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

Abstract

Background: Little is known about the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second generation integrase inhibitors, now the standard of care drug class for HIV-1 treatment globally.Methods: We conducted next-generation sequencing on stored plasma specimens from the ADVANCE trial collected prior to treatment initiation. Our primary outcome was 96-week virologic success, defined as achievement of a viral load < 1000 copies/mL from 12 weeks, < 200 copies/mL from 24 weeks, and < 50 copies/mL from 48 through 96 weeks. We estimated the impact of PDR, defined by the presence of drug resistance on the World Health Organization (WHO) mutation list, on virologic outcomes in the entire cohort, and stratified by EFV-based versus DTG-based regimens. In sensitivity analyses, we allowed virologic failure with re-suppression, assessed FDA 48 and 96-week Snapshot outcomes, and considered minority resistance mutations (5–20% frequency).Results: Of 1,053 trial participants, 873 (83%) had plasma available and successful sequencing completed. Of these, 288 (33%) were randomized to an EFV-based regimen and 585 (67%) were randomized to a DTG-based regimen. Fourteen percent (122/873) had at least one WHO-defined mutation, of which over 98% (120/122) had NNRTI mutations. NRTI mutations were rare (20/873, 2%). Rates of virologic suppression were significantly lower in those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001). This phenomenon was consistent for both EFV-based (60% [12/20] versus 86% [214/248], P = 0.002) and DTG-based ART (61/92 [66%] versus 84% [391/465] P < 0.001, P for interaction by regimen 0.49). In multivariable models adjusted for clinical characteristics and treatment adherence, PDR strongly predicted failure [adjusted OR 0.38 (0.23–0.61), P < 0.001]. Although suppression rates were greater when allowing for non-consecutive visits with failure, PDR significantly predicted greater risk of failure for both regimens in all outcome definitions. We found no effect of mutations at frequencies 5–20% on any of our outcomes.Interpretation: NNRTI resistance prior to treatment initiation is associated with failure of integrase inhibitor-containing first-line regimens. These results portend high rates of first-line treatment failure in sub Saharan Africa, where circulating NNRTI resistance is common.

Clinical Impact of Pretreatment Human Immunodeficiency Virus Drug Resistance in People Initiating Nonnucleoside Reverse Transcriptase Inhibitor–Containing Antiretroviral Therapy: A Systematic Review and Meta-analysis

“…An increased likelihood of VF among people with PDR on EFV/XTC/TDF was also observed in 2 recent large studies: a the phase 3, randomized clinical trial comparing TAF/FTC/DTG, TDF/FTC/DTG or TDF/FTC/EFV for first-line treatment of HIV-1 infection (ADVANCE) [ 44 ], in which VS among those with and without PDR was 65% and 85%, respectively ( P < .001), and a case-cohort substudy of the HIV/AIDS Drug Resistance Surveillance Study (ADReSS), enrolling 1000 patients initiating first-line efavirenz/emtricitabine/tenofovir in KwaZulu-Natal, South Africa [ 45 ], in which PDR was associated with a 3-fold greater risk of VF ( P = .002).…”

“…In addition, it has been suggested that the predictive value for virologic failure in people initiating EFV/XTC/TDF with NNRTI PDR with or without NRTI PDR may be different [ 44 ]. In a large South African study, the presence of NNRTI plus NRTI mutations vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32 [95% CI, .12–.86]), whereas there was no difference in outcome between those with only NNRTI mutations vs no PDR (aHR, 1.05 [95% CI, .82–1.34]) at the 5% or 20% threshold [ 8 ].…”

“…Surprisingly, the ADVANCE study also showed a greater risk of VF among people with PDR vs no PDR receiving DTG-based ART [ 44 ]. These results merit additional investigation, as explanations for this observation remain to be elucidated.…”

Experience With Dolutegravir in Hiv Patients at a Public Sector Hospital in Karachi, Pakistan

“…Most crucially, substitution of a single drug in a failing regimen must never be allowed since the development of resistance is a major concern, and drug resistance testing is not widely available in resource poor settings such as ours. 18 Our study has demonstrated excellent efficacy of DTG in both naïve and experienced patients, good tolerability and outcomes and therefore appears to be a better option for our patient population than an nonnucleoside reverse transcriptase inhibitors (NNRTI) based regimen. However, further studies will be required to determine superiority.…”

Who’s slipping through the cracks? A comprehensive individual, clinical and health system characterization of people with virological failure on first‐line HIV treatment in Uganda and South Africa

“…The implications for virological failure on TLD are not well understood [44], particularly if adherence is not an issue. In fact, recent data suggest that resistance to the NNRTI class of drugs also reduces the efficacy of TLD [45], but data have suggested dolutegravir with two NRTIs to be an effective second-line treatment [46]. The WHO has recently updated treatment guidelines to recommend immediate switching of regimens after a single elevated VL measurement [47].…”