Effects of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir and ritonavir-boosted atazanavir.

A total of 71 HIV-negative healthy adults were randomized to 1 of 6 regimens to receive lopinavir/ritonavir tablets 400/100 mg twice daily (bid) or 800/200 mg once daily (qd) or atazanavir 300 mg + ritonavir 100 mg qd from study days 1 to 15 with a moderate-fat meal. One hour before breakfast, either omeprazole 40 mg qd was administered on study days 11 through 15, or a single dose of ranitidine 150 mg was administered on study day 11. Lopinavir, atazanavir, and ritonavir pharmacokinetics were determined on study days 10, 11, and 15 and compared using point estimates and 90% confidence intervals (CIs). The point estimates for lopinavir Cmax and AUCtau were in the range of 0.92 to 1.08, with 90% CI contained within the range of 0.80 to 1.25 after coadministration of omeprazole or ranitidine. The point estimates for atazanavir Cmax and AUCtau were decreased by 48% to 62% with the upper bound of the 90% CI

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.

Substitution with lopinavir/ritonavir improves patient-reported outcomes including quality of life in patients who were intolerant to their antiretroviral therapy.

PURPOSE: Adverse effects are important determinants of quality of life (QOL) during highly active antiretroviral therapy (HAART). The PLATO study investigated the association between changes in patient-reported outcomes including QOL and substitution with lopinavir/ritonavir in patients experiencing side effects (SEs). METHOD: HIV-1-infected participants (N = 849) with undetectable viral load experiencing Grade-2 SEs of the protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) component of their HAART regimen were randomized to immediate (baseline) or deferred (week 4) substitution with lopinavir/ritonavir soft-gel capsules 400/100 mg bid. The primary endpoint was change in the total score from the AIDS Clinical Trials Group (ACTG) Symptoms Distress Module (ASDM), supplemented with two items for nephrolithiasis. Secondary endpoints included Medical Outcomes Study (MOS)-HIV scores and Center for Epidemiologic Studies-Depression (CES-D) scores. RESULTS: Immediate substitution resulted in improved ASDM total score at week 4 compared with deferred substitution (p <.001) and significant improvements in all MOS-HIV domains, while significant improvement was observed in CES-D scores at week 8. Primary SEs resolved at week 8 in 65% of participants in the immediate substitution group. Suppression of HIV-1 was maintained. Treatment was well-tolerated and associated with elevations in cholesterol and triglycerides. CONCLUSION: Substitution with LPV/r improved patient-reported outcomes including QOL in patients experiencing Grade-2 SEs, while maintaining viral suppression.

Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study.

OBJECTIVE: 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. DESIGN: Long-term, open-label follow-up of a phase II, prospective, randomized, multicenter trial. METHODS: 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. RESULTS: : 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. CONCLUSIONS: LPV/r-based therapy provides durable antiretroviral response and is generally well tolerated through 204 weeks of therapy.