Differential impact of APOBEC3-driven mutagenesis on HIV evolution in diverse anatomical compartments.

OBJECTIVE: Previous studies on HIV quasispecies have revealed HIV compartmentalization in various tissues within an infected individual. Such HIV variation is a result of a combination of factors including high replication and mutation rates, recombination, and APOBEC3-host selective pressure. METHODS: To evaluate the differential impact of APOBEC3 editing in HIV-1 compartments, we analyzed the level of G-to-A hypermutation in HIV-1 protease and reverse transcriptase sequences among 30 HAART-treated patients for whom peripheral blood mononuclear cells and body tissues or fluids [cerebral spinal fluid (CSF), rectal tissue, or renal tissue] were collected on the same day. RESULTS: APOBEC3-mediated hypermutation was identified in 36% (11/30) of participants in at least one viral reservoir. HIV hypermutated sequences were often observed in viral sanctuaries (total n = 10; CSF, n = 6; renal tissue, n = 1; rectal tissue n = 3) compared with peripheral blood (total n = 4). Accordingly, APOBEC3 editing generated more G-to-A drug resistance mutations in sanctuaries: three patients' CSF (i.e. G73S in protease; M184I, M230I in reverse transcriptase) and two other patients' rectal tissues (M184I, M230I in reverse transcriptase) while such mutations were absent from paired peripheral blood mononuclear cells. CONCLUSION: APOBEC3-induced mutations observed in peripheral blood underestimate the overall proportion of hypermutated viruses in anatomical compartments. The resulting mutations may favor escape to antiretrovirals in these compartments in conjunction with a lower penetration of drugs in some sanctuaries. On the other side, because hypermutated sequences often harbor inactivating mutations, our results suggest that accumulation of defective viruses may be more dominant in sanctuaries than in peripheral blood of patients on effective HAART.

Effects of rosuvastatin versus pravastatin on low-density lipoprotein diameter in HIV-1-infected patients receiving ritonavir-boosted protease inhibitor.

OBJECTIVE: HIV infection is associated with an atherogenic lipoprotein profile, and ritonavir-boosted protease inhibitors exacerbate this phenotype. We evaluated the effect of 45 days of rosuvastatin versus pravastatin on the low-density lipoprotein (LDL) size and the distribution of LDL subfractions in HIV-1 patients receiving boosted protease inhibitors with elevated LDL levels. DESIGN: Substudy of the randomized double-blind multicentre ANRS 126 VIHstatine trial. SETTING: Twenty clinical centres in France. PATIENTS: HIV-infected patients receiving boosted protease inhibitors with dyslipidaemia (LDL cholesterol > 4.1 mmol/l and triglycerides < 8.8 mmol/l). INTERVENTION: Rosuvastatin 10 mg/day (n = 39) or pravastatin 40 mg/day (n = 37) for 45 days. MAIN OUTCOME MEASURE(S): LDL size and distribution of LDL subfractions blindly assessed by gradient gel electrophoresis at baseline and at day 45. RESULTS: Rosuvastatin was more effective than pravastatin in increasing the diameter of the LDL peak. The LDL diameter change was 0.33 ± 0.59 nm in the rosuvastatin group versus -0.01 ± 0.52 nm in the pravastatin group (P = 0.021). Rosuvastatin was also more effective in increasing significantly the percentage of large LDL (LDL1, P = 0.038; LDL2, P = 0.031) and in decreasing the percentage of small LDL (LDL3, P = 0.009). CONCLUSION: Rosuvastatin was more effective than pravastatin in normalizing LDL size and LDL subfraction distributions, leading to a less atherogenic phenotype.

Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136.

BACKGROUND: Darunavir/ritonavir (darunavir/r) maintenance strategy, in patients with suppressed HIV RNA viremia, is a potential long-term strategy to avoid nucleoside analogue toxicities and to reduce costs. METHODS: MONOtherapy Inhibitor protease is a prospective, open-label, noninferiority, 96-week safety and efficacy trial in virologically suppressed patients on triple therapy who were randomized to a darunavir/r triple drug regimen or darunavir/r monotherapy. The primary endpoint was the proportion of patients with HIV RNA less than 400 copies/ml at week 48; treatment failure was defined as two consecutive HIV RNA more than 400 copies/ml (time to loss of virologic response) or any change in treatment. The trial had 80% power to show noninferiority for the monotherapy arm (delta =-10%, 90% confidence interval). RESULTS: A total of 242 patients were screened, 225 of whom were randomized. In the per protocol efficacy analysis, treatment success was 99% on darunavir/r triple drug versus 94% on darunavir/r monotherapy (delta = -4.9%, 90% confidence interval, from -9.1 to -0.8). Similar results were found in intent-to-treat population (92 versus 87.5%, delta = -4.5%, 90% confidence interval from -11.2 to 2.1). Three patients experienced virologic failure on darunavir/monotherapy and none on darunavir/r triple drug. No resistance to protease inhibitor emerged in patients with plasma viral load above 50 copies/ml. The two groups did not differ in the number of serious adverse events. CONCLUSION: Darunavir/r monotherapy exhibited efficacy rate over 85% with concordant results in the magnitude of difference with darunavir/r triple drug regimen in both intent-to-treat and per protocol analyses, but discordant conclusions with respect to the noninferiority margin. Patients failing on darunavir/r monotherapy had no emergence of new darunavir resistance mutations preserving future treatment options.