Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Mark J Siedner,Andrew Hill,Celicia M Serenata,Jennifer Giandhari,Richard Lessells,Willem D F Venter,Michelle A Moorhouse,Ravindra K Gupta,Bryony Simmons,Tulio De Oliveira,Benjamin Chimukangara,Godspower Akpomiemie,Stephen A Kemp

doi:10.1038/s41467-020-19801-x

Abstract

Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248], P = 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465] P < 0.001, P for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa.

Highlights

Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors
We report a strong association between drug resistance before treatment initiation, primarily to the nucleoside reverse transcriptase inhibitor (NNRTI) class, and virologic failure for people initiating first-line antiretroviral therapy (ART) in the ADVANCE clinical trial
When we considered a secondary outcome, which focused on persistent virologic failure, the effect of PDR on DTG persisted, but to a lower degree

Summary

Introduction

Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of firstline failure in sub Saharan Africa. A study in Kenya suggested isolated K103N might have limited impact on EFV-based ART17 These conflicting data have generated controversy in the field on optimal first-line regimens to balance safety, tolerability, cost, and the impact of circulating NNRTI drug resistance on virologic outcomes. Additional studies are needed to better elucidate the impact of pretreatment NNRTI drug resistance on virologic outcomes with both EFV-based and DTGbased used first-line regimens in the region. We report results of next-generation sequencing of stored plasma specimens from participants in the ADVANCE clinical trial to determine the contributions of NNRTI pretreatment drug resistance (PDR) on 96-week virologic outcomes for individuals initiating EFV- and DTG-based ART. We hypothesize that NNRTI PDR significantly affects efficacy of EFV-containing regimens but has a negligible effect on outcomes for those initiating DTG-based therapy

Methods

Results

Conclusion