Diarrhea associated with lopinavir/ritonavir-based therapy: results of a meta-analysis of 1469 HIV-1-infected participants.

BACKGROUND: Antiretroviral therapy is associated with adverse events (AEs). The most frequently reported AE associated with lopinavir/ritonavir (LPV/r) containing regimens is diarrhea. The objective of this meta-analysis is to describe the incidence, prevalence, and duration of diarrhea in individuals taking LPV/r. METHODS: This is a meta-analysis of Abbott-conducted clinical trials. Inclusion criteria included prospective randomized clinical trials with the LPV/r tablet formulation and had AE data (moderate/severe diarrhea) available through 48 weeks of treatment. RESULTS: Three trials (total 1469 participants) met the inclusion criteria. In all, 11.2% of participants reported moderate/severe diarrhea by week 8, with median time to resolution of 7.4 weeks. The overall 48-week incidence of moderate/severe diarrhea was 15.5%. The discontinuation rate due to moderate/severe diarrhea was 1.3%. CONCLUSIONS: Moderate/severe diarrhea occurred in less than 1 in 6 participants taking LPV/r, typically started in the first 8 weeks of treatment and infrequently resulted in premature discontinuation.

Evaluation of myocardial infarction and coronary artery disease in subjects taking lopinavir/ritonavir: a study using clinical trial and pharmacovigilance databases.

OBJECTIVE: There is growing interest in studying age-related diseases, such as coronary artery disease (CAD) and resulting myocardial infarction (MI) in HIV-infected patients. While some cohort studies indicate that several antiretrovirals (ARVs), including the protease inhibitor lopinavir/ ritonavir (LPV/r), are associated with an increased relative risk (RR) of MI, other studies show a reduction of MI and CAD in subjects taking ARVs when compared with HIV+ patients not taking ARV therapy. This manuscript reviews data from Abbott-sponsored clinical trials and pharmacovigilance reporting system. METHODS: A systematic search was performed to retrieve cases of MI and CAD in Abbott's clinical trial and pharmacovigilance safety databases. The rates of MI and CAD, and risk factors for the events were reviewed in detail. RESULTS: The rate of MI and CAD per 1,000 patient treatment years (PTY) was 1.24 (95% CI = 0.40 - 2.90) and 2.74 (95% CI = 1.37 - 4.90), respectively, for subjects taking LPV/r during clinical trials. The frequency of pharmacovigilance reports of MI and CAD were 2.9 per 100,000 PTY and 3.6 per 100,000 PTY, respectively. Most subjects who had MI and CAD events had multiple baseline risk factors. CONCLUSIONS: Relatively few subjects experienced MI or CAD during Abbott-sponsored clinical trials of LPV/r. Analysis of clinical trial and pharmacovigilance data did not indicate an increased risk of MI or CAD associated with LPV/r compared with the general population. In general, the subjects that experienced MI or CAD had known traditional risk factors suggesting that addressing modifiable risk factors could decrease the risk of MI or CAD. ARVs have not been thoroughly studied in subjects at high risk for MI and CAD, and further studies of this population could identify whether starting ARVs affects the incidences of cardic events in subjects with many traditional risk factors

Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results.

BACKGROUND: AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥ 10(5) copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients. METHODS: Primary endpoints were times to virologic failure, regimen modification, and safety event. RESULTS: In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14). CONCLUSIONS: In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.

Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1.

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

Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy.

BACKGROUND: The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known. METHODS: In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or > or = 200 copies per milliliter at or after 24 weeks). RESULTS: A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48. CONCLUSIONS: In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

Lopinavir/ritonavir in pregnancy.

OBJECTIVE: The Antiretroviral Pregnancy Registry was established in 1989 to collect data on birth defects after pregnancy exposures to antiretroviral therapy. Using Registry data, this study estimates the birth defect risk after pregnancy exposures to lopinavir/ritonavir. METHODS: The analysis population includes all prospective lopinavir/ritonavir-exposed pregnancies enrolled in the Registry from September 2000 through July 2007. Birth defect prevalence after pregnancy exposure is compared with rates from a population-based surveillance system, and first-trimester exposures are compared with combined second/third-trimester exposures. RESULTS: Among 955 live births prenatally exposed to lopinavir/ritonavir, 23 cases with birth defects were reported [2.4%, 95% confidence interval (CI) = 1.5 to 3.6). Among 267 live births with first-trimester exposures, 5 had birth defects (1.9%, 95% CI = 0.6 to 4.3). These rates are similar to the population-based comparator rate of 2.67% and the rate in infants with second/third-trimester exposures (2.6%, 95% CI = 1.6 to 4.1). No pattern of birth defects suggestive of a common etiology was seen. CONCLUSIONS: The prevalence of birth defects among infants prenatally exposed to lopinavir/ritonavir is not significantly different from internal or external comparison groups. These data provide reassuring information to patients and clinicians about the safety of lopinavir/ritonavir in the treatment of HIV-positive pregnant women.

Lack of effect of gastric acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir in HIV-infected patients.

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.