Impact of baseline HIV-1 tropism on viral response and CD4 cell count gains in HIV-infected patients receiving first-line antiretroviral therapy.

BACKGROUND: Viral tropism influences the natural history of human immunodeficiency type 1 (HIV-1) disease: X4 viruses are associated with faster decreases in CD4 cell count. There is scarce information about the influence of viral tropism on treatment outcomes. METHODS: Baseline plasma samples from patients recruited to the ArTEN (Atazanavir/ritnoavir vs. Nevirapine on a background of Tenofovir and Emtricitabine) trial were retrospectively tested for HIV-1 tropism using the genotypic tool geno2pheno(FPR=5.75%). ArTEN compared nevirapine with atazanavir-ritonavir, both along with tenofovir-emtricitabine, in drug-naïve patients. RESULTS: Of 569 ArTEN patients, 428 completed 48 weeks of therapy; 282 of these received nevirapine and 146 of these received atazanavir-ritonavir. Overall, non-B subtypes of HIV-1 were recognized in 96 patients (22%) and X4 viruses were detected in 55 patients (14%). At baseline, patients with X4 viruses had higher plasma HIV RNA levels (5.4 vs 5.2 log copies/mL, respectively; P = .044) and lower CD4 cell counts (145 vs 188 cells/µL, respectively; P < .001) than those with R5 strains. At week 48, virologic responses were lower in patients with X4 viruses than in patients with R5 viruses (77% vs 92%, respectively; P = .009). Multivariate analysis confirmed HIV-1 tropism as an independent predictor of virologic response at week 24 (P = .012). This association was extended to week 48 (P = .007) in clade B viruses. Conversely, CD4 cell count recovery was not influenced by baseline HIV-1 tropism. CONCLUSIONS: HIV-1 tropism is an independent predictor of virologic response to first-line antiretroviral therapy. In contrast, it does not seem to influence CD4 cell count recovery. CLINICAL TRIALS REGISTRATION: NCT00389207.

Detection of minor populations of drug-resistant HIV-1 in acute seroconverters.

OBJECTIVE: The transmission of drug-resistant HIV-1 is a major health concern. To date, most clinical studies have relied on sequencing techniques for genotypic analyses which do not allow quantification of minority viral populations below 25%. As minor populations of drug-resistant HIV-1 could impact the efficiency of antiretroviral therapy, this study was performed to determine the prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters. DESIGN AND METHODS: Forty-nine acute seroconverters from two clinical centers in Germany were included in the study. Individuals were identified between June 1999 and March 2003, and none had received antiretroviral therapy prior to sampling. Minor populations of drug-resistant variants were detected by quantitative real-time polymerase chain reaction using allele-discriminating oligonucleotides for three key resistance mutations: L90M (protease), K103N and M184V (reverse transcriptase). The approximate discriminative power was between 0.01 and 0.2%. RESULTS: Drug-resistant variants were detected in 10 of 49 patients (20.4%). The L90M mutation was found in one of 49 (2%), the K103N mutation in five of 49 (10.2%) and the M184V mutation in six of 49 (12.2%) patients, respectively. In five of the 10 individuals with detectable drug-resistant virus (50%), the detected population represented a minor viral quasi-species (< 25% of viruses) and was not detected by direct sequencing. CONCLUSIONS: The prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters can be frequently detected and may impact the success of antiretroviral therapy.

Nevirapine versus atazanavir/ritonavir, each combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1 patients: the ARTEN Trial.

BACKGROUND: Selection of first-line antiretroviral therapy requires consideration of efficacy as well as effects on lipids given the increased concern about cardiovascular risk in HIV-1 patients. METHODS: ARTEN is a randomized, open-label, non-inferiority trial that compares nevirapine (NVP) 200 mg twice daily or 400 mg once daily to atazanavir/ritonavir (ATZ/r) 300 mg/100 mg once daily, each combined with fixed-dose tenofovir disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg once daily, in antiretroviral-naive HIV-1 patients with CD4(+) T-cell counts <400 (men) and <250 cells/mm(3) (women). The primary end point was plasma HIV RNA<50 copies/ml at two consecutive visits prior to week 48. RESULTS: A total of 569 patients were randomized and treated. Overall, 66.8% of NVP and 65.3% of ATZ/r patients achieved the primary end point (difference 1.9%, 95% CI -5.9-9.8%). Similar rates of serious adverse events were observed (9.6% on NVP versus 8.8% on ATZ/r), although discontinuations due to adverse events were more frequent with NVP than ATZ/r (13.6% versus 3.6%, respectively). None of the 28 patients virologically failing ATZ/r selected resistance mutations, while they were selected in 29/44 patients virologically failing NVP. NVP induced a significantly greater increase in high-density lipoprotein cholesterol (HDL-c) and apolipoprotein A1 from baseline than ATZ/r, whereas triglycerides increased significantly more with ATZ/r than NVP. Mean change from baseline in TC:HDL-c ratio was -0.24 for NVP and 0.13 for ATZ/r (P=0.0001). CONCLUSIONS: NVP demonstrated at week 48 non-inferior antiviral efficacy compared with ATZ/r when given along with TDF/FTC, despite more drug-related discontinuations with NVP than ATZ/r. NVP was associated with a lower atherogenic lipid profile than ATZ/r although resistance mutations were more frequently selected with NVP than ATZ/r.