This study investigated strategies that may increase the yield of drug resistance testing prior to starting antiretroviral therapy (ART), and whether transmitted and polymorphic resistance-associated mutations (RAMs) correlated with virological outcomes. We carried out retrospective testing of baseline samples from patients entering the SENSE trial of first-line ART in Europe, Russia and Israel. Prior to randomization to etravirine or efavirenz plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), plasma samples underwent routine Sanger sequencing of HIV-1 RT and protease (plasmaSS) in order to exclude patients with transmitted RAMs. Retrospectively, Sanger sequencing was repeated with HIV-1 DNA from baseline peripheral blood mononuclear cells (PBMCSS); baseline plasma samples were retested by allele-specific PCR targeting seven RT RAMs (AS-PCR) and ultra-deep RT sequencing (UDS). By plasmaSS, 16/193 (8.3%) patients showed ≥1 transmitted RAM affecting the NRTIs (10/193, 5.2%), non-nucleoside reverse transcriptase inhibitors (4/193, 2.1%) or protease inhibitors (2/193, 1.0%). No additional RAMs were detected by AS-PCR (n = 152) and UDS (n = 24); PBMCSS (n = 91) yielded two additional samples with one RAM each. Over 48 weeks, 4/79 (5.1%) patients on etravirine and 7/78 (9.0%) on efavirenz experienced virological failure; none had baseline RAMs. Conversely, 11/79 (13.9%) patients randomized to etravirine had one polymorphic RAM from the etravirine score in baseline plasma (V90I, V106I or E138A), without any impact on virological outcomes. The detection of resistance increased marginally with PBMC testing but did not increase with sensitive plasma testing. A careful consideration is required of the cost-effectiveness of different strategies for baseline HIV drug resistance testing.
The aim of this study was to assess the influence of hepatitis B virus or hepatitis C virus co-infection and the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics in HIV-infected subjects without liver function impairment. A cross-sectional, comparative study enrolling HIV-infected adults receiving saquinavir/ritonavir 1000/100 mg twice daily or 1500/100 mg once daily was conducted. Patients with chronic viral hepatitis (HEP+) were grouped as having advanced liver fibrosis (HEP+/FIB+) or not (HEP+/FIB−) based on the FIB-4 index. Saquinavir and ritonavir trough concentrations (Ctrough) in plasma were determined by HPLC. The geometric mean ratio (GMR) was used to compare saquinavir and ritonavir Ctrough between HEP− and HEP+ patients, and the influence of the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics was explored using analysis of variance. One hundred and thirty-eight patients on twice-daily saquinavir/ritonavir (67 HEP−, 71 HEP+) and 36 patients on once-daily saquinavir/ritonavir (12 HEP−, 24 HEP+) were included. Saquinavir Ctrough was comparable between HEP− and HEP+ patients receiving either saquinavir/ritonavir 1000/100 mg twice daily [GMR 0.91, 95% confidence interval (CI) 0.60–1.37; P = 0.655] or 1500/100 mg once daily (GMR 0.88, 95% CI 0.39–1.97; P = 0.752). Similarly, ritonavir Ctrough was also comparable between HEP− and HEP+ patients. The extent of liver fibrosis was not significantly related to saquinavir or ritonavir Ctrough in patients receiving either of the two studied doses. Saquinavir Ctrough was not increased in HIV-infected patients with chronic viral hepatitis in the absence of liver function impairment. These results confirm that no specific dose modification of saquinavir/ritonavir should be recommended in this setting.
The objective of our randomized, multicentre, double-blind, placebo-controlled study was to investigate the safety, tolerability, and antiretroviral and immunological effect of double and triple combination therapy regimens. A total of 105 antiretroviral therapy-naive patients were randomized to receive either zidovudine (300 mg twice per day) plus lamivudine (150 mg twice per day) plus nelfinavir placebo (three times per day) ( n=52), or zidovudine/lamivudine (dose as before) plus nelfinavir (750 mg three times per day) ( n=53) for 28 weeks. After this time, patients were allowed to switch to open-label zidovudine/lamivudine/nelfinavir. The overall log 10 reduction from baseline in plasma HIV-1 RNA was significantly greater in the zidovudine/lamivudine/nelfinavir group than the zidovudine/lamivudine group ( P=0.001; median treatment difference, –1.01 log 10 copies/ml; 95% confidence interval –1.23 to –0.79), as measured by the average area under the curve minus baseline over 28weeks. Increases from baseline in CD4 cell counts were statistically significantly greater in the zidovudine/lamivudine/nelfinavir group (101.5 cells/ml) than the zidovudine/lamivudine group (47.0 cells/ml; P=0.027) at week 28. Of note, the addition of nelfinavir from weeks 28–52 led to an increase in the proportion of subjects with plasma HIV-1 RNA <400 copies/ml from 17% (9/52 patients on zidovudine/lamivudine) to 50% (13/26 patients who switched to zidovudine/lamivudine/nelfinavir). Incidence of drug-related adverse events was similar in the two groups, except for nausea (more common in zidovudine/lamivudine group; 40 versus 17%) and diarrhoea (more common in zidovudine/lamivudine/nelfinavir group; 45 versus 14%). In conclusion, our study confirms the efficacy of triple combination therapy with two nucleoside analogues and a protease inhibitor compared with double-nucleoside therapy. Interestingly, the addition of nelfinavir to zidovudine/lamivudine, even after 6 months of double nucleoside therapy, led to a substantial virological benefit that was sustained over 24weeks in a subset of patients.
Researchers convened in Italy to discuss state-of-the-art antiretroviral treatment, the most recent data on the development of resistance in naive and experienced patients, and ways to reconstruct the immune system in the early and later stages of HIV disease. Participants reviewed data on a new generation of genotypic and phenotypic assays that portend a new model of care for guiding treatment decision-making in the face of treatment failure. Several papers described new mechanisms of resistance for nucleoside, nucleotide, nonucleotide reverse transcriptase inhibitors, and protease inhibitors. Other studies reported on the evolution of drug resistance, the problem of transmission of drug-resistant viruses, and the potency of regimen adjustments. Discussions revealed the need for academia and industry to continue to develop novel antiretroviral agents.
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