Efficacy, safety, and pharmacokinetics of once-daily boosted darunavir in pretreated HIV-infected patients.

OBJECTIVE AND METHODS: The efficacy and safety of switching to a combined regimen containing darunavir/ritonavir (DRV/r) was investigated in a retrospective study. RESULTS: Sixty-six experienced patients receiving once-daily DRV/r (900/100 mg) in various regimens were included (median age 51 y; male 82%; Centers for Disease Control and Prevention (CDC) stages B or C 70%). The number of patients with plasma HIV RNA < 50 copies/ml increased from 71% (45/63) at baseline (before switch) to 84% (52/62) at visit 1 (weeks 3-11), and to 92% (60/65) at visit 2 (weeks 12-24). CD4 cells increased from 498 ± 201 cells/mm³ at baseline to 567 ± 232 cells/mm³ by visit 2. Good digestive and metabolic tolerance was observed. The median steady-state DRV plasma concentration, measured 24 ± 4 h after the last drug intake, was 1427 ng/ml. All DRV plasma concentrations were above the protein-binding corrected median effective concentration (EC50) for the wild-type virus (55 ng/ml). CONCLUSIONS: Once-daily DRV/r (900/100 mg) was efficacious in pretreated patients, with safe responses.

Efficacy and safety of unboosted atazanavir in combination with lamivudine and didanosine in naive HIV type 1 patients in Senegal.

The use of ritonavir as a protease inhibitor boost is rare in sub-Saharan Africa because a heat-stable formula is not available. We report the results of an open-label pilot trial with unboosted atazanavir in combination with lamivudine and didanosine as first-line therapy conducted in Senegal. Treatment-naive HIV-1 infected adult patients without active opportunistic disease were included. The primary endpoint was the proportion of patients with plasma HIV-1 RNA <400 copies/ml at week 48. Forty patients (12 men and 28 women; mean age +/- SD: 40 +/- 9 years) were included. Treatment was changed during the study for two patients (pregnancy, tuberculosis); one patient was lost to follow-up and one patient died (gastroenteritis with cachexia). At week 48, 78% [95% confidence interval (CI): 65-90%] and 68% (95% CI: 53-82%) of the patients had HIV-1 RNA <400 and <50 copies/ml, respectively (intent-to-treat analysis; not completer = failure). Among the seven patients with HIV-1 RNA >or=400 copies/ml at week 48, five were not compliant; genotyping analysis (n = 4) did not reveal a major mutation for protease inhibitors. The mean CD4 cell count change from baseline to week 48 was +238 +/- 79 cells/mm(3). The combination of unboosted atazanavir with lamivudine and didanosine was efficient and well tolerated in HIV-1-infected patients with results similar to those observed in Northern countries. These results suggest that unboosted atazanavir with its high genetic barrier could be a valuable alternative to NNRTIs in resource-limited countries in some HIV-1-infected patients in case of compliance issues with NNRTIs, intolerance to NNRTIs, resistance mutations to NNRTIs, in women with childbearing potential, or as a maintenance therapy in patients with virological suppression.

Tenofovir-emtricitabine-efavirenz in HIV-I-infected adults in Senegal: a 96-week pilot trial in treatment-naive patients.

We report the results of a pilot open-label trial of a tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) combination conducted in Dakar, Senegal. Forty HIV-1-infected patients, naive of antiretroviral treatment and without active opportunistic disease, were included and followed through 96 weeks. At weeks 48 and 96, respectively, 82.5% and 85% of patients had HIV-1 RNA <400 copies/mL (72.5% and 77.5% with HIV-1 RNA <50 copies/mL). Between baseline and week 96, the mean (SD) CD4 count increased from 126 (102) to 338 (155) cells/mm(3). The mean (SD) creatinine clearance decreased from 92 (36) to 73 (19) mL/min (P = .001). Treatment adherence was at least 94% at all scheduled visits. The efficacy and tolerability of a TDF/FTC/EFV combination were high and similar to those observed in Northern countries. This drug combination can be recommended in limited-resource countries, as did the World Health Organization (WHO) and should be made readily available as a fixed-dose combination.

Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HIV-1 infection: TONUS study.

BACKGROUND: To assess the efficacy and safety of the triple NRTI combination of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF) in a once-daily regimen. METHOD: 38 HIV-naive patients (pts) were treated in a prospective open-arm study over 48 weeks (W48). Virological failure was defined as never achieving plasma HIV-1 RNA < 400 copies/mL or rebound of > or = 0.7 log10. RESULTS: 12/36 (33%) pts had virologic failure at W24 and 10 additional pts had HIV RNA > 50 copies/mL at W12 or W24. There was a significant association between baseline viral load (VL) and virologic failure in 0%, 29%, and 64% pts with baseline VL levels < 4, 4-5, and > 5 log10 copies/mL, respectively (p = .014). 76% of pts developed K65R and M184V/I mutations by W24, and 19% developed M184V/I alone. At W4, 86% of pts had adequate plasma Cmin for the 3 drugs. 14 pts with K65R and M184V/I were given a rescue therapy with a successful outcome (< 50 copies/mL; median follow-up 48 weeks). CONCLUSION: Convergent genetic pathway to resistance, in conjunction with lower antiretroviral potency, may explain the high rate of selection K65R and M184V mutations. These mutations did not appear to have a negative effect on rescue therapy with a variety of regimens.

Inhibition studies of dehydroepiandrosterone 7 alpha- and 7 beta- hydroxylation in mouse liver microsomes.

Hydroxylations of dehydroepiandrosterone (DHEA) at the 7 alpha- and 7 beta- positions have been reported in numerous murine tissues and organs, including liver, and the responsible cytochrome P450 (P450) species await identification. Using thin layer chromatography and gas chromatography-mass spectrometry, we report identification of 7 alpha-hydroxy-DHEA and 7 beta-hydroxy-DHEA metabolites produced in mouse liver microsome digests and kinetic studies of their production with apparent KM values of 3.19 +/- 0.292 microM and 2.82 +/- 0.241 microM for 7 alpha- and 7 beta-hydroxylation, respectively. Investigation of P450 inhibitor and of steroid hormone effects on both 7 alpha- and 7 beta-hydroxylation of DHEA showed that, 1) different P450s were involved in 7 alpha- and 7 beta-hydroxylation of DHEA because metyrapone inhibited solely 7 alpha-hydroxylation, 2) P450 2D6, 2B1, and 2B11 were not responsible for 7 alpha- and 7 beta-hydroxylation of DHEA because respective specific inhibitors quinidine and chloramphenicol triggered no inhibition, 3) aside from P450 7b, P450 1A1, and 1A2 may be responsible for a fraction of DHEA 7 alpha- and 7 beta-hydroxylation because alpha-naphthoflavone and furafylline, which inhibit specifically P450 1A1 and 1A2, decreased the 7 alpha- and 7 beta-hydroxylation partly, 4) comparison of these findings with those obtained with brain microsomes suggested that tissue-specific P450 species are responsible for the 7 alpha- and 7 beta-hydroxylation of DHEA, 5) 7 alpha-hydroxylation of DHEA may be shared with other 3 beta-hydroxysteroids, such as 3 beta-hydroxy-5 alpha-androstan-17-one, 5-androstene-3 beta,17 beta-diol and pregnenolone, which acted in a noncompetitive manner. Taken together, these findings will be of use for identification of the P450 species responsible for 7 alpha- and 7 beta-hydroxylation of DHEA and for studies of their activities in liver.