Efficacy and safety of an anti-retroviral combination regimen including either efavirenz or lopinavir–ritonavir with a backbone of two nucleoside reverse transcriptase inhibitors

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.     

Predictive factors of virologic success in HIV-1-infected children treated with lopinavir/ritonavir

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.     

Steady-State pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients

BACKGROUND: In vitro synergy and complementary resistance profiles provide a strong rationale for combining fosamprenavir with saquinavir as part of a potent double-boosted protease inhibitor regimen. This study evaluated the steady-state pharmacokinetics of saquinavir 1000 mg twice daily (bid) and fosamprenavir 700 mg bid administered with 2 different doses of ritonavir (100 and 200 mg bid) in HIV-1-infected subjects. METHODS: On day 1, 12-hour pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg bid) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Fosamprenavir 700 mg bid was then added to the regimen, and pharmacokinetic sampling was repeated for all 3 agents at day 11. The ritonavir daily dose was then increased to 200 mg bid, and a 3rd pharmacokinetic profile was obtained at day 22. RESULTS: The coadministration of fosamprenavir 700 mg bid with saquinavir/ritonavir 1000/100 mg bid resulted in a statistically nonsignificant decrease in saquinavir concentrations (by 14, 9, and 24%, for saquinavir area under the concentration-time curve [AUC]0-12, C(max), and C(trough), respectively). This was compensated for by an increased ritonavir dose of 200 mg bid, which resulted in a statistically nonsignificant increase in saquinavir exposure compared with baseline. Amprenavir levels did not appear to be significantly influenced by coadministration of saquinavir with fosamprenavir. Fosamprenavir significantly reduced ritonavir exposure, but the increased ritonavir dose compensated for this interaction. CONCLUSIONS: Our findings showed that saquinavir/ritonavir/fosamprenavir was well tolerated over the study period. Saquinavir plasma concentrations were slightly lowered by the addition of fosamprenavir to the regimen. However, the addition of a further 100 mg ritonavir bid restored the small and insignificant decrease.     

Efficacy and safety of a quadruple combination Combivir + abacavir + efavirenz regimen in antiretroviral treatment-naive HIV-1-infected adults: La Francilienne

OBJECTIVE: To evaluate the safety and efficacy of a protease inhibitor sparing, quadruple therapy (Combivir + abacavir + efavirenz) in antiretroviral treatment-naive HIV-1-infected adults. DESIGN: Multicenter open-label pilot study. Clinical and biological assessments were performed at baseline and at weeks 2, 4, 8, 16, 24, 32, 40, 48. RESULTS: Thirty-one subjects enrolled with a median baseline viral load (VL) of 4.69 log10 copies/mL and CD4 cell count of 322 cells/mm3. At week 48, 90% (intention-to-treat [ITT] switch included) and 77% (ITT switch = failure) patients had a VL <50 copies/mL. These results were similar in the population (n = 13) with a VL >100,000 copies/mL at baseline. Combivir + abacavir + efavirenz demonstrated an early antiretroviral response: 58% of patients had plasma HIV-1 RNA <50 copies/mL at week 8. Using a modified assay, the percentage of patients with VL <5 copies/mL at week 48 was 55% (17/31) and 42% (13/31) using ITT (switch included) and ITT (switch = failure), respectively. Median VL decreased by -4.0 log10 copies/mL at week 48 (ITT). Median CD4+ cell count change from baseline at week 48 was +129 cells/mm3 (ITT). Most patients experienced at least one drug-related adverse event that was not considered treatment-limiting by the investigator. There were no cases of abacavir hypersensitivity reactions. CONCLUSIONS: Safety and efficacy results from this study demonstrated that the quadruple regimen Combivir/abacavir/efavirenz is generally safe and displays potent and durable antiretroviral activity in antiretroviral treatment-naive HIV-1-infected patients, offering a promising therapeutic option in a PI-sparing strategy.     

Protease inhibitor and nonnucleoside reverse transcriptase inhibitor concentrations in the genital tract of HIV-1-infected women

The pharmacokinetics of antiretrovirals (ARVs) in the female genital tract (FGT) are likely to influence vertical and sexual transmission of HIV, the development of viral resistance, and post-exposure prophylaxis regimens. This study is the first to compare ARV concentrations in direct aspirates of cervicovaginal fluid (CVF) and blood plasma (BP). This unique method provides direct assessment of concentrations without the confounding of cervicovaginal lavage dilution. Of 8 ARVs, CVF concentrations ranged from <10% to >100% of BP concentrations. These large differences in CVF penetration suggest that further research into ARV pharmacokinetics and drug efficacy in the FGT is necessary.