Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial

Abstract

Background: Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial.

Methods: Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation.

Results: PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91-2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12-0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82-1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance.

Conclusions: NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone.

Clinical trials tegistration: NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974.

Keywords: HIV; antiretroviral therapy; next-generation sequencing; pretreatment drug resistance; virological response.

Figure 1.

Cohort flow chart. Abbreviations: ART, antiretroviral therapy; NGS, next-generation sequencing; TasP, Treatment-as-Prevention; VL, viral load.

Figure 2.

Prevalence of any pretreatment drug resistance and nonnucleoside reverse transcriptase inhibitor resistance among 1148 participants with next-generation sequencing data detected at 5% and 20% detection thresholds. Abbreviations: NNRTI, nonnucleoside reverse transcriptase inhibitor; PDR, pretreatment drug resistance.

Figure 3.

Kaplan-Meier plot of the cumulative probability of virological suppression since antiretroviral therapy start; stratified by class of pretreatment drug resistance at the 20% (A) and 5% (B) detection thresholds. Abbreviations: ART, antiretroviral therapy; DRM, drug-resistance mutation; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PDR, pretreatment drug resistance; VL, viral load; VS, virological suppression.