptase inhibitors plus nelfinavir (NFV), lopinavir/ritonavir (LPV/r), or nevirapine (NVP). Blood samples were collected at predose (C(trough)). The following thresholds were used to define therapeutic drug concentrations-NFV: 0.8 microg/mL; LPV: 4.0 microg/mL/1.0 microg/mL (experienced/naive); and NVP: 3.1 microg/mL. At predose sampling, adequate drug concentrations were found in a higher proportion of women receiving NFV (70.8%) and LPV (75.0%) than NVP (55.6%). Median C(trough) plasma concentrations were 1.2 microg/mL for NFV, 5.5 microg/mL for LPV, and 3.1 microg/mL for NVP. Women receiving lopinavir/ritonavir had the lowest rates of detectable (>50 copies/mL) HIV RNA (15.4%) compared with rates of 22.2% and 41.7% among women receiving NVP and NFV, respectively. Genotypic resistance was detected in 50% of women with detectable HIV RNA for whom samples were available for testing. Subtherapeutic predose concentrations among HIV-infected pregnant women were more commonly found with NVP than with protease inhibitors. LPV administration was associated with the best viral load suppression.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Nelfinavir; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Viral Load; Young Adult

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

The combination of atazanavir (ATV) and lopinavir/ritonavir (LPV/RTV) with nucleoside reverse transcriptase inhibitors (NRTI) has been used as a salvage regimen for human immunodeficiency virus (HIV)-positive patients. In this paper, we discuss two cases of HIV-positive patients who had long histories of virological failure following a heavy treatment of antiretroviral drugs, but then achieved virological suppression with double-boosted protease inhibitor (PI) regimens. In patients with multiple genotypic resistance to PIs and NRTIs, virological suppression can be achieved with a combination of ATV plus LPV/RTV with an NRTI backbone. The two cases in this report suggest that a combination of ATV plus LPV/RTV could be a useful salvage regimen for the subset of HIV-positive patients with limited treatment options.

Topics: Adult; Atazanavir Sulfate; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oligopeptides; Pyridines; Pyrimidinones; 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

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Ethnicity; Female; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Randomized Controlled Trials as Topic; Retrospective Studies; Sex Factors

Mutations on HIV protease lead to resistance to protease inhibitors. However, resistance development may be different according to primary, secondary or polymorphic mutations. The present study was designed to assess the impact of natural protease mutations on the effectiveness of a first-line antiretroviral therapy (ART), and secondarily, their effect on the initial viral load (VL). The study was conducted in 175 HIV-1-infected patients, who initiated a first-line lopinavir/r-containing ART regimen and who had an available genotype resistance testing before initiating therapy. We assessed the association between mutations (prevalence > or = 10%) and the initial VL. We assessed the association between mutations and ART effectiveness using two surrogate markers: the slope of VL decrease at 1 month and the time to VL undetectability. For the 175 patients, the initial median VL was 4.94 log(10) copies/ml [interquartile range: 4.44-5.47] and the initial median CD4 lymphocyte count, 219/microl [129-296]. Eighteen mutations had a prevalence > or = 10%. At 1 month, the median VL decrease was 2.35 log(10) copies/ml [1.76-2.82]. The median time to VL undetectability was 128 days [91-196]. No mutation was associated significantly with the initial VL, the slope of VL decrease at 1 month or the time to VL undetectability. This study of antiretroviral-naive patients showed that protease polymorphisms had no impact on the effectiveness of a lopinavir/r-containing ART regimen. However, polymorphisms may affect ART effectiveness differently in other populations, such as ART-experienced patients and/or patients treated with protease inhibitors other than the one used here.

Topics: Adult; Amino Acid Substitution; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV Protease; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation, Missense; Polymorphism, Genetic; Pyrimidinones; Treatment Outcome; Viral Load

Few data exist on the efficacy of the limited regimens for children with HIV, which are available in sub-Saharan Africa.. Retrospective cohort study to evaluate the clinical and laboratory outcomes of 391 children who received protease inhibitor (PI) or non-nucleoside reverse transcription inhibitor (nNRTI)-containing highly active antiretroviral regimens (HAART) from a Cape Town clinic. Endpoints included CD4% and count, viral loads, weight-for-age Z score (WAZ), survival, drug changes, and loss to follow-up over 24 months. A generalized estimating equation population-averaged model was used to identify associations with virological suppression, and a log-rank test explored associations with survival.. Overall, this cohort achieved a sustained doubling of median CD4% from baseline, steady increase of median WAZ, and survival of 91%, despite only 49% virologic suppression at 24 months. However, when analyzed according to regimen, PI-containing regimens had better virologic suppression at all time points. There were no differences in immunologic and growth endpoints between regimens or in survival. In a multivariate model predicting virologic suppression at any duration up to 24 months and adjusting for baseline CD4%, regimen, age, baseline WAZ, duration of HAART, and year of HAART initiation, nNRTI-based regimens (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.19-0.77) and length of time on HAART were inversely associated with virologic suppression. Age (OR: 1.23 per year; 95% CI: 1.09-1.39) was positively associated with virologic suppression.. The benefits of HAART are substantial in this setting, although PI regimens achieved greater virologic suppression than nNRTIs. Further exploration of regimens and dosing of antiretrovirals for children in these settings is needed.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Cohort Studies; Didanosine; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lamivudine; Lopinavir; Male; Multivariate Analysis; Pyrimidinones; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; South Africa; Stavudine; Treatment Outcome; Zidovudine

To assess the correlation between HIV-1 RNA load in blood and semen by antiretroviral therapy status and the relative penetration of antiretroviral drugs in seminal plasma. We performed a cross-sectional cohort study of 119 HIV-1 subjects divided into three groups according to treatment status. Blood and semen were collected concurrently. Seminal viral load determined by NucliSens HIV-1 QT PCR (BioMerieux). Viral suppression over time was assessed in a second semen sample collected from 10 treated subjects. Antiretroviral plasma concentrations were measured by high performance liquid chromatography and recovery experiments were performed on semen samples to validate quantitation in this matrix. All subjects taking non nucleoside reverse transcriptase inhibitors (n = 36, mean treatment 33 months +/- 14) or protease inhibitors (n = 45, mean treatment 31 months +/- 25) had blood viral load < 50 copies/mL and seminal viral load < 250 copies/mL. In untreated subjects (n = 38), blood and semen viral loads were positively correlated (Spearman's rho = 0.489, p = 0.002). Blood and semen nevirapine concentrations were positively correlated (r(2) = 0.795, p = 0.005) and therapeutic concentrations achieved in both compartments. Lopinavir and atazanavir also penetrated semen but efavirenz did not. We find that there is compartmentalisation of HIV-1 within the male genital tract and propose that new infections may originate from untreated men and that suppressive antiretroviral regimens may reduce the risk of sexual transmission.

Topics: Adult; Antiviral Agents; Atazanavir Sulfate; Blood; Chromatography, High Pressure Liquid; Cohort Studies; Cross-Sectional Studies; HIV Infections; HIV-1; Humans; Longitudinal Studies; Lopinavir; Male; Middle Aged; Nevirapine; Oligopeptides; Plasma; Pyridines; Pyrimidinones; RNA, Viral; Semen; Statistics as Topic; Viral Load

Topics: Administration, Oral; Anti-HIV Agents; HIV Infections; Humans; Lopinavir; Pyrimidinones; Quality of Life; Ritonavir

Topics: Adolescent; Animals; Anti-HIV Agents; Drug Combinations; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Macaca mulatta; Pyrimidinones; Sex Offenses; Zidovudine

Topics: Darunavir; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir; Sulfonamides; Virus Replication

We report the first case of a human immunodeficiency virus type 1 (HIV-1)-infected individual receiving combination antiretroviral therapy, which included ritonavir, who developed Cushing syndrome with profound complications after epidural triamcinolone injections. This case highlights the potential of ritonavir interactions even with local injections of a corticosteroid.

Topics: Adult; Cushing Syndrome; Drug Interactions; HIV Infections; HIV-1; Humans; Iatrogenic Disease; Lopinavir; Male; Pyrimidinones; Ritonavir; Triamcinolone

Subacute central nervous system infection must be considered in any infant presenting with progressive encephalopathy. We present the case of an 18-month-old child with normal neuromotor development until the age of 14 months admitted for spastic hypertonia of the legs and arms associated with axial hypotonia. The mother reported that she recently had been found to be HIV-seropositive. HIV antibodies were negative during the first trimester of pregnancy. On the child's blood sample, the HIV test was positive associated with a major decrease in CD4 cell count. Viral load (ARN-PCR) was 720 copies par millilitre. On brain MRI, hypersignals were found in the white matter. HIV related encephalopathy caused by maternal fetal transmission was diagnosed. After 2 months of antiretroviral treatment (azidothymidine, lamivudine, and boosted lopinavir), the child's neurological condition improved. HIV infection must be suspected in all infants with progressive encephalopathy. The HIV test in pregnant women must be proposed at the beginning of pregnancy and repeated during the last trimester.

Topics: AIDS Dementia Complex; Anti-HIV Agents; Anti-Infective Agents; Drug Therapy, Combination; Female; Fluconazole; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; HIV-1; Humans; Infant; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Polymerase Chain Reaction; Pyrimidinones; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Clinical Trials as Topic; Darunavir; Drug Resistance, Multiple; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Sulfonamides; Viral Load

Topics: Adenine; Anti-HIV Agents; Atazanavir Sulfate; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Lopinavir; Multicenter Studies as Topic; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome; Viral Load

Topics: Adult; Biomedical Research; CD4 Lymphocyte Count; Clinical Medicine; Drug Evaluation; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load

Recently, a new tablet formulation of the widely used HIV protease inhibitor lopinavir/ritonavir was licensed. Here, we present a pilot study of the pharmacokinetics of the new adult tablet formulation taken once daily in children.. Lopinavir pharmacokinetics of the new adult tablet formulation were evaluated in 15 HIV type-1-infected children between 4 and 15 years of age. A target dose of 460/115 mg/m2 was administered once daily. Plasma concentrations of lopinavir over the course of 24 h were determined with a validated HPLC method.. The median lopinavir dose was 498 mg/m2 (range 424-548). The mean +/- SD for lopinavir area under the 24 h curve was 217.9 +/- 44.9 mg/l x h, the maximum concentration was 14.8 +/- 2.4 mg/l and the concentration 24 h after intake was 3.1 +/- 2.6 mg/l. The half-life of lopinavir was 5.8 +/- 4.5 h and the median time to maximum concentration was 5.8 h (range 1.8-12.2). Overall, the tablet formulation resulted in greater exposure to lopinavir with less variability compared with the soft-gel capsule formulation. All children treated with the new adult tablet formulation had undetectable viral loads (< 50 copies/ml) during 24 weeks follow-up.. The tablet formulation could probably result in improved lopinavir dosing and increases the feasibility of once-daily lopinavir/ritonavir-based regimens in children.

Topics: Adolescent; Anti-HIV Agents; Area Under Curve; Child; Child, Preschool; Drug Administration Schedule; Female; Half-Life; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Tablets

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Viral Load

The flexibilities in the TRIPS Agreement (Trade Related Aspects of Intellectual Property) have been very useful in lowering the prices of antiretrovirals (ARVs) in Brazil. In this article, based on several presentations made at the conference, Marcela Fogaça Vieira et al describe recent developments in Brazil, including the granting of a compulsory licence for efavirenz.

Topics: Brazil; Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

Topics: Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

The coadministration of protease inhibitors with anticancer drugs in the management of human immunodeficiency virus-related malignancies can cause potential drug-drug interactions. The effect of lopinavir/ritonavir (LPV/RTV) on the pharmacokinetics of irinotecan (CPT11) has been investigated in seven patients with Kaposi's sarcoma. Coadministration of LPV/RTV reduces the clearance of CPT11 by 47% (11.3+/-3.5 vs 21.3+/-6.3 l/h/m(2), P=0.0008). This effect was associated with an 81% reduction (P=0.02) of the AUC (area under the curve) of the oxidized metabolite APC (7-ethyl-10-[4-N-(5-aminopentanoic-acid)-1-piperidino]-carbonyloxycamptothecin). The LPV/RTV treatment also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio (5.9+/-1.6 vs 9.2+/-2.6, P=0.002) consistent with UGT1A1 inhibition by LPV/RTV. This dual effect resulted in increased availability of CPT11 for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase (P=0.0001) in SN38 AUC in the presence of LPV/RTV. The clinical consequences of these substantial pharmacokinetic changes should be investigated.

Topics: Adenine; Adult; Aged; Anti-HIV Agents; Antineoplastic Agents, Phytogenic; Antiretroviral Therapy, Highly Active; Area Under Curve; Camptothecin; Drug Therapy, Combination; HIV Infections; Humans; Irinotecan; Lamivudine; Lopinavir; Male; Middle Aged; Organophosphonates; Pyrimidinones; Ritonavir; Sarcoma, Kaposi; Tenofovir; White People

It is not known whether antiretroviral therapy (ART) including lopinavir/r has a different effect on the lipid metabolism in HIV patients co-infected with HCV. This study investigated changes in lipid levels, comparing patients with HIV infection alone and those with HCV too, in the lopinavir/r cohort of the SCOLTA project.. We analyzed the data for the lopinavir/r nationwide cohort from 25 Italian infectious disease departments, which comprises 743 HIV-infected patients followed prospectively, comparing subjects with HIV-HCV co-infection and those with single-infection.. At enrolment, co-infected patients had significantly lower mean cholesterol than HCV negative cases (162+/-43mg/dL vs. 185+/-52mg/dL, p=0.0009). Total and non-HDL cholesterol and triglycerides rose significantly from baseline in HIV single-infection patients, but not in those with co-infection. The patients with dual HIV-HCV infection, treated with an ART regimen including lopinavir/r, have only limited increases in total and non-HDL cholesterol and triglycerides.. Changes in serum lipids in co-infected patients differed significantly from those in patients without HCV. It remains to be seen whether this is associated with a lower risk of progression of atherosclerotic disease.

Topics: Adult; Anti-HIV Agents; Cholesterol; Cohort Studies; Drug Combinations; Female; Follow-Up Studies; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; Triglycerides

Immune recovery after prolonged highly active antiretroviral therapy (HAART) with lopinavir/ritonavir has been reported in adults but not in children. Our study aimed at evaluating the long-term use of lopinavir/ritonavir among children in a clinical setting.. We carried out a retrospective study on 69 protease inhibitor (PI)-experienced vertically HIV-infected children on HAART containing lopinavir/ritonavir. We analysed the changes in percentage CD4+ cell count (%CD4+) and viral load (VL) and identified prognostic factors to achieve CD4+ >25% and undetectable VL (uVL) ( 100,000 copies/mL. We found that %CD4+ at baseline had a strong positive association with achieving CD4+ >25% at 6, 12, 18, 24, 36 and 48 months of follow-up. We also found that length of PI use had a negative association with reaching CD4+ >25% at 24 and 48 months and achieving uVL at 12 and 24 months. VL at baseline had a negative association with achieving uVL at 18 and 24 months.. Our study demonstrates ongoing immune recovery among children on HAART with lopinavir/ritonavir after 4 years of follow-up. Lopinavir/ritonavir, when given as part of a salvage regimen, is safe and well tolerated in HIV-infected children.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; Time Factors; Treatment Outcome

The aim of the study was to determine the factors that may contribute to decreases in bone mineral density (BMD) in patients with AIDS.. This was a prospective, non-randomized study. Dual X-ray absorptiometry (DXA) was used to determine the BMD of the lumbar spine, femoral neck and distal radius in treatment-naïve HIV-infected male patients with AIDS before and after 1 year of treatment with zidovudine (ZDV)/lamivudine (3TC) plus abacavir (ABC) or lopinavir/ritonavir (LPV/r).. Basal DXA was performed in 50 patients with CD4 counts <200 cells/microL and/or any AIDS-defining condition. Thirty-two patients completed 1 year with full adherence (17 on ABC and 15 on LPV/r) and a second DXA was then performed. At baseline, 19% had osteopenia at the lumbar spine and 19% at the femoral neck. Low body weight was related to low BMD. After 48 weeks, BMD loss was significant at the three locations. The percentage of BMD loss at the femoral neck tended to be greater in the lopinavir group (5.3 vs. 3.2%, P=0.058). The differences became significant at the lumbar spine (5.7 vs. 2.7%, P=0.044). In the multivariate analysis, the treatment with LPV/r remained associated with bone loss at the lumbar spine.. Osteopenia is frequent in treatment-naïve HIV-infected men with AIDS. Bone loss is higher with LPV/r-based regimens compared with triple nucleoside reverse transcriptase inhibitors.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bone Density; Case-Control Studies; Dideoxynucleosides; Femur Neck; HIV Infections; Humans; Lamivudine; Lopinavir; Lumbar Vertebrae; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; Zidovudine

Besides I47A, mutation L76V at the HIV protease gene has recently been proposed to cause lopinavir resistance. This change was present in 37 (2.7%) out of 1376 patients failing protease inhibitor containing regimens. Although 26 (70%) were on lopinavir, most had previously failed other protease inhibitors and carried multiple protease inhibitor resistance mutations. Therefore, L76V does not appear to be a primary lopinavir resistance change when the drug is used in combination therapy.

Topics: Antiretroviral Therapy, Highly Active; Codon; Drug Resistance, Multiple, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Point Mutation; Pyrimidinones; Spain

Rifampicin dramatically reduces plasma lopinavir concentrations (coformulated with ritonavir in a 4:1 ratio). A study in healthy adult volunteers showed that this reduction could be ameliorated if additional ritonavir is given. We evaluated the effect of additional ritonavir on plasma lopinavir concentrations in HIV-infected children receiving rifampicin-based treatment for tuberculosis.. We measured plasma lopinavir concentrations in 2 parallel groups receiving combination antiretroviral therapy that included lopinavir-ritonavir, with and without rifampicin-based antitubercular treatment. Additional ritonavir was given (lopinavir/ritonavir ratio of 1:1) during antitubercular treatment. Lopinavir concentrations were determined using liquid chromatography-tandem mass spectrometry.. There were 15 children (aged 7 months to 3.9 years) in each group. Lopinavir pharmacokinetic measures (median [interquartile range]) for children with and without rifampicin, respectively, were maximum concentration (Cmax) of 10.5 [7.1 to 14.3] versus 14.2 [11.9 to 23.5] mg/L (P = 0.018), area under the curve from 0 to 12 hours (AUC0-12) of 80.9 [50.9 to 121.7] versus 117.8 [80.4 to 176.1] mg/h/L (P = 0.036), and trough concentration (Cmin) of 3.94 [2.26 to 7.66] versus 4.64 [2.32 to 10.40] mg/L (P = 0.468). Thirteen of 15 children receiving antitubercular treatment (87%) had a lopinavir Cmin greater than the recommended minimum therapeutic concentration (1 mg/L).. The effect of rifampicin-based antitubercular treatment on lopinavir concentrations was attenuated by adding ritonavir to rifampicin. Although the median Cmax and AUC0-12 were lowered by 26% and 31%. respectively, the Cmin was greater than the minimum recommended concentration in most children.

Topics: Antibiotics, Antitubercular; Child, Preschool; Drug Interactions; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; Tuberculosis

HIV protease inhibitors (HIV-PIs) are key components of highly active antiretroviral therapy, but they have been associated with adverse side effects, including partial lipodystrophy and metabolic syndrome. We recently demonstrated that a commonly used HIV-PI, lopinavir, inhibits ZMPSTE24, thereby blocking lamin A biogenesis and leading to an accumulation of prelamin A. ZMPSTE24 deficiency in humans causes an accumulation of prelamin A and leads to lipodystrophy and other disease phenotypes. Thus, an accumulation of prelamin A in the setting of HIV-PIs represents a plausible mechanism for some drug side effects. Here we show, with metabolic labeling studies, that lopinavir leads to the accumulation of the farnesylated form of prelamin A. We also tested whether a new and chemically distinct HIV-PI, darunavir, inhibits ZMPSTE24. We found that darunavir does not inhibit the biochemical activity of ZMPSTE24, nor does it lead to an accumulation of farnesyl-prelamin A in cells. This property of darunavir is potentially attractive. However, all HIV-PIs, including darunavir, are generally administered with ritonavir, an HIV-PI that is used to block the metabolism of other HIV-PIs. Ritonavir, like lopinavir, inhibits ZMPSTE24 and leads to an accumulation of prelamin A.

Topics: Animals; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Lamin Type A; Lipodystrophy; Lopinavir; Membrane Proteins; Metabolic Syndrome; Metalloendopeptidases; Mice; Mice, Knockout; Nuclear Proteins; Protein Precursors; Protein Processing, Post-Translational; Pyrimidinones; Ritonavir; Sulfonamides

Topics: Adult; Anti-HIV Agents; Area Under Curve; Drug Therapy, Combination; Female; Half-Life; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Japan; Lopinavir; Male; Middle Aged; Pyrimidinones; Reverse Transcriptase Inhibitors

CYP3A5 genotype has no impact on the trough plasma concentrations of lopinavir and ritonavir in human immunodeficiency virus (HIV)-infected individuals on stable highly active antiretroviral therapy (HAART). This is ascribed to a drug interaction, such that ritonavir by inhibiting CYP3A activity, may occlude the pharmacokinetic consequences of functional polymorphisms in the CYP3A5 gene. In the clinical setting, where lopinavir and ritonavir are always combined, CYP3A5 genotype is of no consequence on the trough plasma concentrations of these drugs.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brazil; Cytochrome P-450 CYP3A; Drug Therapy, Combination; Genotype; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Polymorphism, Genetic; Pyrimidinones; Ritonavir

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Patient Compliance; Pyrimidinones; Ritonavir; Viral Load

Topics: Canada; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Mutation; Pyrimidinones; Ritonavir

The aim of the study was to evaluate the possibility of using lopinavir/ritonavir (LPV/RTV) alone as maintenance therapy in HIV-infected individuals with virological suppression.. This was a single-armed single-centre pilot trial.. Asymptomatic HIV-infected patients on highly active antiretroviral therapy (HAART) including LPV/RTV, and with plasma HIV RNA <40 copies/mL for at least 6 months, were enrolled in the study, during which they continued with LPV/RTV alone. The intention was to recruit 25 patients to be followed for 2 years. Viral failure was defined as two consecutive HIV RNA measurements >40 copies/mL. Nadir and baseline CD4 cell counts, highest ever HIV RNA load, time with undetectable viraemia before monotherapy, number of previous antiretroviral (ARV) regimens, and gene polymorphism at CYP3A4 and CYP3A5 were evaluated.. All patients (27) completed the study. Their median age was 43 years, and 66% were men. Ten patients (37%) failed to maintain virological suppression (the median time to HIV rebound was 10.5 months, with a range of 4-23 months). One patient developed full resistance to LPV and another developed neurocognitive impairment while on LPV/RTV which improved after HAART reintroduction. There were no differences between failures and nonfailures according to the analysed parameters. Patients with viral failure were successfully resuppressed.. LPV/RTV maintenance therapy was associated with 37% failure, a higher than expected failure rate. In order to ensure that unnecessary risks are not being taken in patients on LPV/RTV, this finding should be further evaluated in large randomized trials for longer periods of follow-up.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Brazil; CD4 Lymphocyte Count; Cytochrome P-450 CYP3A; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pilot Projects; Polymorphism, Genetic; Pyrimidinones; Ritonavir; RNA, Viral; Viral Load; Viremia

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

Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure.. Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded.. In group A (n=10), mean +/- standard deviation atazanavir C(min) was 390 +/- 460 ng/mL, C(max) 3051 +/- 1996 ng/mL and AUC(24) 29 913 +/- 17 686 ng/mL/h. In group B (n=9), lopinavir C(min) was 7562 +/- 4292 ng/mL, C(max) 12 944 +/- 4838 ng/mL and AUC(0-12) 122 313 +/- 38 225 ng/mL/h. In group C (n=7), atazanavir C(min) was 876 +/- 460 ng/mL (P=0.039 vs. group A), C(max) 3421 +/- 3399 ng/mL and AUC(0-24) 65 055 +/- 49 843 ng/mL/h (two-sided P>0.05 for each comparison with group A), lopinavir C(min) was 7471 +/- 3745 ng/mL, C(max) 10 143 +/- 5217 ng/mL and AUC(0-12) 104 501 +/- 43 565 ng/mL/h (P>0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir C(min) and with lower lopinavir C(max). Atazanavir C(min) showed a correlation with total bilirubin levels.. Combination with lopinavir/ritonavir provides higher atazanavir C(min) than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure.

Topics: Adult; Aged; Atazanavir Sulfate; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pilot Projects; Prospective Studies; Pyridines; Pyrimidinones; Ritonavir

To evaluate the long-term safety and effectiveness of ritonavir, nelfinavir, and lopinavir/ritonavir in antiretroviral-experienced, initially protease inhibitor (PI)-naive, human immunodeficiency virus (HIV)-1-infected children.. HIV-1-infected children enrolled in the Swiss Mother and Child HIV Cohort Study were eligible for this observational cohort study if they received at least 1 PI of interest between March 1996 and October 2003: ritonavir, nelfinavir, or lopinavir/ritonavir. Data regarding demographics, clinical disease and antiretroviral treatment history, HIV-1 RNA copies/mL, CD4 T-cell counts [absolute (cells/microL) and percentages (%)], adverse events, clinical laboratory values, reasons for discontinuation of PIs, and concomitant medications were extracted from the database for PI-naive (first-line) and PI-experienced (second- or higher-line) PI use.. The total duration of ritonavir, nelfinavir, and lopinavir/ritonavir use for 133 HIV-1-infected children was 163.8, 235.0, and 46.1 patient-years, respectively. In an on-treatment analysis, first-line therapy with any of the PIs significantly reduced HIV-1 concentrations and increased CD4 T-cell counts and percentages from baseline throughout the 288-week study (P

Topics: Adolescent; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Infant, Newborn; Longitudinal Studies; Lopinavir; Male; Nelfinavir; Pregnancy; Pyrimidinones; Ritonavir; Switzerland; Treatment Outcome; Viral Load; Withholding Treatment

There is a lack of standardized programs for HIV counselling and post-exposure prophylaxis (PEP) in the setting of sexual assault.. We conducted an 18-month prospective cohort study assessing universal HIV counselling for all sexual assault survivors presenting to 18 Ontario Sexual Assault Treatment Centres. HIV PEP was universally offered to those at risk of HIV infection (high risk or unknown risk) presenting < or =72 h after the assault, using Combivir one pill and Kaletra three capsules twice a day for 28 days. Those who accepted HIV PEP were monitored via a schedule of frequent follow ups. The primary outcomes were acceptance and completion rates, and their predictors were determined using multivariable logistic regression. Adverse events (AE) were categorized using a standardized toxicity grading system.. Of the 900 evaluable participants eligible for PEP, 798 (69 at high risk and 729 at unknown risk) were offered treatment. Acceptance rates were 66.7% (n=46) and 41.3% (n=301) for participants at high risk and unknown risk, respectively. Participants at high risk were 2.2 times more likely to accept PEP than those at unknown risk (adjusted odds ratio 2.2; 95% confidence interval 1.2-4.0; P=0.01). Overall, 23.9% high-risk (n=11) and 33.2% unknown-risk participants (n=100) completed PEP (P=0.20). Predictors of acceptance and completion included assault by a stranger and participant anxiety. AEs were common, with 77.1% of participants reporting grade 2-4 symptoms.. A province-wide standardized program of universal HIV counselling and offering of PEP to sexual assault survivors with frequent follow up was successfully implemented and feasible.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Child; Child, Preschool; Cohort Studies; Drug Combinations; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Ontario; Pyrimidinones; Rape; Risk Factors; Zidovudine

The human immunodeficiency virus protease inhibitor combination of atazanavir (ATV)-lopinavir-ritonavir was reported to exhibit a mutual pharmacoenhancement of plasma lopinavir and ATV concentrations which may be beneficial for salvage patients. We identified 17 patients in our pharmacokinetic database taking this combination and found conflicting results. Plasma concentrations of both ATV and lopinavir were modestly, although not significantly, decreased when the drugs were coadministered. Therefore, patients should be selected carefully for this regimen and frequent clinical and therapeutic drug monitoring is strongly advised.

Topics: Atazanavir Sulfate; Drug Monitoring; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Salvage Therapy; Treatment Outcome

Topics: Child; Child, Preschool; Developing Countries; Dose-Response Relationship, Drug; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Uganda; World Health Organization

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

Topics: Adult; Antiretroviral Therapy, Highly Active; HIV Infections; HIV Protease Inhibitors; Humans; Hyponatremia; Lopinavir; Male; Pyrimidinones; Ritonavir

Topics: Acute Kidney Injury; Anti-HIV Agents; Drug Interactions; HIV Infections; Humans; Hypertension; Lopinavir; Male; Middle Aged; Nifedipine; Pyrimidinones; Ritonavir

The choice of initial highly active antiretroviral therapy (HAART) should take into account the need to balance efficacy, adverse event risk, resistance concerns for the treatment of HIV and treatment costs. Increased risk of coronary heart disease (CHD) may be of special concern in the selection of HAART therapy, because differences in potential CHD risk have been reported for different regimens. This study aimed to estimate the long-term combined effects of HIV disease and antiretroviral (ARV)-related risk for CHD on quality-adjusted survival and healthcare costs for ARV-naive patients.. A previously validated Markov model was updated and supplemented with the Framingham CHD risk equation. In the model, the average patient was male, aged 37 years and had a baseline 10-year CHD risk of 4.6%. Patients started with either lopinavir/ritonavir or unboosted atazanavir as the first protease inhibitor (PI). Clinical trial data were used to estimate the differences between these two therapies. The daily PI costs were $US18.52 for lopinavir/ritonavir and $US22.08 for atazanavir. Other costs were estimated from Medicaid billing databases and average wholesale drug price reports. All model costs were reported as the 2004 present value in US currency. The model's time horizon reflected a patient's lifetime, and the perspective of the analysis was that of the healthcare system and did not include indirect costs in the model cost estimates. Various CHD risk levels were tested in the sensitivity analysis.. In the base case, the model predicted a median duration of initial PI regimen of 5.6 years for lopinavir/ritonavir and 3.8 years for atazanavir. Over 10 years, patients who started on atazanavir had 30 additional AIDS events per 100 patients. Only 0.7 additional CHD events per 100 patients occurred for those who started on lopinavir/ritonavir. The model estimated 10-year total healthcare cost savings of $US12,543 per patient in the lopinavir/ritonavir group. The lifetime incremental cost effectiveness of lopinavir/ritonavir versus atazanavir was $US6797 per quality-adjusted life-year gained.. Lopinavir/ritonavir is a highly cost-effective regimen relative to atazanavir for the treatment of HIV. The effect of lopinavir/ritonavir on long-term CHD risk was minimal compared with the increased risk of AIDS/death projected for a less efficacious first PI regimen. The cost of lipid-lowering drugs and treatment of CHD for patients taking the lopinavir/ritonavir regimen was only 1.2% of the cost of AIDS care per person, which was too small to have a significant effect on the overall cost savings with lopinavir/ritonavir therapy. Thus, a decision to forgo potency and durability in an ARV regimen for an ARV-naive patient in favour of a less potent regimen with an improved lipid profile may prove to be costly over time, in terms of both budget impact and life expectancy.

Topics: Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Coronary Disease; Cost-Benefit Analysis; Fees, Pharmaceutical; Health Care Costs; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Markov Chains; Models, Statistical; Oligopeptides; Pyridines; Pyrimidinones; Quality-Adjusted Life Years; Ritonavir; Survival Analysis; Survival Rate; Time Factors

To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment.. Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach.. Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively).. Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Topics: Area Under Curve; Chromatography, High Pressure Liquid; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Liver; Liver Function Tests; Lopinavir; Pyrimidinones; Ritonavir

Different approaches using genotypic, pharmacokinetic parameters or combination of both have been recently developed to monitor antiretroviral treatment in HIV-1-infected individuals. Their uses in clinical practice may improve the benefit of protease inhibitor-based salvage therapy while reducing treatment toxicity and emergence of viral resistance.. To assess the prediction of genotypic inhibitory quotient (GIQ) using different genotypic drug resistance interpretation's algorithms and lopinavir plasma concentration in PI-experienced patients treated by lopinavir/ritonavir (LPV/r). Genotypic susceptibility score (GSS) was also evaluated.. Forty-seven HIV-1 PI-experienced, but LPV naïve patients were included in a retrospective cohort study. Plasma HIV-1 viral load (VL), CD4 cell count and LPV plasma concentrations were assessed at weeks (W) 12 and 24. Interpretation of baseline resistance genotype was achieved according to four different algorithms and GSS calculated using two expert systems. GIQ was defined as the ratio of LPV concentration to the number of LPV resistance mutations at day 0 (D0) and patients classified by units of GIQ. The end point of the study was the virological response expressed in HIV VL median decrease from D0 to W24.. The overall median VL decrease from D0 to W24 was -2.42 log(10)copies/mL and 60% of patients had VL below 400 copies/mL. The LPV mutation score was predictive of response for all algorithms whereas plasma concentrations of LPV were not. Mean VL decrease was greater for higher GIQ classes and difference reached statistical significance at W24. When considering virological response at W24, GSS calculated with ANRS and Stanford system were good predictor scores as areas under the receiver operating characteristics (ROC) curves were 0.76 for both.. GIQ was found to be a useful drug-monitoring tool which could be helpful in targeting LPV concentrations in order to achieve long-term undetectable viral load, particularly in genotypic resistant patients.

Topics: Adult; Aged; Algorithms; Cohort Studies; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Ritonavir; Sensitivity and Specificity; Viral Load

This study was made to determine the immunovirological outcome and tolerance to lopinavir/ritonavir (LPV/r) in HIV-infected protease inhibitors-experienced patients with long-term virological failure.. Prospective follow-up was implemented for the French cohort ANRS CO8 Aproco-Copilote of 121 patients starting an LPV/r-containing regimen after a median duration of virological failure of 30.6 months. At baseline the median HIV-RNA plasma level was 4.1 log(10) copies/ml and the median CD4 cell count was 273/mm(3).. On initiation of LPV/r, these patients were heavily pre-treated: 62% had received at least 4 NRTI, 65% at least 1 NNRTI, and 33% at least 3 PI. On prescription of LPV/r, the associated antiretroviral regimen was: no drug to which patients were previously naïve in 49 cases (40%), at least one new drug in 72 cases: 1 NRTI (n=42), 2 NRTI (n=22), 1 NNRTI (n=10), at least one new PI (n=6), enfuvirtide (n=2). The median HIV-RNA level was 2 log(10) copies/ml at M4 and M12, 1.7 log(10) copies/ml at M24 with respectively 74, 71 and 85% of patients achieving plasma HIV-RNA below 2.7 log(10) copies/ml. The median CD4 cell count was 385 and 429/mm(3) at M12 and M24 respectively. Among patients with genotypic testing at the time of LPV/r initiation, Ninety-five percent had at the most 5 protease mutations known to reduce LPV/r susceptibility. Thirty serious adverse events were reported but only 6 were related to LPV/r.. The use of LPV/r in HIV-infected patients failing multiple antiretroviral regimens provided a potent and durable immunovirological response.

Topics: Anti-HIV Agents; Cohort Studies; Drug Resistance, Viral; Drug Tolerance; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pilot Projects; Pyrimidinones; Ritonavir; Treatment Failure

We evaluated the immunologic impact of highly active antiretroviral therapy in subjects who maintained human immunodeficiency virus type 1 (HIV-1) suppression through 6 years of receiving a lopinavir-ritonavir-based regimen.. A total of 100 antiretroviral-naive subjects with any CD4+ T cell count initiated therapy with lopinavir-ritonavir, stavudine, and lamivudine. Sixty-three subjects who remained in the study for 6 years were assessed. Laboratory measurements included plasma HIV-1 RNA levels, multiparameter flow cytometry of immune cells, and markers of maturation and activation.. After 6 years, 62 of 63 subjects had plasma HIV-1 RNA levels <50 copies/mL. The mean increase in CD4+ T cell count was 528 cells/microL (P<.001), and 81% of subjects had CD4+ T cell counts >500 cells/microL, compared with 21% of subjects at baseline. The mean ratio of CD4+ T cell count to CD8+ T cell count increased from 0.38 at baseline to 0.96 at year 6 (P<.001). The percentage of subjects with cell counts below the lower limit of normal at year 6, compared with at baseline, was significantly decreased for total T cells, B cells, and natural killer cells. At year 6, the median CD4+ T cell activation level was 3.4%, and the median CD8+ T cell activation level was 5.8%.. The receipt of a lopinavir-ritonavir-based regimen resulted in ongoing immune reconstitution through 6 years of therapy in a cohort of HIV-1-infected, antiretroviral-naive subjects with suppressed HIV-1 RNA levels. Normalization of activation marker expression on CD4+ and CD8+ T cell subsets was demonstrated.

Topics: Adult; Anti-HIV Agents; Biomarkers; CD4-CD8 Ratio; Clinical Trials, Phase II as Topic; Cohort Studies; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Stavudine

Atazanavir (ATV) is a widely used human immunodeficiency virus (HIV)-1 protease inhibitor (PI) that, like other approved PIs, has been considered as a candidate for therapeutic drug monitoring (TDM). To provide ATV assay results that can be applied to patient management through TDM, the assay would need to perform in a manner consistent with Clinical Laboratory Improvement Amendments (CLIA) standards. To quantitate ATV concentrations in human plasma, the authors added ATV to a previously published reversed-phase high-performance liquid chromatography (HPLC) method from their laboratory. Detection was effected with use of a photodiode-array detector (PDA) collecting spectra at 248 nm. This method allows for detection of ATV to a lower limit of quantitation of 0.05 microg/mL, with an intra-assay coefficient of variation (CV%) of 8.9% or less over 5 days of testing and an interassay CV% ranging from 1.4 to 6.4%. The assay has met passing requirements for interlaboratory proficiency testing for 2 years nationally and internationally, with accuracy within +/-15% over all test samples. During 2 years, more than 100 batches of analyses have been performed and have proved the method is rugged, specific, and accurate. This assay method is currently used in the authors' clinical research program in TDM.

Topics: Atazanavir Sulfate; Calibration; Chromatography, High Pressure Liquid; Drug Monitoring; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Quality Control; Reference Standards; Reproducibility of Results; Ritonavir; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Time Factors

During pregnancy, the absorption of antiretroviral drugs may not be optimal, therefore a prospective study was conducted to investigate the plasma levels of lopinavir in 26 HIV-infected pregnant women. Plasma lopinavir levels were examined in specimens obtained 12 h post-dose. The lopinavir level was found to be subtherapeutic in four women (15.4%); one patient who discontinued treatment and three (13.6%) with therapeutic levels of lopinavir had detectable HIV viral loads at the time of therapeutic drug monitoring.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Pyrimidinones; Ritonavir; Viral Load; Zidovudine

HIV-infected patients receiving protease inhibitors may benefit from therapeutic drug monitoring-assisted dose adjustment to achieve target plasma concentrations. However, efflux pumps such as permeability-glycoprotein, which is encoded by the multidrug resistance (MDR)1 gene, may decrease intracellular drug concentrations, thus reducing the amount of drug at the site of action. Plasma concentrations of protease inhibitors and CD4 cell count response have been associated with the T allele at the MDR1 C3435T locus. We examined MDR1 single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol.. In a multicenter study, genotypic analyses at two MDR1 loci, C3435T and G2677T, were performed by a real-time polymerase chain reaction method using DNA from 103 patients categorized as substance users or nonusers on atazanavir or lopinavir as the primary antiretrovirals. Allelic frequencies were determined as a function of racial/ethnic background, substance use status and trough concentrations of atazanavir and lopinavir.. The C/T and G/T alleles at the MDR1 C3435T and G2677T loci were equally frequent in the Caucasian population, but the wild-type alleles were more prevalent in the African-American population (59% homozygous [CC] and 32% heterozygous [CT] for C3435T; 80% homozygous [GG] and 16% heterozygous [GT] for G2677T). The frequencies in the Hispanic population were 46% CC and 38% CT for C3435T, and 58% GG and 38% GT for G2677T. No significant differences were seen in allele frequencies for MDR1 polymorphisms in substance user versus nonuser groups. Trough plasma concentrations of atazanavir or lopinavir were not correlated with the variant T allele.. These data confirm the higher prevalence of wild-type alleles of the MDR1 gene in African-Americans and the linkage disequilibrium between C3435T and G2677T loci. The T allele at the MDR1 C3435T and G2677T loci was not associated with higher atazanavir or lopinavir trough concentrations.

Topics: Adult; Aged; Atazanavir Sulfate; ATP Binding Cassette Transporter, Subfamily B, Member 1; Female; Gene Frequency; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Polymorphism, Genetic; Pyridines; Pyrimidinones

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Emtricitabine; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Lopinavir; Male; Organophosphonates; Peptide Fragments; Pyrimidinones; Ritonavir; Tenofovir; Viral Load; Viremia

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

Synergy between HIV and malaria is being increasingly recognized. We examined the antimalarial activity of sera from subjects receiving chloroquine, no drugs or HAART. Sera from subjects taking ritonavir-boosted saquinavir or lopinavir significantly inhibited parasite growth (median of 55 and 69% inhibition, respectively). These results indicate that patients on protease inhibitors may be afforded some protection from malaria. The clinical relevance of these observations will require confirmation in controlled studies in malaria-endemic regions.

Topics: Animals; Antimalarials; Antiretroviral Therapy, Highly Active; Chloroquine; Drug Synergism; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Malaria, Falciparum; Plasmodium falciparum; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Treatment Outcome

There are no published reports of the long-term safety and effectiveness of highly active antiretroviral therapy for children and adolescents living in resource-limited settings or of large cohorts of HIV-infected children and adolescents treated long-term (>48 weeks) with lopinavir/ritonavir-containing highly active antiretroviral therapy.. The purpose of this work was to evaluate the long-term outcomes of treatment of HIV-infected children and adolescents with lopinavir/ritonavir-containing highly active antiretroviral therapy in a resource-limited setting.. We studied an inception cohort of 414 HIV-infected children receiving lopinavir/ritonavir-containing highly active antiretroviral therapy between November 2001 and August 2006 at the Romanian-American Children's Center in Constanta, Romania. The center provides comprehensive primary and HIV specialty care and treatment to all known HIV-infected children and adolescents living in Constanta. We measured safety and effectiveness by the percentage of children remaining on treatment, rates of mortality, and changes in plasma HIV RNA concentrations and CD4+ lymphocyte counts.. The study population consisted predominantly of antiretroviral drug-experienced older children and adolescents with advanced HIV disease. Treatment was well tolerated, with 337 children (81%) remaining on therapy after a median duration of >4 years. Thirty-seven deaths occurred; the death rate compared favorably to prospectively collected historical data. The most recent on-treatment plasma HIV RNA concentration was <400 copies per milliliter in 192 of 265 children tested. The mean baseline CD4+ lymphocyte count was 292 cells per microliter (n = 299); the mean change from baseline was +266 (n = 284), +317 (n = 260), +343 (n = 176), and +270 cells per microliter (n = 121) after 1, 2, 3, and 4 years of treatment, respectively.. Highly active antiretroviral therapy can be administered safely and effectively to children and adolescents in resource-limited settings. Lopinavir/ritonavir-containing highly active antiretroviral therapy is a safe, effective, and durable treatment option for antiretroviral drug-experienced older children and adolescents with advanced HIV disease.

Topics: Adolescent; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Cohort Studies; Drug Combinations; Female; Follow-Up Studies; HIV Infections; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Romania

Topics: Analgesics, Opioid; Anti-Retroviral Agents; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Methadone; Middle Aged; Pyrimidinones; Ritonavir; Torsades de Pointes

Stek and colleagues reported low lopinavir levels in the third trimester of pregnancy at standard dosing. Since their initial report in 2003, we have taken steady-state trough lopinavir levels in all pregnant women in the third trimester; the results of 26 women on a lopinavir/ritonavir regimen are reported. The median trough level was 3.66 microg/ml, range 0.25-9.97; the median HIV viral load was 49 copies/ml at delivery. All infants were HIV polymerase chain reaction negative at 3 months.

Topics: Adolescent; Adult; Drug Combinations; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Third; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load

The observation that extremely high levels of medication adherence are required to achieve complete virologic suppression is based largely on studies of treatment-experienced patients receiving HIV protease inhibitor (PI)-based therapy without ritonavir boosting. This study aims to define the level of adherence needed to achieve virologic suppression in patients receiving boosted PI-based highly active antiretroviral therapy (HAART) with lopinavir/ritonavir.. HIV-infected adults receiving a regimen containing lopinavir/ritonavir were recruited into a prospective, observational study of the relation between adherence to lopinavir/ritonavir and virologic outcomes. Adherence was measured using the Medication Event Monitoring System (MEMS; Aardex, Union City, CA). HIV-1 viral load (VL) was measured at week 24.. The final study population contained 64 subjects. Eighty percent had AIDS, 97% received lopinavir/ritonavir before enrollment, and most had more than 7 years of HAART experience. Mean adherence overall was 73%. Eighty percent and 59% achieved a VL <400 copies/mL and a VL <75 copies/mL, respectively. Mean adherence was 75% in those achieving a VL <75 copies/mL. High rates of virologic suppression were observed in all adherence quartiles, including the lowest quartile (range of adherence: 23.5%-53.3%).. Moderate levels of adherence can lead to virologic suppression in most patients taking lopinavir/ritonavir-based HAART.

Topics: Adult; Antiretroviral Therapy, Highly Active; Black People; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Patient Compliance; Pyrimidinones; Retrospective Studies; Ritonavir; Time Factors; Treatment Outcome; Viral Load; White People

Recent studies have shown that coadministration of certain protease inhibitors (PIs) with gastric acid-reducing agents results in decreased plasma concentrations of the PI. To assess the effect of acid-reducing agents on lopinavir/ritonavir, data from two clinical trials (n = 38 and 190) were pooled. Both trials randomized antiretroviral-naïve, HIV-infected patients to receive lopinavir/ritonavir 400/100 mg twice-daily or 800/200 mg once-daily in combination with stavudine and lamivudine, or tenofovir and emtricitabine. Concurrent administration of gastric acid-reducing agents including antacids of various brand names, proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole), and H(2)-receptor antagonists (ranitidine, famotidine, cimetidine, and nizatidine) was reported in both trials. Lopinavir and ritonavir pharmacokinetic parameters were evaluated. Thirty subjects were considered users of acid-reducing agents at the times of pharmacokinetic evaluation. HIV-infected patients who received gastric acid-reducing agents during administration of lopinavir/ritonavir-based treatment regimens did not appear to have a reduction in lopinavir or ritonavir exposures.

Topics: Adult; Antacids; Area Under Curve; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir

Topics: Anti-HIV Agents; Antihypertensive Agents; Drug Interactions; HIV Infections; Humans; Lopinavir; Nifedipine; Pyrimidinones; Ritonavir

Topics: Anti-Retroviral Agents; Clinical Trials as Topic; Congresses as Topic; Cyclohexanes; HIV Fusion Inhibitors; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Maraviroc; Multicenter Studies as Topic; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Treatment Outcome; Triazoles; United States

Multidrug resistant HIV-1 acquired at the time of primary infection in two patients persisted for at least 5 years with and without treatment. In each patient, only one back mutation to wild-type codon in the protease gene occurred, and that was concomitantly associated with a marked CD4 cell count decrease. In both cases, infection was caused by CCR5 viruses and no rapid clinical progression to AIDS after primary infection was observed.

Topics: Adenine; Anti-Retroviral Agents; CD4 Lymphocyte Count; Drug Resistance, Multiple, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Mutation; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Tenofovir; Viral Load

The efficacy and safety of lopinavir/ritonavir monotherapy has been explored with promising results in well-controlled, randomized clinical trials. However, less information about its clinical usefulness in routine clinical practice is currently available. The objective of this study was to assess the effectiveness and safety of monotherapy with lopinavir/ritonavir as a treatment simplification strategy in HIV-infected patients with viral suppression outside a clinical trial setting.. Fifty-one subjects who were switched to lopinavir/ritonavir monotherapy and whose HIV-1 RNA was <50 copies/mL were included in this retrospective study. Data were obtained from a prospectively compiled database. The primary endpoint was the percentage of subjects who maintained viral suppression after 48 weeks of follow-up. Secondary endpoints included the incidence of adverse events and changes in CD4+ T cell count and in lipid profile.. Two patients lost viral suppression, seven patients interrupted lopinavir/ritonavir monotherapy because of adverse events and four patients were lost before completing 48 weeks of follow-up. Thus, 38/40 (95.0%) patients maintained viral suppression when only subjects whose outcomes were available up to week 48 were considered and 38/51 (74.5%) patients maintained viral suppression when subjects who discontinued therapy or who were lost to follow-up were considered as treatment failures. The mean CD4+ T cell count significantly increased, from 541 (280) cells/mm3 at baseline to 609 (212) cells/mm3 at week 48 of follow-up (P=0.034). This increase was similar to that observed in the 48 weeks prior to lopinavir/ritonavir monotherapy (P=0.792). Although total cholesterol remained unchanged, there was a significant decrease in triglyceride levels during follow-up (P=0.029).. Monotherapy with lopinavir/ritonavir is safe and effective as a treatment simplification approach in HIV-1-infected patients with sustained viral suppression in routine clinical practice, particularly in those patients already receiving a lopinavir/ritonavir-based antiretroviral regimen.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cholesterol; Databases, Factual; Endpoint Determination; Female; Genotype; HIV Infections; Humans; Lipids; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Treatment Outcome

To estimate the cost effectiveness and long-term combined effects of HIV disease and antiretroviral (ARV) therapy-related risk for coronary heart disease (CHD) on quality-adjusted survival and healthcare costs for ARV-experienced patients.. A previously validated Markov model was updated and supplemented with the Framingham CHD risk equation. The representative patient in the model was male, aged 37 years and had a baseline 10-year CHD risk of 4.6%. Patients started with either lopinavir/ritonavir (LPV/r) or ritonavir-boosted atazanavir (ATV+RTV) as the protease inhibitor (PI). The proportions of patients with viral suppression below 400 and 50 copies/mL, respectively, at week 48 reported in clinical trials were used to estimate the differences between these two therapies. The daily ARV costs were $US 24.60 for LPV/r capsules (2005 costs) and $US 26.54 for LPV/r tablets (2006 costs), $US 29.76 for ATV and $US 8.57 for ritonavir (2005 costs). Costs of other ARV drugs were taken from average wholesale drug reports for 2005. The cost of AIDS events was estimated from Medicaid billing databases and reflected a medical care system perspective and 2005 treatment costs. Cost-effectiveness calculations assumed a lifetime time horizon. The effects of different model assumptions were tested in a multiway sensitivity analysis by combining extreme values of parameters.. The model estimated a clinical and economic advantage to using LPV/r over ATV+RTV, which varied depending upon the use of LPV/r capsules or tablets. Using LPV/r capsules was comparatively beneficial for ARV-experienced patients in quality-adjusted life-months (QALMs) of 4.6 (corrected for differences in CHD risk) compared with ATV+RTV. In addition, there were 5- and 10-year overall per-patient cost savings of $US 17,995 and $US 21,298, respectively. Estimates for the LPV/r tablet formulation approved in 2005 (assuming similar efficacy) improved cost savings over 5- and 10-year periods to $US 19,598 and $US 23,126 per patient, respectively, because of a drug price differential. Sensitivity analysis tested numerous assumptions about the model cost and efficacy parameters and found that the results were robust to most changes. Model limitations were the uncertainty associated with the model parameters used.. LPV/r appears to be a highly cost-effective regimen relative to ATV+RTV for the treatment of HIV. The long-term CHD risk associated with LPV/r was minimal compared with the increased risk of AIDS/death and costs projected for a less efficacious PI-based regimen.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Coronary Disease; Costs and Cost Analysis; Data Collection; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Markov Chains; Models, Statistical; Pyrimidinones; Quality of Life; Quality-Adjusted Life Years; Ritonavir; Survival Analysis; United States; Viral Load

We report on a patient who received a diagnosis of HIV infection following kidney transplantation some years earlier. As a result of intolerance and failure of nucleoside and non-nucleoside reverse transcriptase inhibitor (NRTI and NNRTI)-containing regimens, he was started on Kaletra single agent HAART. Kaletra was well tolerated and resulted in sustained viral load suppression below the limit of detection for at least 36 months.

Topics: Adult; Antiretroviral Therapy, Highly Active; HIV Infections; HIV Protease Inhibitors; Humans; Kidney Transplantation; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors

HPV infections have become a major problem in immunocompromised patients, particularly in HIV-positive subjects. HPV lesions are observed more frequently in the ano-genital area and rarely in different body areas, such as the skin and oral cavity. However, in HIV-positive subjects there is an increased risk of oral condylomas. We describe the case of an HIV-positive Nigerian young woman, who came to our notice due to the appearance of small labial and mouth mucous membrane lesions, related to HPV infection, as shown by a biopsy. These lesions were not evident in the genital area. After two years in which the patient no longer received therapy, there was a progressive reduction in CD4 count, associated with the development of the oral condylomas. Hence the patient began a new HAART combination, but after seven months, although a slight improvement emerged in the CD4 count with the disappearance of HIV-RNA, there has been no regression of oral condylomas.

Topics: Adenine; Adult; Alphapapillomavirus; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Italy; Lamivudine; Lopinavir; Mouth Mucosa; Nigeria; Organophosphonates; Papillomavirus Infections; Pyrimidinones; Ritonavir; Sex Work; Stomatitis; Tenofovir; Treatment Refusal; Zidovudine

A HIV-infected patient treated since eight years with all antiretroviral classes save boosted protease inhibitors, at the time of changing therapy due to an emerging genotyping resistance to non-nucleoside reverse transcriptase inhibitors, experienced repeated episodes of hypersensitivity reactions to all available boosted protease inhibitors. After documenting a combined ritonavir and lopinavir hypersensitivity by means of a specific in vitro cellular antigen stimulation test (CAST), antiretroviral therapy was safely continued with unboosted atazanavir. According to our knowledge, we report the first case of application of the in vitro CAST assay to antiretroviral intolerance, and the subsequent, specific regimen selection in a HIV-infected subject who showed multiple allergy to all boosted protease inhibitors. Further, controlled investigation is strongly needed to implement in vitro allergometric testing in patients with HIV infection and related diseases, who are prone to show unpredictable drug intolerance reactions. In fact, HIV-infected patients may suffer from frequent allergic drug reactions which may be difficult to be systematically recognized (due to the frequent, multiple concurrent pharmacotherapy), while eventual drug rechallenges are expected to be potentially dangerous.

Topics: Adult; Anti-HIV Agents; Drug Hypersensitivity; HIV Infections; Humans; Immunoassay; Lopinavir; Male; Protease Inhibitors; Pyrimidinones; Ritonavir

Topics: Administration, Oral; Didanosine; Dideoxynucleosides; Drugs, Generic; HIV Infections; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration

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

Lopinavir/ritonavir (LPV/r) has been licensed for the treatment of HIV-infected children >6 months in the US and >2 years in the EU. Limited LPV paediatric pharmacokinetic data are available. We studied LPV pharmacokinetics to determine whether the recommended dose (230/57.5 mg/m2 twice daily) results in optimal LPV exposure in all age groups. Virological efficacy was a secondary objective.. HIV-1-infected children who started treatment with LPV/r and two nucleoside reverse transcriptase inhibitors underwent a 12-h pharmacokinetic curve. LPV plasma concentrations were determined with a validated HPLC method with UV detection. If Cmin was <1.0 mg/l LPV/r dose was increased by 33%. Plasma trough levels were drawn subsequently. HIV-1 RNA was followed-up until week 48.. A total of 23 children were included (seven girls; 16 boys), with a median (range) age of 5.6 (0.4-13.2) years. Mean (+/-SD) AUC0-12h, Cmax and Cmin of LPV were 75.3 (+/-33.7) mg/l.h, 9.33 (+/-3.27) mg/l and 3.68 (+/-2.48) mg/l, respectively, which is similar to previously published data. Interindividual variability was large. Cmin was inadequate in 7/23 children. Significantly more children <2 years had inadequate Cmin compared with children >2 years. Dose increase to +/-300/75 mg/m2 LPV/r led to Cmin >1.0 mg/l. The studied regimen provided excellent viral suppression for naive and pretreated patients.. Mean LPV pharmacokinetic parameters in these HIV-infected children are similar to published data, but exposure is significantly reduced in children <2 years. Prospective pharmacokinetic studies using 300/75 mg/m2 LPV/r in this age population are urgently warranted.

Topics: Adolescent; Anti-HIV Agents; Area Under Curve; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome

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: Anti-HIV Agents; Cyclohexanes; Drug Resistance, Viral; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; Humans; Lopinavir; Maraviroc; Nitriles; Piperazines; Pyridazines; Pyrimidines; Pyrimidinones; Triazoles

The aim of this study was to establish the prevalence and predictors of genotypic resistance of HIV-1 to lopinavir and fosamprenavir from patients failing protease inhibitors (PI)-based regimens. We selected 643 HIV-1-infected patients with available treatment history who underwent genotypic resistance assays for virological failure from a clinical site and from the Stanford database. According to the genotypic resistance interpretation of the Stanford algorithm, proportions of viruses showing full susceptibility to fosamprenavir and lopinavir were 32% and 34%, respectively (p =ns). Proportions of viruses fully susceptible to lopinavir/r and fosamprenavir/r according to the Agence Nationale pour la Recherche sur le SIDA (ANRS) algorithm, were 81% and 81%, respectively. According to the Rega algorithm, proportions of viruses showing full susceptibility to fosamprenavir/r and lopinavir were 80% and 70%, respectively (p<0.001). According to the ANRS and Rega interpretations, the time on therapy predicted susceptibility to lopinavir/r, while susceptibility to fosamprenavir/r according to ANRS was predicted by the number of prior PI regimens experienced. According to the Stanford interpretation, prior indinavir exposure predicted resistance to lopinavir/r and fosamprenavir/r while prior nelfinavir use predicted susceptibility to both drugs. After failing PI-based regimens, the majority of viruses retained a predicted susceptibility to fosamprenavir/r and lopinavir/r. In patients failing PIs, the interpretation of genotypic resistance to fosamprenavir may change considerably according to the different algorithms and in respect to the effect of pharmacokinetic boosting with ritonavir.

Topics: Adult; Algorithms; Antiretroviral Therapy, Highly Active; Carbamates; Drug Resistance, Multiple, Viral; Female; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Organophosphates; Prevalence; Pyrimidinones; Retrospective Studies; Ritonavir; Sulfonamides

Topics: Adult; Aged; Cross-Sectional Studies; Endothelium, Vascular; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Nitroglycerin; Pilot Projects; Proteinuria; Pyrimidinones; Regional Blood Flow; Ritonavir; Vasodilation

To study the impact of lopinavir/ritonavir-containing therapy on plasma lipids and body fat of HIV-infected adults and to assess whether lopinavir plasma levels at steady state are correlated with plasma lipids and body fat after 24 weeks.. Patients had their antiretroviral therapy switched to an antiretroviral regimen containing lopinavir/ritonavir plus one or two non-thymidine analogues. Body composition was assessed by dual energy X-ray absorptiometry at baseline and at week 24 and an intensive pharmacokinetic (PK) 12 h profile was performed at week 2.. Twenty-six patients were included. Plasma triglycerides (from 206 mg/dL to 261 mg/dL, P = 0.09) and total cholesterol (from 201 to 206 mg/dL, P = 0.03) increased from baseline to week 24. There was a significant rise in total fat (from 10.9 to 11.9 kg, P = 0.02) and limb fat (from 3.8 to 4.4 kg, P = 0.02) from baseline to week 24. We did not find any correlation between PK lopinavir levels and changes over time for triglycerides, cholesterol or body fat composition.. There was an increase in plasma triglycerides and total cholesterol levels and a gain in both total and limb fat at 24 weeks, but these changes were not correlated with lopinavir plasma levels.

Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Anti-HIV Agents; Blood Chemical Analysis; Body Composition; Female; HIV Infections; Humans; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

To describe first dose and steady state antiretroviral drug exposure in the female genital tract.. Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women.. Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA).. For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%).. This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.

Topics: Adenine; Administration, Oral; Adult; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; Genitalia, Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Tenofovir; Zidovudine

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Topics: Alanine Transaminase; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Peptide Fragments; Pyridines; Pyrimidinones; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome; Viral Load

Kaletra tablets have the advantage of being stored at room temperature, but potential interactions are poorly documented.

Topics: Anti-HIV Agents; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Pyrimidinones; Ritonavir

The most commonly reported side effects related to lopinavir/ritonavir are diarrhea, vomiting, headache, nausea, and increased serum triglycerides and cholesterol levels. About 4% of the patients prescribed lopinavir/ritonavir stop taking it because of side effects. Alopecia, generally involving the scalp, has been reported in patients with HIV infection treated with indinavir but not with lopinavir/ritonavir. We present a 62-year-old man with HIV infection, stage B2, who experienced alopecia totalis of his scalp, eyebrows, and eyelashes beginning 18 months after initiating antiretroviral treatment including lopinavir/ritonavir. No hair loss on the arms, legs, and pubic area was observed. Our patient's drug regimen consisted of lopinavir/ritonavir, efavirenz, and stavudine; in addition, the patient was receiving treatment for diabetes with glivenclamide and metformin for the last 3 years. These drugs have not been shown to cause alopecia. Alopecia reversed completely 2 months after substituting nelfinavir for lopinavir/ritonavir without any other change of treatment and his eyelashes and eyebrows grew back as well. To our knowledge, this is the second case of lopinavir/ritonavir-associated alopecia totalis reported in the international literature.

Topics: Alopecia; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Nelfinavir; Pyrimidinones; Ritonavir; Treatment Outcome

The objective is to assess patient preferences for attributes associated with third agent HIV medications, including fosamprenavir/ritonavir (FPVr), fosamprenavir (FPV), lopinavir/ritonavir (LPVr), atazanavir (ATZ), and efavirenz (EFV). Subjects with HIV were recruited in the US and Germany to complete a computerized adaptive conjoint survey that assessed 13 attributes, including moderate to severe side effects, regimen convenience, drug resistance and efficacy. Literature on the target third-agent HIV drugs was used to identify percentage risk and severity level descriptions for each attribute. The derived preference (utility) weights for each attribute level informed the calculation of relative importance estimates for each attribute and the desirability of combinations of attributes matching the respective target third agents. The analysis included 288 HIV-positive participants (US: 132; Germany: 156), 205 of whom were treatment-experienced and 83 of whom were treatment-naïve. Of the 13 medication attributes evaluated, developing drug resistance, the risk of lipodystrophy, the risk of gastronitestinal side effects (diarrhoea, nausea and vomiting) and regimen convenience had the greatest impact on preferences. The profile based on FPVr was most preferred. Differences in the risk of developing drug resistance, risk of lipodystrophy, risk of gastrointestinal side effects and regimen convenience would likely be most influential in the perceived relative value of a third-agent medication. Physicians may wish to consider these features, especially when discussing HIV treatment options with their patients.

Topics: Anti-Retroviral Agents; Drug Administration Schedule; Drug Interactions; Drug Resistance, Viral; Female; Germany; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Patient Satisfaction; Pyrimidinones; Ritonavir; Treatment Outcome; United States

Human immunodeficiency virus type 1 (HIV-1) antiviral drug resistance is a major consequence of therapy failure and compromises future therapeutic options. Nelfinavir and lopinavir/ritonavir-based therapies have been widely used in the treatment of HIV-infected patients, in combination with reverse transcriptase inhibitors. The aim of this observational study was the identification and characterization of mutations or combinations of mutations associated with resistance to nelfinavir and lopinavir/ritonavir in treated patients. Nucleotide sequences of 1,515 subtype B HIV-1 isolates from 1,313 persons with different treatment histories (including naïve and treated patients) were collected in 31 Spanish hospitals over the years 2002-2005. Chi-square contingency tests were performed to detect mutations associated with failure to protease inhibitor-based therapies, and correlated mutations were identified using statistical methods. Virological failure to nelfinavir was associated with two different mutational pathways. D30N and N88D appeared mostly in patients without previous exposure to protease inhibitors, while K20T was identified as a secondary resistance mutation in those patients. On the other hand, L90M together with L10I, I54V, A71V, G73S, and V82A were selected in protease inhibitor-experienced patients. A series of correlated mutations including L10I, M46I, I54V, A71V, G73S, and L90M appeared as a common cluster of amino acid substitutions, associated with failure to lopinavir/ritonavir-based treatments. Despite the relatively high genetic barrier of some protease inhibitors, a relatively small cluster of mutations, previously selected under drug pressure, can seriously compromise the efficiency of nelfinavir- and lopinavir/ritonavir-based therapies.

Topics: Amino Acid Substitution; Databases, Protein; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Models, Molecular; Mutation; Nelfinavir; Pyrimidinones; Ritonavir; Spain; Treatment Failure

Atazanavir (ATV) and lopinavir (LPV) are widely used HIV-1 protease inhibitors. Like with other protease inhibitors, careful monitoring of potential drug-drug and drug-disease interactions in clinical practice is necessary. The aim of this study was to assess the impact of substance use and hepatitis virus coinfection on plasma ATV and LPV trough concentrations in HIV-positive substance users and nonusers. Individuals established on ATV (300 mg and 100 mg ritonavir daily) or LPV (400 mg and 100 mg ritonavir twice daily)-containing regimens completed two clinical visits (trough and directly observed therapy) during which dosing characteristics, concomitant medication, and substance use were recorded. Trough plasma concentrations (22-26 hours for ATV and 10-14 hours for LPV) were measured using LCMSMS. The influence of substance use was evaluated by Kruskal-Wallis test. Substance use was associated with a marked decrease in trough LPV concentrations during the trough visit (median, 5.536 and 3.791 microg/mL for nonsubstance users and substance users, respectively, P = 0.029). Significantly lower LPV trough levels were also noted among patients with active hepatitis C virus coinfection evaluated as an independent variable (median, 2.253 and 5.927 microg/mL for active and inactive/no hepatitis C virus infection, respectively, P = 0.032). Substance use and hepatitis virus coinfection had limited effects on ATV trough levels. In this cohort, despite the wide interindividual variability of ATV and LPV trough concentrations, significant associations between substance use and active hepatitis C virus infection and low LPV trough concentrations were observed. Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug Administration Schedule; Drug Monitoring; Female; Hepatitis C; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Substance-Related Disorders; United States

Topics: Africa; Anti-HIV Agents; Drug Approval; Drug Industry; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Tablets

Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Lopinavir; Oligopeptides; Pilot Projects; Pyridines; Pyrimidinones; Ritonavir

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Drug Interactions; HIV Infections; Humans; Lopinavir; Male; Panuveitis; Pyrimidinones; Rifabutin; Ritonavir; Tuberculosis, Pulmonary

Topics: Anti-HIV Agents; Clinical Trials, Phase III as Topic; Darunavir; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Pyrimidinones; Ritonavir; Sulfonamides

Lopinavir/ritonavir-containing antiretroviral therapy can cause hyperlipidaemia. However, most statins are contraindicated due to drug-drug interactions. Rosuvastatin undergoes minimal metabolism by CYP450, so no CYP450-based interaction with lopinavir/ritonavir is expected. This study explored the lipid-lowering effect of rosuvastatin and assessed the effect of lopinavir/ritonavir on the pharmacokinetics of rosuvastatin and vice versa.. HIV-infected patients on lopinavir/ritonavir (viral load < 400 copies/ml) with total cholesterol (TC) > 6.2 mmol/l were treated with rosuvastatin for 12 weeks, starting on 10 mg once daily. If fasting target values (TC < 5.0 mmol/l, high-density lipoprotein-cholesterol > 1.0 mmol/l, low-density lipoprotein-cholesterol [LDL-c] < 2.6 mmol/l and triglycerides < 2.0 mmol/l) were not reached, rosuvastatin was escalated to 20 mg or 40 mg at week 4 and 8, respectively. Plasma lopinavir/ritonavir trough levels (C(min)) were determined at week 0, 4, 8 and 12 and rosuvastatin C(min), at week 4, 8 and 12.. Twenty-two patients completed the study. Mean reductions in TC and LDL-c from baseline to week 4 (on rosuvastatin 10 mg once a day) were 27.6% and 31.8%, respectively. Lopinavir/ritonavir concentrations were not influenced by rosuvastatin (P = 0.44 and 0.26, repeated-measures analysis). Median (interquartile range) rosuvastatin C(min) for 10 mg, 20 mg and 40 mg once daily were 0.97 (0.70-1.5), 2.5 (1.3-3.3) and 5.5 (3.3-8.8) ng/ml, respectively.. Rosuvastatin appeared to be an effective statin in hyperlipidaemic HIV-infected patients. Lopinavir/ritonavir levels were not affected by rosuvastatin, but rosuvastatin levels unexpectedly appeared to be increased 1.6-fold compared with data from healthy volunteers. Until safety and efficacy have been confirmed in larger studies, the combination of rosuvastatin and lopinavir/ritonavir should be used with caution.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Drug Therapy, Combination; Fluorobenzenes; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lopinavir; Middle Aged; Pilot Projects; Pyrimidines; Pyrimidinones; Ritonavir; Rosuvastatin Calcium; Sulfonamides

Selection of antiretroviral therapy (ART) for antiretroviral-experienced patients should involve balancing multiple factors, including clinical efficacy, adverse-event risk, resistance concerns, cost effectiveness and expected budget impact. The efficacy of a regimen and its durability, as demonstrated in controlled clinical trials, must be considered in the light of short- and long-term economic impacts on the healthcare system. These impacts may vary based on drug costs, costs of reported adverse effects, the regimen's likelihood of contributing to viral resistance to second-line therapies and the marginal cost differences between other healthcare resources used over a patient's lifetime. Risk of coronary heart disease (CHD) may be of concern in the selection of ART, because differences in CHD risk factors have been reported for different regimens, and heart disease is both a deadly and costly condition. This study set out to estimate the long-term combined effects of HIV disease and antiretroviral-related risk for CHD on quality-adjusted survival and healthcare costs for antiretroviral-experienced patients in the UK, Spain, Italy and France.. A previously validated Markov model was updated with 2006 cost estimates for each of the four countries and supplemented with the Framingham CHD risk equation. In the model, the average patient was male, aged 37 years, with a baseline 10-year CHD risk of 4.6%. Patients started with either lopinavir/ritonavir (LPV/r) or ritonavir-boosted atazanavir (ATV+RTV) as the protease inhibitor (PI). Clinical trial results, local drug costs and AIDS and CHD cost estimates were used to estimate the differences between these two therapies.. There was a significant advantage using LPV/r over ATV+RTV, which varied depending on the country's cost structure and assumptions related to drug efficacy. There was a comparative benefit for experienced patients in quality-adjusted life-months (QALM) of 4.6 (the net gain after subtracting quality-adjusted life-years [QALYs] lost owing to CHD risk). In addition, there were 5- and 10-year overall cost savings of between euro947 and euro6594 per patient after 5 years, and an impact ranging from a cost increase of euro308 (for France) to a cost saving of euro7388 (for Spain) at year 10. The lifetime incremental cost-effectiveness ratios ranged from dominant for Spain to euro11 856/QALY for Italy.. LPV/r was a highly cost-effective regimen relative to ATV+RTV for the treatment of HIV for each of the four countries examined in this study. The effect of LPV/r on long-term CHD risk was minimal compared with the increased risk of AIDS/death projected for a less efficacious PI-based regimen. The cost of lipid-lowering drugs and treatment for CHD was insignificant compared with the overall cost savings from LPV/r therapy. The choice of regimen for antiretroviral-experienced patients should be based on a regimen's expected efficacy and durability for countries with similar cost structure to those examined here.

Topics: Adult; Atazanavir Sulfate; Coronary Disease; Cost-Benefit Analysis; Drug Combinations; Drug Therapy, Combination; France; Health Care Costs; HIV Infections; HIV Protease Inhibitors; Humans; Italy; Lopinavir; Male; Markov Chains; Oligopeptides; Pyridines; Pyrimidinones; Quality-Adjusted Life Years; Risk Factors; Ritonavir; Spain; Time Factors; United Kingdom

Week 48 HIV-RNA treatment response to the protease inhibitor tipranavir co-administered with ritonavir was compared with that of lopinavir co-administered with ritonavir in patients whose baseline isolates had varying lopinavir genotypic mutation scores. With increasing lopinavir mutation scores, the proportion of patients achieving a week 48 treatment response was increased in the tipranavir/ritonavir compared with the lopinavir/ritonavir arm. Tipranavir/ritonavir therapy improves treatment response rates compared with lopinavir/ritonavir in patients whose viruses have reduced susceptibility to lopinavir/ritonavir.

Topics: Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Drug Resistance, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyridines; Pyrimidinones; Pyrones; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

The effect of the HIV reverse transcriptase K65R mutation on virological response to salvage therapy has not been clearly defined.. From six Italian clinical centres, all consecutive patients starting salvage antiretroviral therapy after virological failure in the presence of the K65R mutation identified by a genotypic resistance test were selected.. Among 145 subjects included over a 197 person-year follow-up, the estimated probability of virological response (VR, defined as reaching HIV RNA < 50 copies/ml after salvage therapy) at 24 and 48 weeks was 36% and 60%, respectively. The strongest independent predictor of VR was the inclusion of a thymidine analogue (TA) in the salvage regimen. The presence of M184V and the introduction of lopinavir/ritonavir as new drug were both marginally associated with better outcome. After 24 weeks of salvage therapy, the median reduction in HIV-1 RNA was -1.36 log10 copies/ml (interquartile range [IQR] 0.10-2.46): at multivariable regression analysis, salvage regimens containing a TA (beta = +0.80; P = 0.02) and lamivudine (beta = +1.21; P = 0.02) as new drug had a positive effect on the reduction of HIV-1 RNA.. Development of the K65R mutation does not preclude a high rate of virological response to rescue therapy. Inclusion of a TA in the salvage regimen and the presence of a M184V mutation could have a favourable effect on virological outcome.

Topics: Adult; Aged; Anti-HIV Agents; Female; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Italy; Lamivudine; Lopinavir; Male; Middle Aged; Mutation; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Salvage Therapy; Thymidine; Treatment Outcome

To evaluate predictive factors for therapy outcome of a boosted double-protease inhibitor (PI) regimen in 58 extensively pre-treated patients with HIV.. Patients received lopinavir/ritonavir 400/100 mg and saquinavir 1,000 mg twice daily without reverse transcriptase inhibitors (RTI). The primary outcome parameter was HIV RNA < 400 copies/ml at week 48, secondary parameters were HIV-1 RNA and CD4+ T-cell count changes from baseline to week 48. Pharmacokinetics, genotypic resistance and clinical and individual parameters were correlated with the clinical outcome in regression analyses. Covariates for the analyses were minimum plasma concentration (C(min)), maximum plasma concentration, area under the concentration versus time curve, half-life and clearance of lopinavir and saquinavir, the genotypic inhibitory quotients (GIQ) of archived (GI6(arch)) and baseline PI resistance mutations, previously taken antiretrovirals, archived and baseline viral resistance mutations, baseline HIV-1 RNA and CD4+ T-cell count.. The analyses detected correlations between the primary outcome parameter and several factors: baseline CD4+ T-cell count (P = 0.001); absence of mutations at V82T/A/F/I/S plus 154M/V/L (P = 0.002) or K20M/R (P = 0.010); and lopinavir C(min)GIQ(arch) (P = 0.046). This regression model had a predictability of 97.0% for response to therapy. Covariates for the decrease of HIV-1 RNA from baseline to week 48 were baseline HIV-1 RNA (P < 0.001), lopinavir C(min)GIQ(arch) (P = 0.013), presence/absence of mutations at V82T/A/F/I/S or 184A/V plus L10I/R/V/F, 154M/V/L or L63P (P = 0.018), and previously taken antiretrovirals (P = 0.034).. Baseline HIV-1 RNA < 5.0 log10 and CD4+ T-cell count > 200 cells/microl, lopinavir C(min)GIQ(arch) > 2,000 ng/ml and the absence of viral resistance mutations at V82T/A/F/I/S and 154M/V/L are highly predictive for therapeutic success of a regimen of saquinavir/lopinavir/ ritonavir without RTI in a heterogenic cohort of patients with an extensive pre-treatment history and highly variable pharmacokinetics.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Saquinavir; Treatment Outcome; Viral Load

Topics: Child; Drug Industry; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

We describe the emergence of the proV47A mutation in three out of five HIV-2-infected individuals failing lopinavir/ritonavir-based HAART. The appearance of such mutated variants resulted in high levels of phenotypic resistance to lopinavir, cross-resistance to indinavir, amprenavir, and hypersusceptibility to saquinavir. A search in HIV-2 databases revealed that proV47A is present in 8.6% of protease inhibitor (PI)-experienced patients but absent in all PI-naive patients. Its selection may be a common mutational pathway for developing resistance to lopinavir/ritonavir in HIV-2.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-2; Humans; Lopinavir; Male; Middle Aged; Mutation; Phenotype; Pyrimidinones; Ritonavir; Treatment Failure

Lopinavir/ritonavir plus indinavir was administered once daily as directly observed protease inhibitor-only therapy in 12 heavily pretreated HIV-1-infected patients with multiple virological failures and advanced immunosuppression (CD4 cell count 95 x 10 cells/microl). The treatment was well tolerated. At weeks 12, 24 and 48, most patients on treatment achieved viral suppression of less than 400 copies/ml and a corresponding median CD4 T-cell count increase. Pharmacokinetic data indicated therapeutic concentrations for both protease inhibitors in most patients.

Topics: Adult; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Middle Aged; Patient Compliance; Pilot Projects; Pyrimidinones; Ritonavir; Treatment Outcome

To describe a case of exacerbated mania potentially related to an interaction between lopinavir/ritonavir and valproic acid (VPA) and propose a mechanism of action for this interaction.. A 30-year-old man with bipolar disorder and HIV initiated treatment with lopinavir/ritonavir, zidovudine, and lamivudine. Prior to beginning therapy with these antiretrovirals, he was receiving VPA 250 mg 3 times daily, with his most recent VPA concentration measured at 495 micromol/L. Twenty-one days after starting antiretroviral treatment, he became increasingly manic. His VPA concentration at admission was 238 micromol/L, a 48% decrease. The daily VPA dose was increased to 1500 mg, and olanzapine was introduced. The VPA concentration following this dose escalation was 392 micromol/L, and the patient improved clinically.. Fifty percent of VPA is metabolized by glucuronidation, 40% undergoes mitochondrial beta-oxidation, and less than 10% is eliminated by the cytochrome P450 isoenzymes. Ritonavir can induce glucuronidation of several medications including ethinyl estradiol, levothyroxine, and lamotrigine. We believe that ritonavir-mediated induction of VPA glucuronidation resulted in a decrease in VPA concentrations and efficacy. An objective causality assessment suggested that the increased mania was probably related to the decrease in VPA concentration and that a possible interaction exists between lopinavir/ritonavir and VPA.. A potential interaction exists between VPA and all ritonavir-boosted antiretroviral regimens. Clinicians should monitor patients closely for a decreased VPA effect when these medications are given concomitantly.

Topics: Adult; Antiretroviral Therapy, Highly Active; Bipolar Disorder; Dose-Response Relationship, Drug; Drug Interactions; Hepatitis C; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; Valproic Acid

We report the case of a 57-year-old man who presented bilateral subacute and painless optic neuropathy after meningopolyradiculitis revealing a primary human immunodeficiency virus infection. Both antiretroviral and steroid treatments were ineffective. Clinical symptoms and evolutive pattern were consistent with a mechanism of microvascular ischaemia of the optic nerve head. Optic neuropathies related to HIV infection are rare compared to those resulting from opportunistic infections. There are several pathophysiological mechanisms involved.

Topics: AIDS Serodiagnosis; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Disease Progression; Drug Therapy, Combination; Evoked Potentials, Visual; Facial Nerve Diseases; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Ischemia; Lamivudine; Lopinavir; Male; Meningitis, Viral; Methylprednisolone; Middle Aged; Optic Disk; Optic Nerve Diseases; Polyradiculopathy; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Visual Fields; Zidovudine

We studied 382 multiexperienced HIV-infected patients followed up for > or =3 months after starting lopinavir/ritonavir (LPV/r) to identify the factors predicting hypertriglyceridemia and high non-HDL cholesterol levels (triglycerides > or =200 mg/dl and/or non-HDL cholesterol > or =190 mg/dl) after 6 and 12 months of LPV/r exposure. The predictors of hypertriglyceridemia were higher baseline triglyceride levels [OR: 2.28 (95% CI: 1.67-3.12) for each additional 100 mg/dl; p = 0.001], the total duration of antiretroviral treatment [OR: 1.26 (95% CI: 1.12-1.41) for each additional year; p = 0.01], CDC stage C (OR: 2.06; 95% CI: 1.24-3.88; p = 0.02), and male gender (OR: 2.52; 95% CI: 1.42-4.74; p = 0.02); intravenous drug abusers seem less likely to develop the event (OR: 0.52; 95% CI: 0.37-0.92; p = 0.03). The predictors of high non-HDL cholesterol levels were higher baseline levels [OR: 3.92 (95% CI: 1.92-6.24) for each additional 100 mg/dl; p = 0.001) and the combination of NRTIs and NNRTIs with LPV/r (OR: 1.83; 95% CI: 1.10-3.69; p = 0.03). The 75 patients stopping LPV/r showed a significant reduction in median triglyceride and non-HDL cholesterol levels after 3 months of 39 mg/dl and 20 mg/dl (p = 0.01 for both), respectively. Patients with high triglyceride and non- HDL cholesterol levels at the start of LPV/r treatment are at higher risk of developing hyperlipidemia.

Topics: Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

The relationship between lopinavir trough plasma concentration at baseline and virological efficacy 3 months after the beginning of the therapy was investigated in an unselected cohort of HIV-1-infected patients. According to initial trough lopinavir plasma level, patients were classified into three groups: the subtherapeutic group (<3 mg/L, n=18), the therapeutic group (between 3 and 8 mg/L, n=50) and the toxic group (>8 mg/L, n=16). The virological response after 3 months of lopinavir treatment, defined as a viral load <200 HIV-1 RNA copies/mL, was compared amongst these groups.. The virological response was significantly different (P<0.05) between the subtherapeutic group (22.% of patients with viral load<200 copies/mL) and the other groups (56.0% of patients with a viral load<200 copies/mL in the therapeutic group and 56.2% in the toxic group).. A lower virological efficacy should be expected for experienced or naive patients with plasma trough lopinavir concentrations<3 mg/L at the beginning of treatment.

Topics: Adult; Chi-Square Distribution; Drug Administration Schedule; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Ritonavir; Time Factors; Treatment Outcome; Viral Load

For 95 protease inhibitor-experienced HIV-1-infected patients, the genotypic inhibitory quotient (GIQ; trough level/number of mutations) was calculated for lopinavir. Three different sets of mutations showed equal predictive value. However, the use of cumulative numbers of mutations for calculation of the GIQ showed significantly better association with the virological response. Furthermore, the predictive value of the GIQ was no different from that of the number of mutations alone.

Topics: Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyrimidinones; Retrospective Studies; Treatment Outcome; Virus Replication

Mutation proI47A has recently been associated with lopinavir/ritonavir (LPV/r) resistance. Only four out of 1859 specimens (0.2%) sent for drug resistance testing (219 drug-naive and 1650 antiretroviral-experienced) showed I47A. All belonged to patients failing LPV/r. The prevalence among protease inhibitor-experienced patients was 0.6%. Phenotypic testing showed that proI47A caused high-level lopinavir resistance (> 100-fold) and cross-resistance to amprenavir, whereas it caused hypersusceptibility to saquinavir. ProI47A should thus be considered the primary lopinavir resistance mutation.

Topics: Carbamates; Codon; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Mutation; Nelfinavir; Phenotype; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides

Topics: Adult; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

The concentrations of lopinavir and ritonavir in seminal and blood plasma and the seminal human immunodeficiency virus (HIV) viral load were quantified by HPLC and the Nuclisens assay, respectively, in a cross-sectional study of 16 HIV-1-infected Brazilian men under stable treatment with a lopinavir/ritonavir containing antiretroviral regimen. Semen and blood samples were collected on 2 occasions: at 6 to 60 minutes before ("trough"), and 5 to 6 hours after ("peak") ingestion of regular doses of lopinavir/ritonavir. Median seminal lopinavir levels were 120.6 ng/mL (range, <20-1481.8 ng/mL) and 233.1 ng/mL (range, 48.4-1133.4 ng/mL) at trough and peak points, respectively. The corresponding values for ritonavir were 9.2 ng/mL (range, <5-47 ng/mL) and 17.1 ng/mL (range, 6.6-66.7 ng/mL). The median concentrations of lopinavir and ritonavir in semen were, respectively, 1.9% to 3% and 3.7% to 4.4% of those measured in blood plasma samples collected within 30 minutes. HIV-1 viral load was detectable in the semen of 2 and in the blood of 6 of 16 patients. These results may have implications for drug-resistant HIV-1 evolution and transmission.

Topics: Biological Availability; Brazil; Cross-Sectional Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Regression Analysis; Ritonavir; Semen; Time Factors; Urogenital System; Viral Load

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

Topics: Anti-HIV Agents; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Viral Load

To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) and atazanavir (ATV) as a double-boosted protease inhibitor regimen in HIV-infected adults.. Sixteen patients who started LPV/RTV (400/100 mg b.i.d.) and ATV (300 mg q.d.) were enrolled in the study group (arm A). LPV pharmacokinetics were compared to those of two historical groups: arm B, 15 patients who received LPV/RTV (400/100 mg b.i.d.); and arm C, 25 patients who received LPV/RTV/saquinavir (SQV) (400/100/1000 mg b.i.d.). ATV pharmacokinetics were compared to those of 15 consecutive patients who received ATV and RTV (300/100 mg q.d.) (arm D). Drug concentrations were measured by HPLC.. LPV concentrations were significantly higher in arm A than in arms B and C. Median (interquartile range) LPV area under the curve (AUC)0-12 values were 115.7 (99.8-136.5), 85.2 (68.3-109.2) and 85.1 (60.6-110.1) microg/h/ml, respectively. C(max) values were 12.2 (10.7-14.5), 9.5 (6.8-13.9) and 10.0 (6.9-13.6) microg/ml, respectively. C(min) values were 9.1 (7.1-10.4), 5.6 (4.7-8.2) and 5.5 (4.2-7.5) microg/ml, respectively. No difference was observed for ATV AUC0-24 or C(max) between arms A and D. ATV C(min) values were 1.07 (0.61-1.79) in arm A and 0.58 (0.32-0.83) in arm D (P = 0.001). Treatment was not discontinued in any patient because of adverse effects. At 24 weeks, viral load was < 50 copies/ml in 13 of 16 patients.. The combination of ATV and LPV/RTV provided high plasma concentrations of both PI, which seemed to be appropriate for patients with multiple prior therapeutic failures, yielding good tolerability and substantial antiviral efficacy.

Topics: Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug Combinations; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oligopeptides; Pilot Projects; Pyridines; Pyrimidinones; Ritonavir; Salvage Therapy; Treatment Failure; Treatment Outcome; Viral Load

Topics: Antiretroviral Therapy, Highly Active; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypothyroidism; Lopinavir; Middle Aged; Pyrimidinones; Ritonavir; Thyroxine

Nevirapine (NVP) resistance may decrease the effectiveness of viral suppression with NVP-based antiretroviral therapy (ART) in women infected with human immunodeficiency virus (HIV) with previous exposure to single-dose NVP. However, the alternative lopinavir-ritonavir-based ART regimen is more expensive. Our objectives were to project the tradeoffs regarding life expectancy, cost, and cost-effectiveness of these ART regimens for NVP-exposed, HIV-infected women in South Africa.. We developed a simulation model in which NVP-exposed, HIV-infected South African women received 1 of 5 treatment strategies: HIV care without ART, NVP-based ART, lopinavir-ritonavir-based ART, NVP-based ART followed by lopinavir-ritonavir-based ART, or lopinavir-ritonavir-based ART followed by NVP-based ART. The prevalence of NVP resistance was 39%; other data were obtained from the published literature.. Projected life expectancy was 43.7 months for women who did not receive ART, 77.4 months for women who received a single NVP-based regimen, and 84.5 months for women who received a single lopinavir-ritonavir-based regimen. NVP resistance reduced survival time by up to 11.6 months among women who received NVP-based ART. The cost-effectiveness of NVP-based ART was $800 (US dollars) per year of life saved, compared with no ART, and the cost-effectiveness of lopinavir-ritonavir-based therapy was $4400 per year of life saved, compared with NVP-based ART. Lopinavir-ritonavir followed by NVP-based ART yielded the greatest life expectancy (105.4 months), had a cost-effectiveness of $2300 per year of life saved, and, if the efficacy of NVP-based regimens improved >6 months postpartum, further increased survival.. NVP resistance substantially decreased the projected survival time associated with NVP-based ART, and lopinavir-ritonavir-based ART resulted in a superior survival time but at higher cost. A sequential regimen starting with lopinavir-ritonavir-based ART followed by NVP-based ART maximized projected survival and was cost effective in South Africa.

Topics: Adult; Anti-HIV Agents; Computer Simulation; Cost-Benefit Analysis; Decision Support Techniques; Female; HIV Infections; Humans; Lopinavir; Models, Biological; Nevirapine; Pyrimidinones; Ritonavir; South Africa

Tenofovir-related tubule damage characterized by Fanconi syndrome, renal insufficiency and nephrogenic diabetes insipidus has been reported in the adult HIV-infected population. To our knowledge there has been no reported case of such complications in the pediatric population. We report the case of a 12-year-old perinatally HIV-infected African-American girl who developed nephrogenic diabetes insipidus, renal insufficiency and Fanconi-like syndrome while taking tenofovir (Viread) in combination with lopinavir-ritonavir (Kaletra) and didanosine (Videx).

Topics: Adenine; Anti-HIV Agents; Child; Diabetes Insipidus, Nephrogenic; Didanosine; Drug Therapy, Combination; Fanconi Syndrome; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Kidney; Kidney Diseases; Lopinavir; Organophosphonates; Pregnancy; Pregnancy Complications; Pyrimidinones; Ritonavir; Tenofovir

Topics: Adult; Drug Combinations; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir; United States; United States Food and Drug Administration

The authors evaluated the pharmacokinetics and tolerability of indinavir/lopinavir/ritonavir in a protease inhibitor only combination.. Plasma drug levels of patients taking indinavir/lopinavir/ritonavir 800/400/100mg twice daily (n = 24, group 1) were compared to patients taking either lopinavir/ritonavir 400/100mg (n = 35, group2) or indinavir/ritonavir 800/100mg (n = 33, group3) twice daily plus nucleos(t)ide reverse transcriptase inhibitors (NRTI). Steady-state drug concentrations were measured by LC/MS/MS. Minimum and maximum concentrations (C subsetmin, C subsetmax), area under the concentration-time curve (AUC subset0-12h), total clearance (CL subsettot) and half-life (t1/2) were calculated. HIV viral load, CD4 cell count and adverse events causing early termination of therapy were correlated over a period of 48 weeks.. Plasma levels of lopinavir/ritonavir were significantly enhanced when combined with indinavir compared to a regimen of lopinavir/ritonavir+NRTI: Mean lopinavir AUC subset(0-12h) 80,912 ng*h/mL vs. 60,548 ng*h/mL; C subsetmin 4,633 ng/mL vs. 3,258 ng/mL; C subsetmax 8,023 ng/mL vs. 6,710 ng/mL. Mean ritonavir AUC(0-12h) 6,907 ng*h/mL vs. 3,467 ng*h/mL; Cmin 220 ng/mL vs. 125 ng/mL; C subsetmax 1,059 ng/mL vs. 522 ng/mL. Indinavir levels were comparable for both indinavir containing regimen. A significantly smaller number of patients stopped indinavir/lopinavir/ritonavir therapy (group1: 16.7%) than indinavir/ritonavir + NRTI treatment (group3: 45.5%) due to adverse events. Virological failure was the main reason for early termination of treatment with indinavir/lopinavir/ ritonavir before week 48 (group1: 50%).. indinavir/lopinavir/ritonavir 800/400/ 100mg twice daily represents a therapy option with an adequate safety but only short term efficacy for extensively pretreated patients.

Topics: Adult; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Mass Spectrometry; Maximum Tolerated Dose; Metabolic Clearance Rate; Pyrimidinones; Ritonavir; Viral Load

A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in MT-4 cells). Select imidazolidine-2,4-dione containing PIs were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 microg h/mL.

Topics: Crystallography, X-Ray; Drug Design; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Imidazolidines; Lopinavir; Magnetic Resonance Spectroscopy; Mutation; Pyrimidinones; Structure-Activity Relationship

We present a case with important pharmacogenetic and pharmacokinetic aspects of antiretroviral therapy in a patient with high efavirenz concentrations, severe CNS side-effects and low lopinavir concentrations. Despite therapeutic drug monitoring and subsequent efavirenz dosage reductions, side-effects did not resolve completely and lopinavir concentrations remained relatively low.

Topics: Adult; Alkynes; Anti-HIV Agents; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Monitoring; Genotype; HIV; HIV Infections; Humans; Lopinavir; Male; Oxazines; Oxidoreductases, N-Demethylating; Pyrimidinones

Tenofovir disoproxil fumarate (TDF) is renally excreted by a combination of glomerular filtration and active tubular secretion, and its renal safety profiles have been reported based on a limited increase of serum creatinine (sCr) levels. However, renal tubular function has not previously been well monitored. We measured sCr and urinary beta2-microglobulin (U-beta2MG) levels cross-sectionally in 70 patients treated with TDF [TDF+] and 90 patients on other antiretroviral therapy who had never been exposed to TDF [TDF-]. The mean U-beta2MG was significantly higher in TDF+ patients than that in TDF- patients (p < 0.0001), though no statistical difference was detected in their creatinine clearance estimated by using the Cockcroft-Gault equation. Multivariate analysis showed that coadministration of boosted lopinavir (LPV) and patients' body weight were associated with U-beta 2MG levels in TDF+ patients. U-beta2MG levels were significantly higher in those who also received boosted LPV [TDF+LPV+] (p = 0.0007), and abnormally high levels were noted in 67.7% of them. Furthermore, in the TDF+LPV+ group, U-beta2MG levels showed significant negative correlation with patients' body weight (p = 0.0029) and abnormal U-beta2MG was observed in all six patients with body weight less than 55 kg. In four patients, a rapid fall in U-beta2MG occurred after cessation of TDF. Relative to sCr, U-beta2MG could be a more sensitive marker of renal tubular injury caused by TDF. Boosted LPV co-administration and low body weight may be risk factors for TDF-induced renal tubular dysfunction, probably because these factors are associated with an increase in TDF concentration.

Topics: Adenine; Adult; Anti-HIV Agents; beta 2-Microglobulin; Biomarkers; Creatinine; Female; HIV Infections; HIV-1; Humans; Kidney Tubules; Lopinavir; Male; Middle Aged; Organophosphonates; Pyrimidinones; Tenofovir; Thinness

Antiretroviral combination therapies, including nevirapine (NVP) and protease inhibitors (PI), are increasingly used in the treatment and for the prophylaxis of vertical HIV-1 transmission in HIV-1 infected pregnant women.. To determine pharmacokinetics and placental transfer of NVP and different PI in pregnancy we measured drug levels in maternal and foetal compartments at the day of delivery.. We conducted a prospective study in 40 eligible HIV-1 infected pregnant women who gave birth in our hospital. A pre-dose to 6 h post-dose steady-state pharmacokinetic analysis (n = 35) of the drugs on the day of the scheduled Caesarean section was performed. In addition cord blood and amniotic fluid drug levels were measured (n = 40).. In all women NVP plasma concentrations (n = 20) were below the recommended level. PI plasma concentrations (nelfinavir, n = 5; saquinavir, n = 3; lopinavir, n = 10; ritonavir, n = 13) were extremely variable. Cord blood and amniotic fluid drug levels suggested that NVP passes the placenta unrestricted whereas PI were detected in smaller concentrations in the foetal compartment.. Because of the changed pharmacokinetics of antiretroviral drugs in pregnancy therapeutic drug monitoring could be important and dose adjustment should be considered. The minimal placental transfer of PI is desirable from the perspective that the foetus is protected from potentially teratogenic agents. However, it is not known if antiretroviral compounds in the foetal compartment contribute to the risk reduction of vertical HIV-1 transmission, and whether the property of missing placental transfer is in fact beneficial for the newborn.

Topics: Amniotic Fluid; Antiretroviral Therapy, Highly Active; Drug Combinations; Drug Interactions; Female; Fetal Blood; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Nevirapine; Placenta; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Pyrimidinones; Viral Load

This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects.. In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2.. In Part 1, a single RTV dose increased the APL AUC(0-infinity) by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported.. Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.

Topics: Adolescent; Adult; Animals; Benzoates; CCR5 Receptor Antagonists; Diketopiperazines; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Male; Mice; Middle Aged; Piperazines; Pyrimidinones; Rats; Ritonavir; Spiro Compounds

To examine differences among four protease inhibitor (PI)-based drug regimens in adherence to therapy and rate of achievement of virological suppression in a cohort of antiretroviral-naive patients initiating highly active antiretroviral therapy (HAART).. Participants were antiretroviral-naive and were first dispensed combination therapy containing two nucleosides and a ritonavir (RTV)-boosted PI, or unboosted nelfinavir, between 1 January 2000 and 30 September 2003. Logistic regression analysis was used to examine associations between the prescribed PI and other baseline factors associated with being >90% adherent to therapy and then to determine the associations of prescribed drug regimen, adherence to therapy and baseline variables with the odds of achieving two consecutive viral loads of <500 HIV-1 RNA copies/mL. RESULTS A total of 385 subjects were available for analysis. Lopinavir (LPV)/RTV was prescribed for 168 patients (42% of total); 86 (22%) received indinavir (IDV)/RTV; 91 (24%) received nelfinavir (NFV) and 40 (10%) received saquinavir (SQV)/RTV. SQV/RTV-based HAART was associated with reduced adherence to therapy [odds ratio (OR)=0.40; 95% confidence interval (CI) 0.19-0.83]. In multivariate models, IDV/RTV (OR=0.45; 95% CI 0.22-0.92), SQV/RTV (OR=0.18; 95% CI 0.07-0.43) and NFV were associated with reduced odds of achieving virological suppression within 1 year in comparison to LPV/RTV-based therapy. For patients receiving NFV, adjusting for adherence (OR=0.73; 95% CI 0.36-1.47) rendered this association nonsignificant.. Patients prescribed IDV/RTV, NFV or SQV/RTV were less likely to achieve virological suppression on their first regimen compared with patients prescribed LPV/RTV. Reduced adherence to these therapies only partly explained these observed differences.

Topics: Adult; Antiretroviral Therapy, Highly Active; British Columbia; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Nelfinavir; Patient Compliance; Pyrimidinones; Ritonavir; Saquinavir; Viral Load

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

Topics: Atazanavir Sulfate; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Patient Selection; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome

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

Lopinavir is one of the most-widely used protease inhibitors in the treatment of HIV-1 infected patients. Concentration-effect relationships have been described for both antiviral activity and toxicity. Less is known about patient characteristics that may determine interpatient variability in lopinavir plasma concentrations. A database was created containing all Therapeutic Drug Monitoring (TDM) results collected at our Department. Patients were included if they were using lopinavir twice daily for at least two weeks; subjects who were known to be nonadherent (based on either a lopinavir concentration <0.2 mg/L or suspected by the physician) were excluded. Demographic data were collected from TDM application forms and patient charts. Patients attending one of the 22 HIV treatment centers in The Netherlands. The Department of Clinical Pharmacy is a national referral center for TDM of antiretroviral agents. Lopinavir concentration ratios (CRs) were calculated for each patient by dividing the individual plasma concentration by the time-adjusted population value. Relationships with lopinavir CRs were tested using regression analysis and analysis of variance. A total of 802 patients were included (607 males; 150 females; 45 unknown). The age and body weight of the patients ranged from 18 to 74 years (mean 42) and 42 to 121 kg (mean 72), respectively. Race was known for 756 persons: Caucasian 76%, African 18% and Asian 6%. The median (+ interquartile range, IQR) lopinavir CR was 0.98 (IQR: 0.67-1.31). Body weight showed an inverse relationship with lopinavir CR (F = 23.1; P < 0.001). Age was not related with lopinavir CR (P = 0.99). Female patients had a significantly higher lopinavir CR than males: 1.18 vs. 1.03 (P = 0.005); race was not associated with differences in lopinavir CR. In a multivariate regression analysis body weight, but not gender, remained significantly related to lopinavir CR. Body weight is the only demographic factor that could be related to lopinavir exposure; clinicians should be alert for an increased risk of suboptimal antiviral efficacy in patients with high body weight, and for an increased risk of toxicity in patients with a low body weight.

Topics: Adolescent; Adult; Aged; Body Weight; Databases, Factual; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Regression Analysis; Retrospective Studies; Tissue Distribution

The genotypic inhibitory quotient (GIQ) is the ratio between drug concentration and the number of resistance mutations. However, as different resistance scores can be calculated for the same protease inhibitor, the ability of a GIQ to predict the virological outcome may vary depending on the resistance score used as the denominator. Forty-four highly treatment-experienced HIV-infected patients failing on their current regimen were treated with a lopinavir/ritonavir-containing combination for at least 48 weeks. Three GIQs were calculated for each patient: the denominator of the first (GIQ-A) was the lopinavir/ritonavir score calculated using the mutations listed by IAS-USA as being related to lopinavir/ritonavir resistance; the denominator of the second (GIQ-B) was the total number of mutations related to resistance to any protease inhibitor as reported by IAS-USA; and the denominator of the third (GIQ-C) was the lopinavir/ritonavir score proposed by Parkin et al. The median (IQR) of the GIQ-A, B, and C was 4.69 (3.83-9.76), 0.97 (0.74-1.62), and 1.02 (0.68-2.52), respectively. At week 48, the median decrease in HIV-RNA was 1.09 (0.32-2.34) log(10) copies/ml (P < 0.0001), with 13 subjects (29.5%) attaining undetectable levels. All of the GIQs independently predicted the change in viral load from baseline and undetectable HIV-RNA at week 48. The partial R(2) of GIQ-C was greater than that of GIQ-B, which was greater than that of GIQ-A. All of the GIQs were independent predictors of the 48-week virological response. The predictive value of the GIQ for lopinavir/ritonavir may vary depending on the algorithm used to score drug resistance.

Topics: Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Multivariate Analysis; Predictive Value of Tests; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Outcome

Topics: Developing Countries; Drug Industry; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Private Sector; Pyrimidinones; Ritonavir

To determine whether the level of persistent HIV-1 viremia is affected by simplifying standard antiretroviral therapy to lopinavir/ritonavir (LPV/r) alone.. Measurement of HIV-1 RNA levels < 50 copies/ml in longitudinal plasma samples from 41 of 42 subjects enrolled in the 'Only Kaletra' study that compared maintenance therapy with LPV/r alone to standard of care (SOC) with two nucleoside reverse transcriptase inhibitors (NRTI) and LPV/r.. Plasma samples for each subject from study screening to week 48 were tested using a modified Roche Amplicor HIV-1 RNA assay with a quantification limit of 3 copies/ml.. Median plasma HIV-1 RNA values at baseline and weeks 4, 8, 12, 24 and 48 were not significantly different between the LPV/r alone and the SOC arms, being 5.1 versus 3.0 (P = 0.29), 4.5 versus 2.9 (P = 0.44), 3.3 versus 2.9 (P = 0.99), 1.9 versus 1.0 (P = 0.68), 3.7 versus 3.6 (P = 0.49), and 2.8 versus 1.6 copies/ml (P = 0.78), respectively. In the 17 of 21 subjects who maintained virus suppression < 50 copies/ml on LPV/r alone, median HIV-1 RNA values did not increase significantly from baseline at any time point after discontinuing NRTI, in comparison to the three subjects with virologic failure whose median HIV-1 RNA levels began to rise at week 8.. The level of persistent viremia did not increase after stopping NRTI therapy among subjects who maintained virus suppression < 50 copies/ml on LPV/r alone through 48 weeks. This supports further studies of induction-simplification therapy for treatment of HIV-1 infection including the identification of factors predicting success or failure of simplified therapy.

Topics: Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Longitudinal Studies; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Failure; Viral Load; Viremia

Topics: Anti-Retroviral Agents; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Ritonavir; RNA, Viral

Topics: Adult; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Exanthema; Female; HIV Infections; HIV Protease Inhibitors; Humans; Kidney Diseases; Lopinavir; Myelopoiesis; Pyrimidinones

The combination of atazanavir (ATV) plus lopinavir/ritonavir (LPV/r) has been used in practice. However, clinical data supporting its use are limited. The objective of this study was to evaluate the efficacy and tolerability of regimens with ATV + LPV/r in protease inhibitor (PI)-susceptible and PI-resistant patients. A retrospective review of 2703 charts was performed to identify all patients who received ATV + LPV/r. From June 2003 to January 2005, 33 patients received ATV + LPV/r with nucleoside reverse transcriptase inhibitors (NRTIs) for 3 months or more. Virologic success (HIV-RNA < 400 copies per milliliter) was achieved in 30 patients (91%) in a median of 10 weeks (range, 2-68). Nineteen of the 23 patients (83%) who had ultrasensitive viral load (VL) assays were nondetectable. Among patients with 6 or more protease resistance (PR) mutations (PI-resistant), 11 of 14 (79%) achieved virologic success. Eleven of those received phenotypic testing (10 Virtual Phenotype, VircoLab, Baltimore, MD). Despite predicted phenotypic resistance to ATV (6 patients) and LPV/r (7 patients), virologic success was achieved in 4 of 6 (67%) and 4 of 7 (57%), respectively. The 3 PI-resistant patients who were virologic failures had extensive prior LPV/r use, 8-11 PR mutations, and predicted phenotypic resistance to LPV/r, but 2 of 3 had CD4 increases with ATV + LPV/r. Overall, 28 patients (85%) continue to tolerate ATV + LPV/r for a median of 32 weeks follow-up (range, 12-76). Combination ATV + LPV/r with NRTIs appears safe, tolerable, and efficacious in PI-resistant patients (>/=6 PR mutations) and predicted phenotypic resistance to ATV and LPV/r. Further studies of ATV + LPV/r in HIV-treatment are warranted.

Topics: Adult; Aged; Atazanavir Sulfate; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Retrospective Studies; Ritonavir

The long-term immunological efficacy of regimens including lopinavir/ritonavir (LPV/r) has not been assessed in HIV-infected HAART-experienced subjects. The present study included 452 consecutive HIV-infected outpatients starting LPV/r before May 2003 after failing (HIV-RNA > 1000 copies/ml) HAART. Four groups were considered according to CD4 cell counts at LPV/r initiation: group 1 (G1, n = 115) < 100 cells/mm(3); group 2 (G2, n = 113) 100-199 cells/mm(3); group 3 (G3, n = 115) 200-349 cells/mm(3); group 4 (G4, n = 109) >/= 350 cells/mm(3). The majority of patients were males (n = 320, 70.8%), the median age was 38 years, and 180 (39.6%) were on CDC stage C. The median time of previous HAART was 51.1 months (12-81.7) and a median of 7 antiretroviral regimens and of 3 protease inhibitors was changed before LPV/r. The mean CD4 cell count increase was 105, 113, 128, and 144 cells/mm(3) after 12 months (p < 0.01 for each group) and 128, 106, 90, and 100 cells/mm(3) at month 48 (p < 0.01 for each group) in G1, G2, G3, and G4, respectively. The mean increase was comparable among the four groups. The on treatment analysis showed a better immunologic response among G1 and G2 patients from month 36. Forty-seven patients (10.4%), mainly in G1 and G2, maintained LPV/r despite persistent HIV-RNA > 1000 copies/ml. A mean increase of 64 and 65 cells/mm(3) and of 88 and 56 cells/mm(3) at month 12 and 48 was observed in G1 and G2, respectively. The use of LPV/r-based regimens also provided a durable immunologic recovery in highly pretreated HIV-infected subjects.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Ritonavir; Time Factors

Topics: Acquired Immunodeficiency Syndrome; CCR5 Receptor Antagonists; Clinical Trials as Topic; Darunavir; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Ritonavir; Salvage Therapy; Sulfonamides

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Anti-HIV Agents; Antifungal Agents; Biopsy; Female; Histoplasma; Histoplasmosis; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Lopinavir; Pyrimidinones; Skin; Treatment Outcome

Topics: HIV Infections; Humans; Lopinavir; Pilot Projects; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load

Topics: Cholesterol; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Multicenter Studies as Topic; Pyrimidinones; Randomized Controlled Trials as Topic; Saquinavir; Triglycerides

Topics: CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Viral Load

Topics: Anti-HIV Agents; Contraindications; HIV Infections; Humans; Lopinavir; Pyrimidinones

A HIV-positive patient, 3 months after the treatment initiation with lopinavir-/ritonavir (LPV/r) acquired macroglossia. The tongue biopsy revealed mature adipose tissue accumulated into submucosa. The drug was discontinued and the patient showed a significant improvement. This case is the first case in the medical literature of acquired macroglossia because of LPV/r, a drug causing changes in body fat composition.

Topics: Aged; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Macroglossia; Pyrimidinones; Ritonavir

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

Topics: Adult; Aged; Female; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

Topics: Atazanavir Sulfate; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir

Topics: Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Viral Load

The human immunodeficiency virus type 1 (HIV-1) resistance profile, K65R, K70E and M184V, on reverse transcriptase gene was associated with the virologic rebound consecutively to the switch of lopinavir/r to tenofovir DF in a stable regimen with nucleoside backbone of abacavir, lamivudine and didanosine. The high selective pressure on the same resistance pathway was probably associated with the loss of antiviral potency, even in well-controlled patient.

Topics: Adenine; Adult; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Gabon; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lopinavir; Microbial Sensitivity Tests; Mutation; Organophosphonates; Pyrimidinones; Tenofovir; Viral Load

Tenofovir disoproxil fumarate (TDF) has been anecdotally associated with isolated hypophosphatemia (HP) as well as proximal tubular toxicity and renal dysfunction in which HP has consistently been a feature. Consequently, routine phosphate measurements in TDF recipients have been recommended. We identified and compared the frequency of HP in TDF recipients with that in non-TDF recipients; assessed the reproducibility of HP; identified the incidence of renal dysfunction in hypophosphatemic patients; and evaluated associations between HP and host, HIV infection, or treatment factors. This prospective observational study measured serum phosphate, urea, and creatinine in HIV-positive individuals among the following treatment groups: TDF-containing highly active antiretroviral therapy (HAART, group A), TDF-sparing HAART (group B), HAART naive (group C), and off HAART but treatment experienced (group D). Phosphate measurements were obtained in 252 patients. Seventy-two percent of patients prescribed TDF received a phosphate measurement. The frequency of HP in groups A, B, C, and D was 31%, 22%, 10%, and 14%, respectively. Seventy-eight percent of phosphate measurements were reproducible. Kaletra (P = 0.016) administration and duration of antiretroviral therapy (P = 0.023) were independently associated with HP, but elevated creatinine and urea or use of TDF was not. The etiology of HP seems to be multifactorial and unrelated to TDF or renal dysfunction. This questions the utility of routine phosphate testing, in isolation, in TDF recipients.

Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blood Chemical Analysis; Creatinine; Fanconi Syndrome; Female; HIV Infections; Humans; Hypophosphatemia; Lopinavir; Male; Organophosphonates; Phosphates; Prospective Studies; Pyrimidinones; Reproducibility of Results; Tenofovir; Urea

Identify the determinants and consequences of interrupting and discontinuing highly active antiretroviral therapy (HAART) among a population-based cohort of HIV-infected men.. Longitudinal analyses were applied to 2916 person-visit pairs (589 men) of continuous HAART use, 243 person-visit pairs (154 men) during which HAART was interrupted, and 151 person-visit pairs (130 men) in which HAART was discontinued by the second visit. HIV RNA increase was defined as > or =1 log10 copies/mL across the visit pairs.. : Younger age, black race, geographic location, higher HIV RNA level, depression, shorter time on HAART, lower medication adherence, and not taking a lamivudine-containing regimen predicted interrupting HAART use. Younger age, higher HIV RNA level, depression, and taking an abacavir- or lopinavir-containing regimen predicted discontinuing HAART. Among men with < or =1000 HIV RNA copies/mL, approximately 5% of those who interrupted HAART for < or =7 days and those who continued HAART had an HIV RNA increase. Men with longer interruptions and HAART discontinuers had significantly higher rates of HIV RNA increases (35.7% and 70.5%, respectively). Discontinuation and long interruptions resulted in lower CD4 cell counts.. Host characteristics play a role in short interruptions, whereas longer interruptions may be clinically indicated. These longer stoppages had further virologic and immunologic consequences, however.

Topics: Adult; Age Factors; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Depression; Dideoxynucleosides; Ethnicity; HIV; HIV Infections; Humans; Logistic Models; Lopinavir; Male; Middle Aged; Pyrimidinones; Risk Factors; RNA, Viral; Treatment Refusal

Topics: Antiretroviral Therapy, Highly Active; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pilot Projects; Pyrimidinones; Ritonavir

To describe the evolution of the lipidic profile among LPV/r treated patients in a 'real life' situation.. Lipids measurements at LPV/r initiation time and every 3 months, and pharmacological measurements at M3 and M6 were collected retrospectively in 142 patients attending our clinic. Dyslipidaemia was defined as total cholesterol > or =6.2 mmol/l, HDL-cholesterol > or =1 mmol/l, total/HDL-cholesterol ratio > or =6.5 and triglycerides > or =2.3 mmol/l.. Eighty-nine percent of patients had previously received a regimen with protease inhibitors, 4% were treatment naive. At baseline, 17% of patients had high total cholesterol, 49% high triglycerides, 63% low HDL-cholesterol, 25% a high total/HDL-cholesterol ratio. At M12, the mean HDL-cholesterol increase per patient was 21%. Lipids levels significantly increased over the study period, as early as the 3rd month (6th month for ratio) and continuously until the 12th month. Among the patients with available LPV/r plasma determinations at M3, a higher lopinavir residual concentration was observed in those with high triglycerides (6.78 vs 3.02 mg/l, p = 0.05) as, at M6, in those with an elevated ratio (9.19 vs 0.96 mg/l, p = 0.02).. Those results suggest that LPV/r may induce a significant rise in the total/HDL-cholesterol ratio, despite an increase in HDL-cholesterol levels. The association between triglycerides and total/HDL-cholesterol ratio elevated levels and high residual concentrations of lopinavir may also argue for systematic drug monitoring.

Topics: Adult; Cholesterol; Cholesterol, HDL; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Ritonavir; Time Factors

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

To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy.. A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response.. The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/microL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002).. A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Failure

The long-term virological efficacy of lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART) in HIV-infected patients failing a first-line protease inhibitor (PI)-based regimen is still unclear.. An observational study was carried out from December 2000-December 2002 on 111 consecutive patients starting lopinavir/ritonavir. The primary end-point was virological success (HIV RNA <50 copies/mL in two consecutive determinations). CD4 outcome, lipid levels and adverse events were recorded. The Kaplan-Meier method and log-rank test were used to estimate the time-dependent probability of reaching the end-point using intention-to-treat and on-treatment approaches.. Ninety-six patients obtained virological success during follow-up; Kaplan-Meier analysis showed that the time-dependent probability of obtaining this end-point was 78.4% at month 12 and 85.8% at month 24. The median CD4+cell count increased by 118 cells/mm(3) from baseline to month 12 and by 153 cells/mm(3) to month 24. Thirty-one patients discontinued lopinavir/ritonavir: 16 because of drug-related toxicities, six for simplification, five because of virological failure, one patient was lost at follow-up and three died. An elevation in lipid parameters was observed, but only a minority of patients developed a grade 3 or higher hypertriglyceridaemia and/or hypercholesterolaemia. Among the 15 patients not reaching virological success, five had < or =5 mutations in the protease region known to reduce susceptibility to lopinavir/ritonavir (one discontinued lopinavir/ritonavir because of gastrointestinal intolerance), five had no mutations (two discontinued lopinavir/ritonavir because of gastrointestinal intolerance) and five showed > or =6 mutations (all discontinued lopinavir/ritonavir); however, of the patients who discontinued lopinavir/ritonavir none achieved HIV RNA <50 copies/mL on subsequent regimens.. Lopinavir/ritonavir was highly effective and well tolerated in HIV-infected patients failing a first-line PI-based HAART.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Anti-HIV Agents; Antifungal Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Fluconazole; Flucytosine; HIV Infections; Humans; Immunologic Memory; Lamivudine; Lopinavir; Male; Meningitis, Cryptococcal; Pyrimidinones; Recurrence; Ritonavir; Syndrome; T-Lymphocyte Subsets; Zidovudine

Intensification therapy adding a boosted protease inhibitor (PI) to a failing regimen has the potential to worsen the resistance profile. Sixty-six patients included in four different boosted PI intensification studies were assessed and resistance mutations in the reverse transcriptase and protease genes were evaluated at baseline and 4 weeks after the initiation of the intensification strategy. Only one of the 66 patients developed changes in their pattern of mutations able to generate or increase resistance to new drugs.

Topics: Antiretroviral Therapy, Highly Active; Carbamates; Drug Resistance, Multiple, Viral; Follow-Up Studies; Furans; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lopinavir; Mutation; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides; Treatment Failure; Viral Load

The objective of this study was to find predictive factors of lopinavir/ritonavir (LPV/r) discontinuation for drug-related toxicities in highly pre-treated human immunodeficiency virus (HIV)-infected subjects. The study was an observational study of HIV patients starting LPV/r with HIV RNA > 3log10 copies/mL and a follow-up > or = 6 months. Parameters studied were HIV RNA, CD4+ cell counts, metabolic parameters and drug-related adverse events. Acquired immune deficiency syndrome (AIDS) events and deaths were recorded. The Kaplan-Meier (KM) model was used to estimate time-dependent probability, and the multivariable Cox model to identify predictors of LPV/r discontinuation for adverse events. The study evaluated 416 HIV-infected patients. Seventy-seven patients (18.5%) discontinued LPV/r for toxicities. Adverse events leading to LPV/r discontinuation were gastrointestinal symptoms in 40 cases, hyperlipidaemia in 27 and increase of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in 10 patients. Nineteen patients (4.6%) developed an AIDS event during observation and 15 (3.6%) died. The KM probability of LPV/r discontinuation for toxicities was 5.3% (range 3.1-7.5%) at month 12 and 15.7% (range 12.1-19.3%) at month 24. Subjects with hepatitis C virus (HCV)-HIV co-infection (odds ratio (OR) 7.40; 95% confidence interval (CI) 3.73-14.66 versus HCV-negative; P = 0.001) and receiving LPV/r plus nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitor (PI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) (OR 1.74; 95% CI 1.04-2.91 versus LPV/r plus only NRTIs; P = 0.04) showed a higher risk of LPV/r discontinuation by a Cox analysis, whereas non-intravenous drug abusers (IVDUs) (OR 0.40; 95% CI 0.24-0.67 versus IVDUs; P = 0.001) had a lower risk. The rate of discontinuation for toxicity decreased by 17% for each additional month of LPV/r exposure (OR 0.83; 95% CI 0.80-0.86 for each additional month; P < 0.001). LPV/r was substantially well tolerated. Diarrhoea was the most frequent adverse event leading to discontinuation. HCV-HIV co-infected patients and patients with a short exposure to LPV/r have a higher risk of discontinuing LPV/r and should be strictly monitored.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Cohort Studies; Drug Administration Schedule; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Odds Ratio; Prospective Studies; Pyrimidinones; Risk Factors; Ritonavir

Lopinavir (LPV) is highly bound to plasma proteins and is a substrate for active drugs transporters, which may greatly limit the access of LPV to the central nervous system (CNS). However, even low lopinavir concentrations may be sufficient to inhibit HIV replication. Prior anecdotal reports indicated that lopinavir concentrations were below detection in cerebrospinal fluid (CSF).. LPV was measured by liquid chromatography/mass spectrometry in 31 CSF-plasma pairs from 26 HIV-infected individuals who were taking LPV-containing antiretroviral regimens. The lower limit of quantification was 3.7 microg/l.. Seven of the sample pairs had very low plasma (and CSF) LPV concentrations, with a mean estimated plasma trough of 274 microg/l (range, < 3.7 to 608; typical trough values approximately 4000 microg/l), suggesting poor recent adherence. In the remaining 24 sample pairs, the median LPV concentration was 5889 microg/l [interquartile range (IQR), 4805-9620] and all CSF samples had measurable LPV concentrations: median 17.0 microg/l (IQR, 12.1-22.7). The median CSF-plasma ratio was 0.23% (range, 0.12-0.75). All CSF concentrations in these samples were more than double the 50% inhibitory concentration for wild-type HIV virus.. In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.

Topics: Adult; Antiretroviral Therapy, Highly Active; Chromatography, Liquid; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Mass Spectrometry; Middle Aged; Prospective Studies; Pyrimidinones

We studied the pharmacokinetics of lopinavir/ritonavir dosed at 800/200 mg a day in 20 HIV-1-infected patients, and evaluated the effect of dose modifications in the case of trough concentration (Ctrough) levels less than 1.0 mg/l. Ctrough levels after the daily administration of lopinavir/ritonavir were lower than with twice daily administration. Dose modifications in four patients with Ctrough levels less than 1.0 mg/l succeeded in only one patient. Therapeutic drug monitoring can identify patients with lower-than-expected lopinavir exposure in a larger study.

Topics: Dose-Response Relationship, Drug; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

Topics: Administration, Oral; AIDS Serodiagnosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Early Diagnosis; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Prognosis; Pyrimidinones; Survival Rate; Treatment Outcome; United States

The SCOLTA project (Surveillance Cohort Long-term Toxicity Antiretrovirals) is a system for online surveying of adverse reactions to recently commercialized antiretroviral drugs and a "sentinel" for unexpected and late adverse reactions arising during any antiretroviral treatment (available at: http://www.cisai.info). To date, 25 Italian departments of infectious diseases have participated at the project. The New Drugs Project is a prospective, multicenter, observational pharmacovigilance study involving 1 cohort of patients for each new drug. All patients who were consecutively started on lopinavir (LPV), tenofovir (TDF), peginterferon (IFN), atazanavir (ATZ), enfuvirtide (T-20), and tipranavir (TPV) were enrolled. All grade III or IV adverse events (according to the AIDS Clinical Trials Group definitions) are reported on the web site. The Unexpected Events Project identifies unexpected adverse reactions during treatment and reports them. This paper presents the preliminary findings for the New Drugs Project. Between October 1, 2002, and March 30, 2004, 1184 patients were enrolled. The lopinavir/ritonavir (LPV/r) cohort comprises 703 patients, the TDF cohort 585, IFN 35, ATZ 95, T-20 10, and TPV 8. So far 100 grades III and IV adverse events have been reported, 73 in the LPV/r group. In this cohort the rate of adverse events per 100 person-years was 14.2 on the basis of all patients treated, 9.8 for treatment-naive patients, and 15 for treatment-experienced patients. These findings, though preliminary, show that this data collection method gives timely real-life information from which to assess the impact of short- and long-term toxicity of new antiretroviral drugs.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Female; HIV Infections; Humans; Italy; Lopinavir; Male; Middle Aged; Product Surveillance, Postmarketing; Pyrimidinones; Ritonavir; Safety

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones; Risk Assessment; Treatment Outcome; United States; United States Food and Drug Administration; Viral Load

We describe the hepatotoxicity encountered in a cohort of HIV-positive patients treated with lopinavir/ritonavir. We used the database from the SCOLTA project, an on-line pharmacovigilance programme involving 25 Italian infectious disease centres. A total of 755 patients were followed, over a mean observation period of 16 months. The incidence of severe events was low despite the high prevalence of patients co-infected with hepatitis virus at enrollment.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Italy; Liver Diseases; Lopinavir; Male; Middle Aged; Product Surveillance, Postmarketing; Pyrimidinones; Ritonavir

The aim of this study was to evaluate the correlation between liver function markers (necrosis and cholestasis) and plasma lopinavir levels in a cohort of HIV-infected patients treated with lopinavir and ritonavir.. The blood samples for determining steady-state C(trough) lopinavir levels and analysing liver function were drawn from fasting patients. Steady-state C(trough) lopinavir levels, liver function and immuno-virological markers were assessed on the same day. Plasma lopinavir and ritonavir levels were determined by means of high-performance liquid chromatography.. One hundred and forty-nine patients were included in the analysis [57 were HCV co-infected (34%) and 10 were HBV co-infected (6.7%)]; they had been treated with lopinavir/ritonavir for a median of 232 days (range 132-282). All patients received lopinavir/ritonavir [400/100 mg twice daily or 533/133 mg twice daily if amprenavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI) was part of therapy] and concomitant therapy with NRTI(s). Median (interquartile) lopinavir trough levels were 6391 ng/mL (4121-8726), 5662 (3585-8893) and 6819 ng/mL (5324-8726) in the patients with HIV alone and those with HIV/HCV (or HBV) co-infection, respectively (P = not significant). Univariate analysis showed a significant association between the cholestasis markers and C(trough) lopinavir level. Multivariate analysis selected only gamma glutamyltranspeptidase (GGT) (OR = 1.010, 95% CI: 1.002-1.021) as being independently associated with plasma lopinavir levels of >6425 ng/mL; alkaline phosphatase (OR = 1.004, 95% CI: 1.000-1.010; P = 0.08) and total bilirubin (OR = 3.118, 95% CI: 0.980-11.715; P = 0.07) were not associated.. Elevated lopinavir concentrations are associated with raised GGT.

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Anti-HIV Agents; Bilirubin; Biomarkers; Cholestasis; Female; gamma-Glutamyltransferase; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Retrospective Studies

To develop a population pharmacokinetic model for lopinavir in combination with ritonavir, in which the interaction between both drugs was characterized, and in which relationships between patient characteristics and pharmacokinetics were identified.. The pharmacokinetics of lopinavir in combination with ritonavir were described using NONMEM (version V, level 1.1). First, ritonavir data were fitted to a previously developed model to obtain individual Bayesian estimates of pharmacokinetic parameters. Hereafter, an integrated model for the description of the pharmacokinetics of lopinavir with ritonavir was designed.. From 122 outpatients 748 lopinavir and 748 ritonavir plasma concentrations were available for analysis. The interaction between the drugs was described by a time-independent inverse relationship between the exposure to ritonavir over a dosing-interval and the apparent clearance (CL/F) of lopinavir. The model parameters volume of distribution and absorption rate constant were 61.6 l (95% prediction interval (PI) 22.4, 83.7) and 0.564 h(-1) (95% PI 0.208, 0.947), respectively. The model yielded a theoretical value for the CL/F of lopinavir without ritonavir of 14.8 l h(-1) (95%PI 12.1, 20.1), which translates to a value of 5.73 l h(-1) in the presence of ritonavir. The only factor with significant effect on the pharmacokinetics was concurrent use of non-nucleoside reverse transcriptase inhibitors (NNRTI), which increased the CL/F of lopinavir by 39% (P < 0.001).. We have developed a model that has defined a time-independent inverse relationship between the exposure to ritonavir and the CL/F of lopinavir, and provided an adequate description of the pharmacokinetic parameters for the latter. Concomitant use of the NNRTIs efavirenz and nevirapine increased the CL/F of lopinavir.

Topics: Adult; Anti-HIV Agents; Capsules; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Models, Chemical; Pyrimidinones; Retrospective Studies; Ritonavir

Lopinavir/ritonavir is a protease inhibitor (PI) that has shown great effectiveness as salvage therapy in PI-experienced HIV-infected children.. To study whether mutations in the HIV-1 protease gene can reliably predict virological responses to salvage therapy with lopinavir/ritonavir in HIV-infected children.. We carried out a prospective study in 56 HIV-infected children. PI-associated resistance mutations were determined by genotypic testing and were scored according to the IAS-USA guidelines 2005.. Children with a 'lopinavir mutation score' (LMS) > or = 6 had a negative association for achieving viral load (VL) control [undetectable viral load (uVL) < or = 400 copies/mL] and maintaining uVL for at least 6 months. Moreover, children with protease-associated mutations (PRAMs) > or = 2 had a negative association for achieving VL control but not for maintaining uVL for at least 6 months. The relative proportion (RP) to uVL was 0.32 (CI95%: 0.16; 0.33; P = 0.002) in children with I54V (46% of total) and 0.48 (CI95%: 0.24; 0.97; P = 0.041) in children with V82A/F (52% of total). Children with I54V and V82A/F had higher prevalence of lopinavir-associated resistance mutations and showed RP of 0.36 (CI95%: 0.17; 0.76; P = 0.007) for achieving uVL.. LMS and PRAMs in HIV-infected children were associated with virological failure in pre-treated HIV-infected children on salvage therapy with lopinavir/ritonavir. Moreover, I54V and V82A/F led to the poorest virological response.

Topics: Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Child, Preschool; Drug Resistance, Viral; Female; HIV Infections; HIV Protease; HIV-1; Humans; Infant; Lopinavir; Male; Mutation; Prognosis; Prospective Studies; Pyrimidinones; Ritonavir; Salvage Therapy; Viral Load

Topics: Acute Disease; Adult; Anti-HIV Agents; Drug Eruptions; Exanthema; HIV Infections; Humans; Lopinavir; Male; Occupational Exposure; Pyrimidinones; Ritonavir; Skin Diseases, Vesiculobullous

Topics: Adult; Antiretroviral Therapy, Highly Active; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome

Topics: Administration, Oral; Adult; Antineoplastic Agents, Phytogenic; Antiretroviral Therapy, Highly Active; Camptothecin; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Irinotecan; Lopinavir; Male; Pyrimidinones; Ritonavir; Sarcoma, Kaposi

Topics: Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome

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: CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Combinations; Drug Resistance, Viral; Drug Synergism; Early Diagnosis; HIV; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; Humans; Lopinavir; Pyrimidinones; Treatment Outcome; Viral Load

Topics: Age Factors; Anti-HIV Agents; Child; Child, Preschool; Clinical Trials as Topic; Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Pyrimidinones; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; RNA, Viral; Viral Load

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; HIV Infections; Humans; Lopinavir; Nevirapine; Oxazines; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load

Topics: Atazanavir Sulfate; Dose-Response Relationship, Drug; Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Treatment Outcome; Viral Load

Topics: Chemical and Drug Induced Liver Injury; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Liver; Lopinavir; Pyrimidinones; Ritonavir

Despite the increasing number of antiretroviral compounds, the number of useful drug regimens is limited owing to the high frequency of cross-resistance.. We studied in vitro two-drug combinations using three protease inhibitors (PIs), tipranavir, amprenavir and lopinavir, on isolates (003 and 004) derived from patients with resistance to multiple PIs compared with the drug-susceptible isolate 14aPre in peripheral blood mononuclear cells. Drug interactions were determined by median dose-effect analysis, with the combination index calculated at several inhibitory concentrations (IC).. In 14aPre experiments, the combination tipranavir + lopinavir demonstrated synergy at low concentrations (IC(50)), an additive effect at IC(75) and antagonism at IC(90)-IC(95); tipranavir + amprenavir were antagonistic at all concentrations except IC(95), where they were synergic; and the lopinavir + amprenavir combination was always antagonistic. In 003 and 004 infections, tipranavir + lopinavir and tipranavir + amprenavir combinations were antagonistic, and lopinavir + amprenavir were synergic, at all concentrations, with the exception of being additive at IC(95).. Our in vitro experiments did not show any advantage in combining second generation PIs as a therapeutic strategy in naive or multi-treatment failure subjects, with the exception of tipranavir + amprenavir at IC(95) in infections by a wild-type isolate.

Topics: Carbamates; Drug Resistance, Viral; Enzyme-Linked Immunosorbent Assay; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyridines; Pyrimidinones; Pyrones; RNA, Viral; Sulfonamides

The goal of this study was to use X-ray crystallography to investigate the structural basis of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors. We overexpressed, purified, and crystallized a multidrug-resistant (MDR) HIV-1 protease enzyme derived from a patient failing on several protease inhibitor-containing regimens. This HIV-1 variant contained codon mutations at positions 10, 36, 46, 54, 63, 71, 82, 84, and 90 that confer drug resistance to protease inhibitors. The 1.8-angstrom (A) crystal structure of this MDR patient isolate reveals an expanded active-site cavity. The active-site expansion includes position 82 and 84 mutations due to the alterations in the amino acid side chains from longer to shorter (e.g., V82A and I84V). The MDR isolate 769 protease "flaps" stay open wider, and the difference in the flap tip distances in the MDR 769 variant is 12 A. The MDR 769 protease crystal complexes with lopinavir and DMP450 reveal completely different binding modes. The network of interactions between the ligands and the MDR 769 protease is completely different from that seen with the wild-type protease-ligand complexes. The water molecule-forming hydrogen bonds bridging between the two flaps and either the substrate or the peptide-based inhibitor are lacking in the MDR 769 clinical isolate. The S1, S1', S3, and S3' pockets show expansion and conformational change. Surface plasmon resonance measurements with the MDR 769 protease indicate higher k(off) rates, resulting in a change of binding affinity. Surface plasmon resonance measurements provide k(on) and k(off) data (K(d) = k(off)/k(on)) to measure binding of the multidrug-resistant protease to various ligands. This MDR 769 protease represents a new antiviral target, presenting the possibility of designing novel inhibitors with activity against the open and expanded protease forms.

Topics: Binding Sites; Crystallization; Crystallography, X-Ray; Drug Resistance, Multiple, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Models, Molecular; Molecular Sequence Data; Pyrimidinones

Topics: Anticonvulsants; Drug Industry; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Levetiracetam; Lopinavir; Piracetam; Pyrimidinones; United States; United States Food and Drug Administration

To evaluate the interindividual variability in the plasma concentrations of lopinavir in the context of routine monitoring with or without treatment with a non-nucleoside reverse transcriptase inhibitor and to assess the interaction between the coformulation of lopinavir/ritonavir and efavirenz or nevirapine.. Plasma trough and peak concentrations (C(trough), C(max)) of lopinavir from 182 HIV-1-infected patients were analysed by high-performace liquid chromatography. Three lopinavir/ritonavir regimens were assessed, namely (A) 400 mg lopinavir/100 mg ritonavir twice daily given alone (n = 125), (B) 400/100 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 25), and (C) 533/133 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 32).. Median (ng ml(-1)) C(trough) and C(max) lopinavir (interquartile range, CV) were: (A) 4852 (3198-6891, 56%) and 8501 (6333-11 584, 41%), (B) 2979 (1704-5186, 74%) and 5612 (3362-11 704, 76%) and (C) 5082 (2696-7226, 74%) and 9757 (4883-12 963, 60%). Median C(trough) of lopinavir was lower in patients taking both efavirenz [P = 0.01, 95% confidence interval (CI) for difference between medians 343, 2713] and nevirapine (P = 0.019, 95% CI for difference between medians 354, 3681) compared with those taking lopinavir/ritonavir alone. A higher interindividual variability was observed when lopinavir/ritonavir was given with a non-nucleoside reverse transcriptase inhibitor. The risk of achieving a 'suboptimal'C(trough) of lopinavir (below a threshold of 3000 ng ml(-1)) was statistically higher in patients treated with a non-nucleoside reverse transcriptase inhibitor (P < 0.001, 95% CI for difference between percentages 8.8, 43.1%) compared with those receiving lopinavir/ritonavir alone.. Our results confirmed the interaction between lopinavir and efavirenz, and also demonstrated a significant interaction between the former drug and nevirapine, resulting in lower C(trough) of lopinavir. The wide interpatient variability in this interaction suggests that therapeutic drug monitoring may be useful in optimizing the dose of lopinavir.

Topics: Adolescent; Adult; Drug Evaluation; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir

We compared immunovirological outcomes and toxicities of HAART regimens including LPV/r and IDV/r in antiretroviral naïve HIV-1 patients. We retrospectively selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART. Immunovirological and metabolic parameters were recorded at baseline and every 3 months as were side effects, AIDS-defining events and deaths. Demographic characteristics and NRTIs included in the regimens were comparable. Both groups reached undetectable HIV-RNA plasma viremia from third month and maintained during follow-up. However, patients receiving IDV/r had a lower probability to obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21 on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of discontinuation in the latter group. In our clinical setting IDV/r showed to be less effective and more toxic than LPV/RTV as first-line HAART.

Topics: Adult; Antiretroviral Therapy, Highly Active; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Viremia

The evolution of fasting glucose, triglyceride, and total and high-density lipoprotein (HDL) cholesterol level and the factors associated with development of clinically significant abnormalities in these metabolic parameters at 6 months were assessed in 353 consecutive human immunodeficiency virus (HIV)-infected patients who were receiving antiretroviral therapy containing lopinavir-ritonavir. Although glucose and HDL cholesterol levels did not change, triglyceride and total cholesterol levels significantly increased (P<.0001 for each), as did the proportion of patients with a triglyceride level of >400 mg/dL and a total cholesterol level of >240 mg/dL (P=.002). A baseline triglyceride level of >400 mg/dL and a baseline total cholesterol level of >240 mg/dL were identified as independent factors predicting clinically significant hypertriglyceridemia and hypercholesterolemia, respectively, at 6 months. These findings may have clinical implications when the therapeutic option of lopinavir-ritonavir is considered.

Topics: Adult; Antiretroviral Therapy, Highly Active; Cholesterol; Cholesterol, HDL; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Metabolic Diseases; Pyrimidinones; Risk Factors; Ritonavir; Triglycerides

Topics: Antiretroviral Therapy, Highly Active; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Pyrimidinones; Ritonavir; Stavudine; Time Factors; Treatment Failure

To investigate the effects of salvage therapy with lopinavir-ritonavir on HIV-1 phenotype in heavily antiretroviral experienced HIV-infected children.. Twenty antiretroviral experienced HIV-infected children were studied during a mean of time of 16.1 months from initiation of the treatment with lopinavir-ritonavir.. Besides CD4 T cells, viral load and clinical status, we analyzed 91 serial viral isolates to study the phenotype, and biological clones derived from co-cultivation techniques.. We observed an increase in CD4 T cells, a statistically significant decrease in viral load and clinical benefits from 3 months after treatment. Ninety per cent of children had SI/X4 bulk isolates in peripheral blood mononuclear cells at study entry. The viral phenotype changed to non syncitium-inducing (NSI)/R5 in 94% of the children after a mean of 5.7 months (95% confidence interval, 2.1-9.3 months) of salvage therapy. The remaining 10% of children had NSI/R5 isolates at entry and at all follow-up study. Similar results were found at the clonal level. Thus, at study entry in PBMC of three children with bulk syncitium-inducing (SI) phenotype, we recovered 65 biologic clones, 56 being SI and nine NSI. After salvage therapy bulk isolates changed to NSI and of 40 biologic clones recovered only five were SI and the rest were NSI.. Our data suggest that lopinavir-ritonavir salvage therapy led not only to a viral load decrease but also to a phenotypic change. X4 virus appeared to be preferentially suppressed. Shifts in co-receptor usage may thereby contribute to the clinical efficacy of anti-HIV drugs in vertically infected infants.

Topics: Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Infectious Disease Transmission, Vertical; Leukocytes, Mononuclear; Lopinavir; Male; Phenotype; Pyrimidinones; Ritonavir; Salvage Therapy; T-Lymphocyte Subsets; Viral Load; Virus Replication

Topics: Adult; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lithiasis; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir.. Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed.. Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography-tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated.. Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). Lopinavir levels were similar to historical data.. Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir. This boosted double PI combination could be an effective option for patients with limited RTI options.

Topics: Adult; Antiretroviral Therapy, Highly Active; Capsules; Cohort Studies; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Saquinavir; Viral Load

Genotypes in nine highly protease inhibitor (PI)-experienced patients were studied before and after lopinavir/ritonavir (LPV/r) treatment. Resistance to amprenavir was the rule both before and after LPV/r treatment. Treatment with LPV/r can select for the 50 V mutation. In this setting, significant differences in the inference of the amprenavir phenotype from genotype were observed when using different algorithms.

Topics: Adult; Anti-Retroviral Agents; Carbamates; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; Genotype; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Mutation; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Sulfonamides

We describe a drug-drug interaction between coformulated lopinavir/ritonavir and itraconazole in a patient infected with human immunodeficiency virus type 1 who had disseminated histoplasmosis. Coadministration of these agents led to a strong increase in itraconazole concentrations and a decrease in concentrations of its metabolite, hydroxyitraconazole, which is equally active pharmacologically. The dosage of itraconazole was reduced when it was used in combination with lopinavir/ritonavir.

Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Antiretroviral Therapy, Highly Active; Drug Interactions; Drug Therapy, Combination; Histoplasmosis; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

Topics: Adult; Drug Combinations; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Failure

Topics: Drug Combinations; Drug Labeling; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

The predictive value of virological response to lopinavir (LPV)/ritonavir (r) was assessed in 126 HIV-infected patients who failed antiretroviral therapy and had begun a rescue intervention based on LPV/r. At 3 months, subjects with < or =6 protease (PRO) resistance mutations showed a higher rate of virological response (HIV-RNA drop > 1 log or to <50 copies/ml) than patients with >6 PRO resistance mutations (77% versus 48%; p = 0.01). On the other hand, virological responders had greater mean LPV plasma trough levels than nonresponders (6.4 versus 3.9 microg/ml; p = 0.02). A positive correlation was found between LPV trough concentration and viral load reductions at 3 months under LPV/r (r = 0.23; p = 0.017). Overall, virological response was seen in 80.8% of patients with LPV trough levels >4.8 microg/ml while in only 52.5% of patients with lower LPV trough concentrations (p = 0.002). In the multivariate analysis, both < or =6 PRO resistance mutations and LPV trough levels >4.8 microg/ml were independent predictors of virological response to salvage therapy with LPV/r. A genotypic inhibitory quotient (GIQ) was estimated for each patient based on the ratio between LPV trough levels and the number of PRO resistance mutations. A positive strong correlation was found between GIQ and viral load reductions (r = 0.42; p = 0.002). Virological response was seen in 78% of patients with a GIQ >0.7 but only in 41.6% of those with lower GIQ (p = 0.004). When LPV trough levels >4.8 microg/ml, PRO resistance mutations < or =6, and GIQ >0.7 were all included in a stepwise multivariate analysis, GIQ remained as the main independent predictor of response to LPV/r.

Topics: Adult; Drug Resistance, Viral; Female; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Mutation; Predictive Value of Tests; Pyrimidinones; Ritonavir; RNA, Viral; Salvage Therapy; Viral Load

Topics: Anti-HIV Agents; Drug Administration Schedule; Drug Resistance, Viral; HIV Infections; Humans; Lopinavir; Pyrimidinones; Viral Load

Topics: Drug Resistance, Multiple; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Microbial Sensitivity Tests; Predictive Value of Tests; Pyrimidinones; Ritonavir

Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Time Factors

To determine and compare rates of diarrhea in patients receiving an antiretroviral regimen containing lopinavir-ritonavir versus nelfinavir and in patients who received these drugs sequentially.. Retrospective cohort analysis.. Hospital-based human immunodeficiency virus (HIV) clinic.. Four hundred one participants in the HIV Atlanta VA Cohort Study who were prescribed lopinavir-ritonavir or nelfinavir from 1996-2002.. Chart review identified episodes of diarrhea that potentially were associated with an antiretroviral agent. Data collected included antidiarrheal agents dispensed, baseline viral load and CD4+ cell counts, demographic variables, and previous therapy Diarrhea associated with an antiretroviral regimen occurred in 175 (49%) of 354 patients receiving nelfinavir and 17 (17%) of 99 patients receiving lopinavir-ritonavir (p < 0.001). Treatment for the diarrhea occurred in 118 (33%) of 354 patients receiving nelfinavir and 9 (9%) of 99 receiving lopinavir-ritonavir (p < 0.001). Patients in the lopinavir-ritonavir group were more likely to have received highly active antiretroviral therapy and azithromycin than patients receiving nelfinavir, and they had lower baseline CD4+ cell counts (p < or = 0.01 for each comparison). The average number of months/person-year of diarrhea treatment was 2.0 for the nelfinavir group and 0.13 for the lopinavir-ritonavir group. Of the 10 antiretroviral-naive patients who received lopinavir-ritonavir, none needed treatment for diarrhea, whereas 78 (36%) of 217 antiretroviral-naive patients who received nelfinavir required treatment for diarrhea. Of the 52 patients who had been taking nelfinavir and were switched to lopinavir-ritonavir, they were more likely to start antidiarrheal treatment while taking nelfinavir (14 [27%]) than while receiving lopinavir-ritonavir (3 [6%]) (p = 0.004).. Patients receiving lopinavir-ritonavir were significantly less likely to have diarrhea or to require treatment for diarrhea than patients receiving nelfinavir. The same results occurred when the drugs were given to the same patients sequentially (nelfinavir followed by lopinavir-ritonavir). The diarrhea associated with lopinavir-ritonavir was less frequent, less severe, and shorter in duration than diarrhea associated with nelfinavir.

Topics: Adult; Anti-Retroviral Agents; Antidiarrheals; Antiretroviral Therapy, Highly Active; Cohort Studies; Diarrhea; Georgia; HIV Infections; Humans; Incidence; Lopinavir; Middle Aged; Nelfinavir; Pyrimidinones; Retrospective Studies; Ritonavir; United States; United States Department of Veterans Affairs

Topics: Anti-HIV Agents; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperlipidemias; Lipids; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir

This study aimed at identifying HIV-1 protease amino acid changes associated with protease inhibitor (PI) exposure and susceptibility. New amino acid substitutions were correlated with the number of experienced PIs, reaching statistical significance only for those at positions 3, 44, and 74. The correspondence multivariate model demonstrated that > or =3 experienced PIs and substitutions or mutations at positions 3, 46, 54, 73, 74, and 84 were correlated with PI cross-resistance, including resistance for lopinavir and amprenavir in this cohort of patients who were naive for these drugs.

Topics: Amino Acid Substitution; Carbamates; Cohort Studies; Drug Resistance, Multiple, Viral; Furans; Genes, Viral; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Multivariate Analysis; Mutation; Phenotype; Pyrimidinones; Regression Analysis; Sulfonamides

Liver toxicity is a common side effect of antiretroviral therapy, particularly in subjects coinfected with the hepatitis C virus (HCV). The incidence of severe liver toxicity after initiation of treatment with lopinavir (LPV) as well as its possible association with LPV plasma levels were assessed in 120 HIV-infected patients (52% coinfected by HCV). The incidence of severe liver toxicity at 3 months was 1.7% and the cumulative incidence at 12 months was 4%. The development of severe liver toxicity was associated with HCV coinfection but not with LPV plasma levels.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Female; Hepatitis C; HIV Infections; Humans; Incidence; Liver; Lopinavir; Male; Pyrimidinones

Topics: Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Middle Aged; Pyrimidinones; Ritonavir; Thrombocytopenia

Topics: Adult; Anti-HIV Agents; Drug Resistance, Multiple, Viral; HIV Infections; Humans; Lopinavir; Male; Mutation; Pyrimidinones; Ritonavir; RNA, Viral

To assess the impact of HIV-1 protease mutations and intracellular and plasma lopinavir minimum concentrations (Cmin) on virological success or failure on lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART).. HIV-1-infected HAART-experienced patients included in an observational study, received lopinavir/ritonavir (400/100 mg twice a day) plus two to three nucleoside reverse transcriptase inhibitors (NRTI) or one NRTI plus one non-NRTI. A viral load less than 50 copies/ml at month 6 defined virological success.. Intracellular and plasma lopinavir concentrations were determined by high-pressure liquid chromatography with mass-spectrometry detection. Reverse transcriptase and protease genes were sequenced at baseline and the time of virological failure.. When the 38 patients started the lopinavir/ritonavir-based regimen, baseline median (25-75th percentile) values were: CD4 cell count 218 cells/microl (133-477); plasma HIV-1-RNA load 5.3 log10 copies/ml (3.8-5.1); number of lopinavir mutations four per protease gene (two to six). Univariate analysis associated virological success or failure at month 6 (21/38 patients) with the number of baseline lopinavir mutations, intracellular and plasma lopinavir Cmin, and the genotype inhibitory quotient (GIQ) at months 1 and 6. Multivariate analysis showed that the number of baseline lopinavir mutations and intracellular and plasma lopinavir Cmin were independently associated with virological success or failure. We defined the most discriminating intracellular and plasma lopinavir Cmin efficacy thresholds (8 and 4 microg/ml, respectively) and GIQ thresholds (1 and 3, respectively).. The monitoring of lopinavir/rironavir-based HAART efficacy should include the number of baseline lopinavir/ritonavir mutations, intracellular and plasma lopinavir Cmin and GIQ calculation.

Topics: Adult; Antiretroviral Therapy, Highly Active; Chi-Square Distribution; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Intracellular Fluid; Lopinavir; Male; Middle Aged; Multivariate Analysis; Mutation; Pyrimidinones; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Load

To evaluate the risk factors for lopinavir/ritonavir (LPV/r)-related liver enzyme elevation (LEE) in HIV antiretroviral-experienced patients.. An open prospective observational study was carried out to analyse the incidence and time of LEE development during LPV/r treatment, and to determine whether LEE development was correlated with epidemiological, clinical and biochemical data, immune and virological profiles, concomitant hepatic diseases, antiretroviral therapy, or histological and ultrasonography liver examination results. A diagnosis of LEE was considered when LEE symptoms occurred after LPV/r introduction and was confirmed by a second control within 2 weeks.. A total of 782 HIV-positive outpatients have been enrolled in six different Infectious Diseases Departments in Northern Italy since August 2000. Of these patients, 71 (9.1%) developed LEE within 115+/-85 days (mean+/-standard deviation); 13 of these subjects discontinued LPV/r and four were hospitalized. Of the patients with LEE, 74.6% and 25.4% had grade 2 and > or =3 toxicity, respectively. No correlation between LEE and sex, baseline CD4 cell count, viral load, HIV stage, triglyceride values, histological and ultrasonography liver examination results, nevirapine use, or increase in CD4 cell count was observed. Higher baseline alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) values (P < 0.0001 and P=0.004, respectively), younger age (P=0.008), previous hepatitis B virus (HBV) infection (P=0.012), efavirenz use (P=0.04), and hepatitis C virus (HCV) and/or HBV coinfection (P < 0.0001, relative risk 4.78) were significantly related to LEE. No correlations between LEE and the same risk factors as investigated in the whole study population were found in subgroups of patients with HCV and/or HBV infection.. HCV and HBV testing and measurement of baseline ALT values are essential for screening subjects at risk of LEE before starting LPV/r. Strict monitoring of clinical and biochemical parameters should be performed in these patients.

Topics: Adult; Aged; Alanine Transaminase; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Female; Follow-Up Studies; gamma-Glutamyltransferase; Hepatitis B; HIV Infections; Humans; Liver; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Risk Factors; Ritonavir; Statistics, Nonparametric

Topics: Adult; Atazanavir Sulfate; Clinical Trials as Topic; Delayed-Action Preparations; Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Treatment Outcome

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Delayed-Action Preparations; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Long-Term Care; Lopinavir; Pyrimidinones; Ritonavir; Viral Load

Topics: Atazanavir Sulfate; Blood Glucose; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lipids; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; 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

Predictive factors of the virologic success of the use of lopinavir/ritonavir (LPV/r) in HIV-infected children are unknown, especially in children who have been pretreated with protease inhibitors (PIs). This longitudinal, single-center, observational study included 69 children (21 PI-naive and 48 PI-experienced) who had received LPV/r for at least 3 months. The mean (+/- SD) age was 10.3 +/- 4.8 years, and the mean baseline of CD4 percentage and HIV-1 RNA was 14.9% +/- 9.8% and 4.8 +/- 1.05 log10 copies/mL, respectively. The mean duration of follow-up was 16.5 +/- 8.3 months. At 6, 12, and 18 months, 52%, 57%, and 49% of all children, respectively, had a viral load less than 50 copies/mL. The risk of virologic failure, defined as 2 consecutive viral loads greater than 1000 copies/mL, was significantly higher when the children were previously treated with PIs and when the baseline LPV mutation score exceeded 3 mutations. In the pretreated children, the ratio of the plasma LPV maximal concentration to the baseline LPV score mutation was also associated with failure, independently of resistance score. Finally, in children failing an LPV-containing regimen, accumulation of additional PI-associated resistance mutations was evidenced in viral isolates from children with prior PI treatment, even with viral replication levels less than 10,000 copies/mL. In pretreated children, LPV plasma levels should be optimized in an attempt to achieve sufficient drug concentrations to overcome the resistance level.

Topics: Child; Child, Preschool; Drug Interactions; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir

Cost and inconvenience limit the application of full 12-hour pharmacokinetic (PK) analysis for routine therapeutic drug monitoring of antiretroviral medications. We explore whether lopinavir (LPV) and ritonavir (RTV) exposures can be estimated with limited sampling for patients taking twice-daily LPV/RTV. One hundred and one PK profiles from 81 patients, most receiving salvage therapies including twice-daily LPV/RTV, were obtained for the analysis. After a minimum of 2 weeks on a stable regimen, blood was drawn immediately before and at 1, 2, 4, 6, 8, 10, and 12 hours after a timed medication dose. Plasma drug concentrations were determined by a validated HPLC-MS-MS assay. Peak concentrations, evening troughs, and AUC0-12 h were entered into linear and log10-log10 linear regression models to determine the best correlation with LPV and RTV plasma concentrations using a maximum of 2 time points. The accuracy and precision of PK parameter estimates of the resultant models were tested on data collected for an additional 25 patients. Twelve models using various combinations of 2 timed LPV concentrations afforded accurate (maximum % bias = -6.45) and precise (relative standard deviation < 15%) estimates for the LPV peak concentration or AUC0-12h. Four sets of 2 concentrations provided simultaneous estimates of both PK parameters, with the best estimates derived from data collected at 2 and 6 hours postdose. Evening trough concentrations were the best estimators of the daily nadir; however, no adequate substitute for collecting blood 12 hours postdose emerged from this analysis.

Topics: Adult; Area Under Curve; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

The predictive values of HIV-1 protease genotype and virtual phenotype (vPhenotype) results on the HIV-1 RNA response to lopinavir/ritonavir (LPV/r)-containing salvage regimens were assessed. Data were evaluated from patients with antiretroviral (ARV) resistance testing prior to initiating an LPV/r-containing salvage ARV regimen, from two independent cohorts from Toronto, Ontario and British Columbia, Canada. Multivariate logistic regression models controlling for previous non-nucleoside reverse transcriptase inhibitor use, baseline viral load and AIDS-defining illness were used to assess the impact of different protease genotypic mutations (individual and in combination) and lopinavir vPhenotyping on virological suppression to <50 copies/ml by 12 months. We confirmed that the 11-mutation 'lopinavir mutation score' (LMS) was significantly inversely associated with the probability of virological suppression within 12 months [odds ratio (OR)=0.91; P=0.02]. The only single specific protease mutation found to predict virological response in multivariate analyses was 461 (OR=0.55; P=0.02). The most predictive three-mutation combination was 10F/I/R/V, 461, 82A/F/T (OR=0.18; P=0.0004). We confirmed that a 10-fold increase of lopinavir IC50 is an appropriate clinical cut-off for lopinavir vPhenotype. In univariate analyses, a cut-off of the LMS as low as 3 was significantly associated with a lack of virological suppression (P=0.04). This finding, which is in contrast to those of other studies, may be due to the high degree of ARV experience of our population and lack of active agents in the salvage regimen. Selecting the 11 specific mutations to make the LMS is potentially arbitrary; we determined that when different combinations of 11 protease mutations were chosen randomly from a set of 30, similar associations with virological response were found, probably due to the co-linearity of these mutations.

Topics: Adult; Canada; Cohort Studies; Female; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Logistic Models; Lopinavir; Male; Multivariate Analysis; Mutation; Phenotype; Predictive Value of Tests; Pyrimidinones; Ritonavir; Salvage Therapy

Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C(0)) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC(0-24)s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC(0-8)s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C(0) and 8-h VPA concentrations versus the control (n = 11) were -1.0 (-9.4, 7.4) microg/ml and -2.1 (-11.1, 6.9) microg/ml for EFV (n = 10) and -5.0 (-13.2, 3.3) microg/ml and -6.7 (-17.6, 4.2) microg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

Topics: Adult; Alkynes; Anti-HIV Agents; Anticonvulsants; Area Under Curve; Benzoxazines; Cognition Disorders; Cyclopropanes; Drug Interactions; Female; Half-Life; HIV Infections; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Valproic Acid

(1) There is still no cure for HIV infection. The short-term treatment aims are to drive viral load below the current detection limit and to increase the CD4+ T cell count, in order to reduce morbidity and prolong survival. (2) Early initiation of treatment has both advantages and disadvantages. If the patient is symptomatic or if the CD4+ T cell count is below 200 per mm3, antiretroviral treatment should be started immediately. If the patient is asymptomatic, the CD4+ T cell count is above 350 per mm3, and viral load is below 50 000 copies/ml, antiretroviral treatment can often be deferred. Other situations should be considered case by case. (3) The benefits of treating symptomatic primary infection have not been adequately documented, and current recommendations diverge. (4) The advent of new antiretroviral drugs has increased the choice, but cross-resistance often limits treatment options. The new antiretroviral family to have emerged since 1999 is the fusion inhibitor; the only representative of this class, enfuvirtide, is reserved for patients with multiple treatment failure. (5) There is broad agreement on the principles of first-line antiretroviral treatment. It should combine at least two nucleoside (or nucleotide) inhibitors of HIV reverse transcriptase and one non nucleoside inhibitor, or at least one HIV protease inhibitor. Comparative studies have now identified the most effective combinations in terms of virological efficacy and tolerability. The combination should be chosen according to its established efficacy, adverse effects, risks of interactions, and convenience. There is no reference combination suitable for all patients. Among the combinations containing a non nucleoside inhibitor, those based on efavirenz are the most effective after 48 weeks of follow-up. There is less agreement on the optimal treatment of pregnant women. (6) Among the HIV protease inhibitor-based combinations, those containing nelfinavir or the lopinavir + ritonavir combination must be taken during meals. The lopinavir + ritonavir combination showed better virological efficacy than nelfinavir in a comparative trial. Experience and safety evaluation are in favour of nelfinavir, but recent American guidelines issued in November 2003 recommend the lopinavir + ritonavir combination. (7) There is no major difference in virological efficacy between non nucleoside inhibitors and protease inhibitors as first line therapy. (8) In combination with protease inhibitors or non

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Clinical Trials as Topic; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Nelfinavir; Oligopeptides; Organophosphonates; Oxazines; Pregnancy; Pyrimidinones; Ritonavir; Stavudine; Sulfonamides; Treatment Outcome; Viral Load; Zidovudine

Therapeutic drug monitoring of protease inhibitors (PIs) is usually performed on plasma samples although their antiretroviral effect takes place inside cells. Little is known, however, about the intracellular accumulation and related plasma pharmacokinetics of PIs such as lopinavir/ritonavir (LPV/RTV). Therefore, we studied the plasma and intracellular (cell-associated) steady-state pharmacokinetics of this PI combination in a dosage of 400/100 mg twice daily in a non-randomized cohort of HIV-1-infected individuals. Plasma (0-12 h) and peripheral blood mononuclear cell (PBMC; 0-8 h) samples were drawn during a 12-h dosing interval in 11 subjects. The plasma concentrations versus time curves of LPV and RTV were characterized by an irregular absorption phase showing double-peaks (Cmax) in most subjects and single-peaks in the remaining patients between 1 and 3 h after drug intake. Pre-dose concentrations of both agents in plasma were significantly higher than the concentrations at the end of the dosing interval indicating the presence of a circadian rhythm in their pharmacokinetics. The course of the intracellular concentrations versus time curves appeared to be similar to the plasma concentration curves, with the highest intracellular concentration measured 3 h after drug intake. The intracellular RTV concentrations were higher than reported in vitro EC50 values and might therefore contribute to the antiretroviral effect of LPV/RTV. The median intracellular-to-plasma concentration ratios (interquartile range) were 1.18 (0.74-2.06) and 4.59 (3.20-7.70) for LPV and RTV, respectively. In conclusion, both LPV and RTV accumulate to potential therapeutic concentrations in PBMCs. Irregular absorption and circadian plasma clearance patterns were observed for the PI combination LPV/RTV.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Leukocytes, Mononuclear; Lopinavir; Male; Pyrimidinones; Ritonavir

To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development.. Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy.. The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >/= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level.. The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity.. Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.

Topics: Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Chronic Disease; Drug Therapy, Combination; Female; Hepatitis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver; Lopinavir; Male; Nelfinavir; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Saquinavir; Treatment Outcome

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

The possibility of using Kaletra alone for selected patients instead of three or more antiretrovirals has led to controversy among HIV physicians, reviewed in a short article published by the American Foundation for AIDS Research.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones

The protease inhibitor lopinavir (LPV; [1S-[1R*(R*), 3R*,4R*]]-N-[4-[[(2,6-dimethylphenoxy)-acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl) pentyl] tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimide acetamide) is widely used in anti-human immunodeficiency virus (HIV) therapy. Knowledge of the plasma and intracellular concentrations of the drug would be useful for a better understanding of LPV action and for therapeutic monitoring. The aim of this study was to develop a sensitive and specific immunoassay for LPV in plasma and cells. Anti-LPV polyclonal antibodies were raised in rabbits using a synthetic LPV derivative coupled to keyhole limpet hemocyanin (KLH) as immunogen. The enzyme tracer was prepared by chemically coupling the LPV derivative with acetylcholinesterase. These reagents were used to develop a competitive enzyme immunoassay (EIA) performed in microtitration plates. The assay was performed on a minimum of 50 microl of plasma or 2 x 10(6) cells. It showed good precision and efficiency in as much as recovery from human plasma and cell extracts spiked with LPV ranged between 87% and 104%, with coefficients of variation of less than 10%. The limit of detection (LOD) was 100 pg/ml, i.e., a value at least 10 times lower than those currently achieved using previously described techniques. Cross-validation with high-performance liquid chromatography (HPLC) revealed a good correlation between methods (r2=0.96). Intracellular concentrations of LPV were measured in cultured human T lymphoblastoid cells (CEM). A pharmacokinetic analysis of plasma and intracellular LPV was performed on a healthy volunteer, and measurements were done in patients infected with HIV. The results obtained indicated a high intracellular/extracellular concentration ratio in cultured cells (19.3) but not in cells from HIV patients (1.3). In contrast, in peripheral blood mononuclear cells (PBMC) the accumulation of ritonavir (RTV) was six times higher than LPV. To date, this is the first reported immunoassay for LPV, and this method is sensitive enough for monitoring plasma and intracellular LPV levels in HIV-infected patients and for intracellular studies.

Topics: Adult; Antibodies; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; HIV Infections; HIV Protease Inhibitors; Humans; Leukocytes, Mononuclear; Lopinavir; Male; Pyrimidinones; Sensitivity and Specificity

Topics: Drug Therapy, Combination; Hepatitis B; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir

Topics: CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Viral Load

Topics: Adult; Drug Combinations; Female; Gastrectomy; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

The immunovirological outcome of lopinavir/ritonavir was evaluated in 70 antiretroviral-experienced HIV patients; at baseline, median CD4+ cell count was 218 cells/mm(3) and median plasma viraemia 4.58 log(10) copies/mL. After 12 months, we observed an increase in CD4+ cell count to 322 cells/mm(3) (P = 0.0001) and a decrease in plasma viraemia to 2.35 log(10) copies/mL (P = 0.0001). Four patients discontinued lopinavir/ritonavir during observation. Among metabolic parameters, only triglyceride concentrations increased during treatment (P = 0.02). Twenty-six patients had a genotypic resistance test at baseline; four had > or =6 mutations known to reduce susceptibility to lopinavir/ritonavir. Undetectable plasma viraemia was obtained only in patients with < or =5 mutations (61.9%).

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Cohort Studies; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Multivariate Analysis; Pyrimidinones; Retrospective Studies; Ritonavir; Treatment Outcome

Topics: Adult; Antiretroviral Therapy, Highly Active; Arteriosclerosis; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Lipoproteins, LDL; Lopinavir; Pyrimidinones; Ritonavir

Topics: Clinical Trials, Phase II as Topic; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

To investigate the efficacy and tolerability of using lopinavir/ritonavir concurrently with a third protease inhibitor (PI), the authors reviewed the medical records of 47 HIV-infected patients treated with antiretroviral regimens containing lopinavir/ritonavir and amprenavir, saquinavir, indinavir, or nelfinavir. The baseline mean HIV RNA level was 4.6 log(10) copies/mL, and the median CD4 cell count was 123/mm3. By week 40, one patient (2%) was lost to follow-up, and 21 (44%) discontinued their lopinavir/ritonavir plus a third PI regimens: 4 (8%) due to virologic failure as determined by the clinician; 13 (28%) due to toxicity; and 4 (8%) due to social reasons. By intent-to-treat analysis, 12 (26%) of 47 patients had an HIV RNA level of less than 400 copies/mL at 40 weeks. By multivariate analysis, factors associated with virologic response were no prior lopinavir exposure (p =.03) and no prior exposure to nonnucleoside reverse transcriptase inhibitors among patients taking a nonnucleoside reverse transcriptase inhibitor (p =.05). Some HIV-infected patients concurrently treated with lopinavir/ritonavir and a third PI have viral suppression; many eventually discontinue therapy because of toxicity or virologic failure.

Topics: Adult; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Treatment Outcome

Current genotypic algorithms suggest that the HIV-1 protease inhibitors (PI) lopinavir (LPV) and amprenavir (APV) have distinct resistance profiles. However, phenotypic data indicate that cross-resistance is more common than expected.. Protease genotype (GT) and phenotype (PT) from 1418 patient viruses with reduced PI susceptibility and/or resistance-associated mutations (training data) were analyzed. Samples were classified as LPV resistant by GT (GT-R) if six or more LPV mutations were present, and by PT (PT-R) if the 50% inhibitory concentration (IC(50)) fold-change (FC) was over 10.. There were 182 samples (13%) that were GT-S but PT-R for LPV. A comparison of the mutation prevalence in PT-R/GT-S samples with that in PT-S/GT-S samples identified mutations associated with LPV PT-R. Several previously defined LPV mutations were found to have a stronger than average effect (e.g., M46I/L, I54V/T, V82A/F), and new variants at known positions (e.g., I54A/M/S, V82S) were identified. Other mutations, including known APV resistance mutations, were found to contribute to reduced LPV susceptibility. A new LPV genotypic interpretation algorithm was constructed that improved overall genotypic/phenotypic concordance from 80% to 91%. The algorithm demonstrated a concordance rate of 90% when tested on 523 new samples. Cross-resistance between APV and LPV was greater in samples with primary APV resistance mutations than in those lacking them.. The current LPV mutation score does not fully account for many resistant viruses. Consequently, cross-resistance between LPV and APV is underappreciated. Phenotypic results from large and diverse patient virus populations should be used to guide the development of more accurate GT interpretation algorithms.

Topics: Algorithms; Carbamates; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Phenotype; Pyrimidinones; Sulfonamides

Topics: Anti-HIV Agents; Carbamates; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Phenotype; Pyrimidinones; Sulfonamides

Topics: Adult; Anti-HIV Agents; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones

Hypertriglyceridemia (HTG) is frequently observed during highly active antiretroviral therapy (HAART) including protease inhibitor. Apolipoprotein (apo) CIII could be involved in this HTG by inhibition of triglyceride (TG) hydrolysis, which leads to the occurrence of small dense low density lipoprotein (sdLDL), a recognized cardiovascular risk factor.. To characterize the influence of lopinavir/ritonavir-containing regimen on lipoprotein profile.. 24 antiretroviral-experienced HIV infected adults (including 14 patients in therapeutic interruption of at least 2 months) and 14 HIV uninfected healthy controls were enrolled. Serum lipid parameters (total cholesterol (TC), HDL-C, LDL-C, TG, apoA1, apoB, apoCIII), lipoprotein composition and LDL size were determined before initiation of lopinavir/ritonavir-containing regimen, and at 1 and 3 months thereafter.. At baseline an atherogenic lipid profile was evidenced, characterized by a moderate HTG associated to a smaller mean LDL size (25.16 vs 25.93 nm, P<0.001), an enrichment in TG of LDL (11.4 vs 6.0%, P<0.01) and a high prevalence of sdLDL (75 vs 7%, P<0.01) when compared to controls. After 1 month of lopinavir/ritonavir-containing regimen, a significant reduction of LDL size (24.81 vs 25.16 nm, P<0.05) and a significant increase in cholesterol total (5.53 vs 4.49 mmol/l, P<0.001), in TG (4.20 vs 2.01 mmol/l, P<0.001), in apoA1 (1.28 vs 1.11 g/l, P<0.001), in apoB (1.08 vs 0.94 g/l, P<0.01), in apoCIII (0.16 vs 0.10 g/l, P<0.001), in TG percentage in LDL (14.4 vs 11.4, P<0.05) and in TG percentage in HDL (10.2 vs 8.3, P<0.05) were observed.. Advanced stage of HIV infection is associated with an atherogenic lipid profile including a high prevalence of sdLDL. Lopinavir/ritonavir-containing regimen accentuates the reduction of LDL size. Since fibrates decrease TG and increase LDL size, they appear as a logical option to manage HAART-induced HTG.

Topics: Adult; Antiretroviral Therapy, Highly Active; Apolipoprotein A-I; Apolipoprotein C-III; Apolipoproteins B; Apolipoproteins C; Biomarkers; Cholesterol, HDL; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lipoproteins, LDL; Lipoproteins, VLDL; Lopinavir; Male; Phospholipids; Pyrimidinones; Ritonavir; Statistics as Topic; Time Factors; Treatment Outcome; Triglycerides; Viral Load

Topics: Anti-HIV Agents; Dermatitis, Irritant; Diagnosis, Differential; Drug Eruptions; HIV Infections; Humans; Lipodystrophy; Lopinavir; Male; Middle Aged; Nevirapine; Pyrimidinones

A case report of drug-induced rhabdomyolysis in a 34-year-old HIV-infected male with a history of liver disease and concomitant use of clarithromycin, atorvastatin, and lopinavir/ritonavir is presented.

Topics: Adult; Anti-Bacterial Agents; Atorvastatin; Clarithromycin; Drug Interactions; Drug Therapy, Combination; Heptanoic Acids; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lopinavir; Male; Pyrimidinones; Pyrroles; Rhabdomyolysis; Ritonavir

Recent evidence suggests that as a group protease inhibitors (PIs) may accelerate certain factors associated with atherosclerosis. The objective of this study was to evaluate the effect of individual PIs (indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) on certain factors associated with atherosclerosis. Persons who took saquinavir and/or ritonavir were compared with those on other PIs. Between May 2000 and July 2001, the lipid profiles, C-reactive protein (CRP) levels, coronary artery calcium (CAC) scores, and blood cell morphologic parameters were measured in 98 black adult participants aged 25 to 45 years with HIV-1 infection in Baltimore, Maryland. Among these 98, there were 55 (56.1%) taking PIs. Students' t-test and chi2 test were used to detect the between-group differences. Study participants in both the PI and non-PI groups were similar in age, sex, body mass index, blood pressure, red and white blood cell counts, time since HIV diagnosis, and duration on anti-retroviral therapy. Compared with those who took non-PI regimens, those who took indinavir, nelfinavir, or saquinavir had significantly higher levels of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Those taking any PI had significantly higher total cholesterol and low-density lipoprotein. Those taking nelfinavir, ritonavir, or saquinavir were more likely to have a higher CAC score (>5) than those on non-PI regimens. There were no differences in the lipid profiles, MCV, MCH, CRP, and CAC between those taking saquinavir and/or ritonavir and those taking other PIs. Overall, the changes noted might lead to anticipation of clinical changes linked to accelerated atherosclerosis in patients on PIs.

Topics: Adult; Arteriosclerosis; Biomarkers; Black People; C-Reactive Protein; Calcium; Cholesterol; Coronary Artery Disease; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Nelfinavir; Pyrimidinones; Ritonavir; Saquinavir

Patients receiving a lopinavir/ritonavir and saquinavir dual protease inhibitor-based antiretroviral salvage regimen were studied to evaluate the pharmacokinetics, tolerability and efficacy of the regimen. Pharmacokinetic curves were obtained for lopinavir and saquinavir. Patient records were studied for adverse events and efficacy data. The pharmacokinetics of lopinavir and saquinavir were comparable with literature data, except for the saquinavir 0-12 h area under the curve and maximum concentration. The tolerability of the regimen was good and efficacy was encouraging.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Area Under Curve; Drug Monitoring; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Salvage Therapy; Saquinavir

Topics: Antiretroviral Therapy, Highly Active; Bronchoalveolar Lavage Fluid; Epithelial Cells; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Lung; Male; Pyrimidinones

Topics: Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Methadone; Middle Aged; Narcotics; Pyrimidinones; Ritonavir

This study examines the pharmacokinetic/pharmacodynamic interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV disease, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone, an opiate frequently used in substance abuse pharmacotherapy for opioid (heroin)-dependent injection drug users, many of whom are infected with HIV. L/R was associated with significant reductions in the methadone area under the concentration-time curve (P<.001), maximum concentration (P<.001), and minimum concentration (P<.001), as well as increased methadone oral clearance (P<.001) and increased opiate withdrawal symptoms (P=.013), whereas ritonavir use alone modestly and nonsignificantly increased methadone concentrations. Lopinavir is a potent inducer of methadone metabolism, and treatment with L/R requires clinical monitoring and increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Methadone; Narcotics; Opioid-Related Disorders; Pyrimidinones; Ritonavir; Substance Withdrawal Syndrome

There is limited knowledge about how to treat and interpret results from genotypic resistance assays in HIV-2 infection. Here, genetic variation in HIV-2 pol gene was studied in 20 of 23 known HIV-2 cases in Sweden. Five patients with signs of virological treatment failure were longitudinally studied. Clinical, virological and immunological data were collected and the protease (PR) and first half of the reverse transcriptase (RT) was amplified and directly sequenced from plasma samples. Moderate to extensive genetic evolution was observed in four of the five patients who failed treatment. Some mutations occurred at positions known to confer resistance in HIV-1, but many occurred at other positions in PR and RT. All patients had been treated with zidovudine alone or in combination with other antiretroviral drugs, but none displayed a mutation at position 215, which is the primary zidovudine resistance site in HIV-1. Instead, a E219D mutation evolved in virus from two patients and a Q151M mutation evolved in two other patients. A M184V mutation indicative of lamivudine resistance was detected in three patients. The virus of one patient who had been treated with ritonavir, nelfinavir, and lopinavir successively acquired nine unusual mutations in the protease gene, most of which are not considered primary or secondary resistance mutations in HIV-1. Our data indicate that the evolutionary pathways that lead to antiretroviral resistance in HIV-2 and HIV-1 exhibit both similarities and differences. Genotypic HIV-2 resistance assays cannot be interpreted using algorithms developed for HIV-1, instead new algorithms specific for HIV-2 have to be developed.

Topics: Adolescent; Adult; Africa, Western; Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Codon; Drug Resistance, Multiple, Viral; Evolution, Molecular; Female; Genes, pol; Genetic Variation; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Nelfinavir; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sequence Alignment; Sequence Homology, Amino Acid; Sweden; Treatment Failure; Viremia; Zidovudine

Topics: Anti-HIV Agents; Capsules; Delayed-Action Preparations; Drug Administration Schedule; Drug Packaging; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones

Our objective was to accurately predict, from complex mutation patterns, human immunodeficiency virus type 1 resistance to the protease inhibitor lopinavir, by use of artificial intelligence. Two neural network models were constructed: 1 based on changes at 11 positions in the protease that were previously recognized as being significant for lopinavir resistance and another based on a newly derived set of 28 mutations that were identified by performing category prevalence analysis. Both models were trained, validated, and tested with 1322 clinical samples. A procedure of determining the optimal neural network parameters was proposed to speed up the training processes. The results suggested that the 28-mutation set was a more accurate predictor of lopinavir susceptibility (correlation coefficient, R2=0.88). We identified potentially significant new mutations associated with lopinavir resistance and demonstrated the utility of neural network models in predicting phenotypic susceptibility from complex genotypes.

Topics: Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Microbial Sensitivity Tests; Mutation; Neural Networks, Computer; Phenotype; Predictive Value of Tests; Pyrimidinones

With the advent of highly active antiretroviral therapy (HAART), HIV positivity is no longer a contraindication for liver transplantation. Some of the antiretroviral agents, particularly protease inhibitors (e.g., ritonavir, indinavir, and nelfinavir) have been described as potent inhibitors of the metabolism of certain immunosuppressive drugs. In this article we describe a profound interaction between tacrolimus and Kaletra (Abbott Laboratories, Chicago, IL) (a combination of lopinavir and ritonavir) in 3 liver transplantation patients. Patient 1, who was maintained on a 5 mg twice daily dose of tacrolimus with a trough blood concentration around 10.6 ng/mL, required only 0.5 mg of tacrolimus per week after addition of Kaletra to achieve similar tacrolimus blood concentrations, with a half-life of 10.6 days. In patient 2, the area under the blood concentration versus time curve for tacrolimus increased from 31 ng/mL/h to 301 ng/mL/h after addition of Kaletra, with a corresponding half-life of 20 days. When the patient was subsequently switched to nelfinavir, the half-life decreased to 10.3 days. Patient 3, who was maintained with 4 to 8 mg/d of tacrolimus and a corresponding blood concentration of 10 ng/mL before Kaletra, required a tacrolimus dose of 1 mg/wk and tacrolimus concentrations of 5 ng/mL with Kaletra. In conclusion, a combination of lopinavir and ritonavir led to a much more profound increase in tacrolimus blood concentrations than use of single protease inhibitor, nelfinavir. A tacrolimus dose of less than 1 mg/wk may be sufficient to maintain adequate blood tacrolimus concentrations in patients on Kaletra. Patients may not need a further dose of tacrolimus for 3 to 5 weeks depending on liver function when therapy with Kaletra is initiated. Great caution is required in the management of tacrolimus dosage when Kaletra is introduced or withdrawn in HIV-positive patients after liver transplantation, particularly in the presence of hepatic dysfunction.

Topics: Adult; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Tacrolimus

Topics: Adolescent; Adult; Drug Combinations; Female; Hemophilia A; Hemorrhage; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir

Lopinavir (LPV)/ritonavir (RTV) used in combination, is a potent antiretroviral drug. However, its benefit is limited by its inherent effect on lipid metabolism, causing dislypemia in a large proportion of treated patients. Fasting triglyceride (TG) and cholesterol levels were assessed in 126 HIV-infected patients who initiated salvage therapy based on LPV/RTV. Both TG and cholesterol significantly increased from baseline to month 3. A positive correlation was found between the percentage increase in TG and LPV trough levels (r = 0.32; p = 0.003). Moreover, patients with TG elevations above the median (27%) showed higher LPV Ctrough levels than those with lower TG elevations (7.1 vs. 4.7 microg/ml, p = 0.004). In contrast, no correlation was found between LPV Ctrough and increases in cholesterol levels. Cholesterol elevations were positively correlated with RTV Ctrough concentrations (r = 0.32; p = 0.003).

Topics: Adult; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Lopinavir; Male; Pyrimidinones; Ritonavir; Triglycerides

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

Topics: Clinical Trials, Phase III as Topic; Drugs, Investigational; HIV Infections; Humans; Lopinavir; Protease Inhibitors; Pyrimidinones; Ritonavir; Viral Load

The wide use of protease inhibitors (PI) as part of a highly active antiretroviral (HAART) regimen is associated with the development of several side effects. Among these, the development of avascular necrosis (AVN) of the bone is being reported more frequently and it has been related both to the use of PI and to HIV-1 infection itself. We report here a case of AVN of the bone in a patient taking the new PI lopinavir (LPV)/ritonavir (RTV) as part of a HAART regimen.

Topics: Adult; Antiretroviral Therapy, Highly Active; Femur Head Necrosis; HIV Infections; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

Topics: CD4 Lymphocyte Count; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Viral Load

In a retrospective study of HIV patients under antiretroviral therapy, we investigated the influence of the MDR1 genotype (C3435T) on plasma levels of lopinavir (LPV) and efavirenz (EFV).. The MDR1 genotype was analysed from 67 patients who were treated with LPV (n = 32; mean treatment period 53 weeks) and/or EFV (n = 43, mean treatment period 105 weeks) between 1999 and 2003. Plasma levels of LPV (trough levels) and EFV (12-h-levels) were determined every three months. Data were analysed by the Kruskal-Wallis test.. There were no significant differences in the LPV and EFV plasma levels with respect to the MDR1 3435 genotype.. We did not find evidence for an influence of the MDR1 3435 genotype on plasma levels of LPV and EFV.

Topics: Adult; Aged; Alkynes; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzoxazines; Cyclopropanes; Female; Genotype; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oxazines; Polymorphism, Genetic; Pyrimidinones; Retrospective Studies

Topics: Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nelfinavir; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Time Factors; Viral Load

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Oligopeptides; Organophosphates; Pilot Projects; Pyridines; Pyrimidinones; Ritonavir; Sulfonamides; Time Factors; Viral Load

Topics: Adult; Alopecia; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Nelfinavir; Pyrimidinones; Ritonavir; Stavudine

Topics: Adenine; CD4 Lymphocyte Count; Didanosine; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organophosphonates; Organophosphorus Compounds; Pyrimidinones; Reverse Transcriptase Inhibitors; Tenofovir; Viral Load

Topics: Anti-HIV Agents; Drug Synergism; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Pyrimidinones; Ritonavir; Saquinavir; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure; Treatment Outcome

Topics: HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Semen

Lopinavir/ritonavir was administered to 35 HIV-infected patients after therapeutic failure with other protease inhibitors. The pharmacokinetics (trough concentrations) and baseline viral genotype were determined, together with the immunovirological outcome. The 22 responders had significantly higher mean lopinavir concentrations and lower baseline numbers of mutations. On multivariate analysis, a lopinavir concentration of 5.7 microg/ml or greater was an independent predictor of viral suppression over a 9-month follow-up period.

Topics: CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Mutation; Pyrimidinones; Ritonavir; Salvage Therapy; Treatment Outcome; Viral Load

Topics: HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pleural Effusion; Pyrimidinones; Sarcoma, Kaposi

Genotypic correlates of reduced phenotypic susceptibility to amprenavir (APV) and lopinavir (LPV) were examined in 271 HIV isolates from 207 protease inhibitor (PI)-experienced subjects. All samples were from LPV-naive subjects; two were from APV-experienced subjects. Using a fold resistance (FR) of <2.5, 179 (66%) were APV susceptible. Using FRs of <2.5 and <10, 107 (39%) and 194 (72%), respectively, were LPV susceptible. The I84V mutation was the strongest APV resistance marker in PI-experienced subjects in both univariate and multivariate analyses, with an increased relative incidence (RI) of 6.9 with >2.5 FR. Mutations L10I (RI, 1.7), M46I (RI, 2.3), and L90M (RI, 1.9, but 65% linked with the I84V) were associated with decreased APV susceptibility in the univariate analysis (p < 0.001). Mutations L10I, G48V, I54T, I54V, and V82A were significantly associated with decreased LPV susceptibility (p < 0.001 for each) and had increased RIs of 2.2, 4.4, 13, 4.6, and 3.2, respectively. Decreased susceptibility to LPV (FR, >or=10) was significantly associated with prior exposure to the following PIs: ritonavir (RTV) (p < 0.001), saquinavir (SQV) (p < 0.001), nelfinavir (NFV) (p = 0.008), and indinavir (IDV) (p = 0.028). Decreased APV susceptibility (FR, >or=2.5) was significantly associated with prior exposure to RTV (p = 0.009), NFV (p = 0.003), and IDV (p = 0.021) but not with prior SQV (p = 0.103). These results suggest that APV and LPV have different cross-resistance mutation patterns that may help determine choice of PI therapy after therapy failure.

Topics: Carbamates; Cross-Sectional Studies; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Microbial Sensitivity Tests; Mutation; Phenotype; Pyrimidinones; Retrospective Studies; RNA, Viral; Sulfonamides; Viremia

Topics: Adult; Antiretroviral Therapy, Highly Active; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Spinal Cord Diseases

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

Topics: Carbamates; Drug Synergism; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pilot Projects; Pyrimidinones; Ritonavir; Sulfonamides

Researchers continue to find evidence that the combination of lopinavir/ritonavir (Kaletra) provides prolonged potency while avoiding drug resistance. The Kaletra findings come on the heels of another study that found a high rate of drug resistance among HIV patients with measurable levels of virus in their blood.

Topics: Drug Combinations; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

Topics: Adult; Antiretroviral Therapy, Highly Active; Edema; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones

Topics: Carbamates; Dose-Response Relationship, Drug; Drug Interactions; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Salvage Therapy; Sulfonamides

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Carbamates; Delavirdine; Drug Synergism; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; 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

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

The in vitro inhibition of wild-type human immunodeficiency virus (HIV) by combinations of lopinavir and six other protease inhibitors over a range of two-drug combination ratios was evaluated. Combinations of lopinavir with indinavir, nelfinavir, amprenavir, tipranavir, and BMS-232632 generally displayed an additive relationship. In contrast, a consistent, statistically significant synergistic inhibition of HIV type 1 replication with combinations of lopinavir and saquinavir was observed. Analysis of the combination indices indicated that lopinavir with saquinavir was synergistic over the entire range of drug combination ratios tested and at all levels of inhibition in excess of 40%. Cellular toxicity was not observed at the highest drug concentrations tested. These results suggest that administration of combinations of the appropriate dose of lopinavir with other protease inhibitors in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity. More importantly, the observed in vitro synergy between lopinavir and saquinavir provides a theoretical basis for the clinical exploration of a novel regimen of lopinavir-ritonavir and saquinavir.

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV; HIV Infections; HIV Protease Inhibitors; Lopinavir; Microbial Sensitivity Tests; Pyrimidinones

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nelfinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Topics: CD4 Lymphocyte Count; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Pyrimidinones; Viral Load

Topics: Adolescent; Adult; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Pyrimidinones; Ritonavir

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antiprotozoal Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Leishmaniasis; Lopinavir; Male; Pyrimidinones; Renal Dialysis; Renal Insufficiency; Ritonavir

Topics: Adult; Carbamates; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Sulfonamides

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Edema; Female; HIV Infections; HIV Protease Inhibitors; Humans; Inflammation; Leg; Lopinavir; Male; Middle Aged; Pyrimidinones

Topics: Drug Combinations; Drug Resistance, Microbial; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome

Topics: Clinical Trials as Topic; Drug Combinations; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load

Topics: Biological Availability; Drug Administration Schedule; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome

Topics: Antiretroviral Therapy, Highly Active; Drug Resistance, Microbial; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutagenesis; Pyrimidinones; Retrospective Studies; Salvage Therapy; Time Factors

Topics: Drug Approval; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Pyrimidinones; Ritonavir; United States; United States Food and Drug Administration

The association of genotypic changes in human immunodeficiency virus (HIV) protease with reduced in vitro susceptibility to the new protease inhibitor lopinavir (previously ABT-378) was explored using a panel of viral isolates from subjects failing therapy with other protease inhibitors. Two statistical tests showed that specific mutations at 11 amino acid positions in protease (L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M) were associated with reduced susceptibility. Mutations at positions 82, 54, 10, 63, 71, and 84 were most closely associated with relatively modest (4- and 10-fold) changes in phenotype, while the K20M/R and F53L mutations, in conjunction with multiple other mutations, were associated with >20- and >40-fold-reduced susceptibility, respectively. The median 50% inhibitory concentrations (IC(50)) of lopinavir against isolates with 0 to 3, 4 or 5, 6 or 7, and 8 to 10 of the above 11 mutations were 0.8-, 2.7-, 13.5-, and 44.0-fold higher, respectively, than the IC(50) against wild-type HIV. On average, the IC(50) of lopinavir increased by 1.74-fold per mutation in isolates containing three or more mutations. Each of the 16 viruses that displayed a >20-fold change in susceptibility contained mutations at residues 10, 54, 63, and 82 and/or 84, along with a median of three mutations at residues 20, 24, 46, 53, 71, and 90. The number of protease mutations from the 11 identified in these analyses (the lopinavir mutation score) may be useful for the interpretation of HIV genotypic resistance testing with respect to lopinavir-ritonavir (Kaletra) regimens and may provide insight into the genetic barrier to resistance to lopinavir-ritonavir in both antiretroviral therapy-naive and protease inhibitor-experienced patients.

Topics: Drug Resistance; Genome, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Nelfinavir; Pyrimidinones; Ritonavir; Viral Load

Topics: Aged; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; Humans; Lopinavir; Male; Patient Compliance; Pyrimidinones; Ritonavir; Stavudine; Sulfonamides; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Carbamates; CD4 Lymphocyte Count; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load

Topics: Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones

Topics: Clinical Trials as Topic; Drug Approval; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors

Topics: Drug Approval; Drug Combinations; Drug Costs; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Lopinavir; Pyrimidinones; Ritonavir; United States; United States Food and Drug Administration

Topics: Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

Details and information sources on Kaletra (lopinavir plus low-dose ritonavir), a protease inhibitor approved last week.

Topics: Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; United States; United States Food and Drug Administration

Topics: Adenine; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Resistance; HIV Infections; Humans; Lopinavir; Organophosphonates; Organophosphorus Compounds; Pyrimidinones; Ritonavir; Tenofovir

Topics: Anti-HIV Agents; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Peptide Fragments; Pyrimidinones; South Africa

Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Treatment Failure; Viral Load

Topics: Drug Administration Schedule; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Treatment Outcome

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Buprenorphine; Child; Drug and Narcotic Control; Drug Combinations; Drugs, Investigational; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Leukemia, Promyelocytic, Acute; Lopinavir; Opioid-Related Disorders; Oxides; Pyrimidinones; Receptors, Opioid; Ritonavir; United States; United States Food and Drug Administration

Topics: Adult; Child; Clinical Trials as Topic; Drug Approval; Drug Combinations; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; United States; United States Food and Drug Administration

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.

Topics: Adult; Child; Child, Preschool; Drug Combinations; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Infant; Lopinavir; Molecular Structure; Pyrimidinones; Ritonavir

Topics: Anti-HIV Agents; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones

Topics: Anti-HIV Agents; Drug Resistance, Microbial; HIV Infections; HIV-1; Humans; Lopinavir; Microbial Sensitivity Tests; Phenotype; Pyrimidinones; Treatment Outcome

Topics: Animals; Anti-HIV Agents; Drug Administration Schedule; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Mutation; Ontario; Pyrimidinones; Reverse Transcriptase Inhibitors; Viral Load

Topics: Drug Combinations; Drug Interactions; Drug Resistance, Microbial; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir

Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Viral Load

Many at the 6th Conference on Retroviruses and Opportunistic Infections expressed concern regarding the significant amount of drug resistance that is developing among treatment-naive patients. The threat of drug failure has created an acute need for new treatments that are not affected by resistance to older treatments. Three promising drugs that are on the horizon are discussed. Amprenavir (Agenerase) is expected to receive marketing approval in the next few months, and ABT-378 and T-20 are in phase II trials and should be available in the next 2 years. Additional information on these drugs is presented.

Topics: Anti-HIV Agents; Carbamates; Congresses as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; Drugs, Investigational; Enfuvirtide; Furans; HIV Envelope Protein gp41; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Peptide Fragments; Pyrimidinones; Salvage Therapy; Sulfonamides; Viral Load; Virus Replication

The new protease inhibitor ABT-378/r, which is ABT-378 combined with a small amount of Ritonavir, is available to a limited number of patients outside of clinical trials through an Early Access Program. Due to the limited drug availability, ABT-378/r will be offered only to patients who have failed two or more protease inhibitor-containing therapies, and either have a CD4 count less than 50 or have had an opportunistic infection while on highly active antiretroviral therapy. Since ABT-378/r is still experimental, doctors cannot prescribe the drug without approval from an IRB (institutional review board). The article cautions that ABT-378/r should be combined with other new drugs in patients who have multidrug resistance. Contact information is provided.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Patient Selection; Pyrimidinones

This fall, ABT-378 will be available in a limited supply through Abbott Labs= compassionate use program. ABT-378 is a new protease inhibitor that may be effective in patients who have developed a resistance to other protease inhibitors, including Fortovase and Norvir. The drug will be available to 200 to 300 people with CD4 counts below 50 who do not have other treatment options. Gilead=s newest nucleotide reverse transcriptase inhibitor, PMPA, will also be available through a compassionate use program. PMPA appears to be more powerful than adefovir, PMPA's predecessor, but the potential side effects of PMPA are unknown. Contact information is provided.

Topics: Adenine; Anti-HIV Agents; Clinical Trials as Topic; Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organophosphonates; Organophosphorus Compounds; Patient Selection; Pyrimidinones; Reverse Transcriptase Inhibitors; Tenofovir

In November, Abbott Laboratories expanded its early access program criteria for ABT-378/r in the United States. Patients who have up to 200 CD4 T cells and who have failed numerous antiretroviral regimens are now eligible for the program. In February 2000, the program will be expanded further. At that time, patients who have no viable therapy with any of the approved antiretrovirals may have access to ABT-378/r regardless of their viral loads, CD4 T cell counts, or history of protease inhibitor use. Contact information is provided.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones

ABT-378, a new drug from Abbott Laboratories, may hold promise for patients who are infected with drug-resistant HIV. ABT-378 made in a combination pill with ritonavir can suppress HIV viral loads to fewer than 400 copies/mL in 78 percent of protease inhibitor-experienced patients and 95 percent of treatment-naive patients. It is well tolerated, with the most common side effects being diarrhea, nausea, asthenia, and headaches. It is taken twice a day in a single pill; researchers are evaluating the effectiveness of taking it only once a day.

Topics: Clinical Trials, Phase III as Topic; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir

Abbott Laboratories has approximately 300 slots available in the expanded access program for ABT-378/ritonavir. ABT-378/ritonavir is an experimental protease inhibitor combined with a small amount of ritonavir to increase bioavailability. There is a limited supply of ABT-378/ritonavir and the drug is only available to individuals most in need. Eligibility requirements for the program are listed. All participants will continue to receive the drug until it is approved. People who meet eligibility requirements may already have developed resistance to all currently approved regimens. Other drugs may soon be available, including the fusion inhibitor, T-20, and the nucleotide reverse transcriptase inhibitor, tenofovir (PMPA). These drugs may be used to construct a new regimen, if current medications will not work. Contact information is provided.

Topics: Anti-Infective Agents; Clinical Trials as Topic; Drug Approval; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Patient Selection; Pyrimidinones

Updates are provided for new anti-HIV drugs currently in development. ABT-378, Tipranavir, and DMP-450 are among the new protease inhibitors discussed. Drugs from other classes that are discussed include emivirine (Coactinon, formerly MKC-442), FTC (emtricitabine, Coviracil), adefovir (Preveon), and pentafuside (T-20). A small study has found that women using Ritonavir (Norvir) may be at a greater risk for anemia (a decrease in red blood cells), caused by excessive menstrual bleeding or hypermenorrhea. New formulations of Ritonavir and ddI (Didanosine, Videx) are described.

Topics: Adverse Drug Reaction Reporting Systems; Anti-HIV Agents; Capsules; Carbamates; Chemistry, Pharmaceutical; Didanosine; Drug Synergism; Drug Therapy, Combination; Drugs, Investigational; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Menorrhagia; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

Three drugs - ABT-378, adefovir, and tenofovir (PMPA) - are currently awaiting FDA approval and are being made available, free of charge, through expanded access programs. ABT-378 from Abbott Laboratories initially will be available to 700 people; tenofovir will be made available to 300 people in the United States. Enrollment criteria for each of the drugs are listed. In addition, contact information is provided.

Topics: Adenine; Anti-HIV Agents; Drug Approval; Drugs, Investigational; Health Services Accessibility; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organophosphonates; Organophosphorus Compounds; Pyrimidinones; Reverse Transcriptase Inhibitors; Tenofovir

Reports at the 5th Conference on Retroviruses and Opportunistic Infections addressed new anti-HIV agents in primary phases of development that offer treatment alternatives to people with little or no treatment history and individuals with few treatment choices. FTC, a new nucleoside analog produced by Triangle Pharmaceuticals, is an alternative to 3TC. F-ddA (lodenosine), a nucleoside analog licensed by US Bioscience, is structurally similar to ddI and is reported to have good bioavailability, once-a-day dosing, and no bone marrow suppression. F-ddA has also shown in vitro activity against multidrug-resistant strains of HIV. Adult and pediatric studies are currently being conducted by the National Cancer Institute (NCI) and US Bioscience. Oral versus IV PMPA shows promising results as a possible alternative for 3TC- and AZT-experienced patients. Further testing is being done by Gilead Sciences and HIV Network for Prevention Trials (HIVNET). Abbott Laboratories is developing a second-generation protease inhibitor, ABT-378, which has a ten-fold greater antiviral activity in vitro than the original, ritonavir. It is administered with ritonavir to increase ABT-378 levels in the blood, but has no food requirements, and less severe side effects. Two trials are being conducted: one for patients who are treatment-naive and the second for patients who are failing other protease inhibitors. Immune-based therapies, such as Leukine (GM-CSF), are used to handle neutropenia and offset bone marrow toxicities from drugs. Concerns that GM-CSF may increase viral replication may be balanced by using highly active antiretroviral therapy. FP-21399, developed by Lexigen Pharmaceuticals, is being tested as an HIV fusion inhibitor.

Topics: Adenine; Animals; Anti-HIV Agents; Biological Availability; Chlorobenzenes; Clinical Trials as Topic; Codon; Dideoxyadenosine; Drug Resistance, Microbial; Drugs, Investigational; Granulocyte-Macrophage Colony-Stimulating Factor; HIV Infections; HIV Protease Inhibitors; Humans; Naphthalenes; Organophosphonates; Pyrimidinones; Receptors, CCR5; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Tenofovir

Current treatment strategies need to be planned carefully, because there is an inadequate supply of new types of drugs available to treat people who have failed previous therapies. It is important to fully use existing therapies so as not to limit future options. Drugs in development include: ABT-378, a protease inhibitor from Abbott Laboratories; tipranavir (PNU-140690), a protease inhibitor by Pharmacia & Upjohn; and S-1153, a non-nucleoside reverse transcriptase inhibitor from Agouron Pharmaceuticals. All were effective and well-tolerated in recent trials. A warning was issued for adefovir, a nucleoside reverse transcriptase inhibitor, regarding the development of kidney toxicity for people taking the drug more than 20 weeks. Information on expanded access programs for abacavir, adefovir, amprenavir, and efavirenz is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Imidazoles; Kidney Diseases; Lopinavir; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load