Drug-resistance development differs between HIV-1-infected patients failing first-line antiretroviral therapy containing nonnucleoside reverse transcriptase inhibitors with and without thymidine analogues.

OBJECTIVES: We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non-thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group). METHODS: Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia ≥ 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non-TA. RESULTS: A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non-TA. No significant differences were observed between the non-TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log10 copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors (RTIs) occurred at a significant lower frequency in the non-TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non-TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non-TA group (18.5%; P < 0.001). CONCLUSIONS: At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non-TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure.

Evaluating the extent of potential resistance to pre-exposure prophylaxis within the UK HIV-1-infectious population of men who have sex with men.

OBJECTIVES: Recent studies have shown that pre-exposure prophylaxis (PrEP) can substantially reduce the chance of acquiring HIV infection. However, PrEP efficacy has been found to be compromised in macaque studies if the challenge virus is antiretroviral therapy (ART)-resistant. Our objective was to evaluate the likelihood that a UK man who has sex with men (MSM) would be exposed to PrEP-resistant HIV in a homosexual encounter with an HIV-infectious partner. METHODS: Data from the UK Collaborative HIV Cohort (UK CHIC) study were linked to the UK HIV Drug Resistance Database for HIV-1-positive MSM patients seen between 2005 and 2008. Patients were categorized as undiagnosed; diagnosed but ART-naïve; ART-experienced and on treatment; and ART-experienced and on a treatment interruption. Considering current PrEP regimens, resistance to (a) tenofovir (TDF) alone, (b) TDF and emtricitabine (FTC), and (c) TDF or FTC was estimated. Patients without resistance tests had PrEP resistance imputed using bootstrapping and logistic regression models. RESULTS: The population-level prevalence of PrEP resistance in HIV-infectious individuals in 2008 was estimated to be 1.6, 0.9 and 4.1% for PrEP resistance definitions a, b and c, respectively. Prevalence in ART-experienced patients was highest, with negligible circulating resistance amongst ART-naïve individuals. The levels of resistance declined over the period of study. CONCLUSIONS: Our analysis indicates low levels of resistance to proposed PrEP drugs. The estimated PrEP resistance prevalence in UK HIV-infected MSM is towards the lower range of values used in simulation studies which have suggested that circulating PrEP drug resistance will have a negligible impact on PrEP efficacy at the population level.