Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya
Ingrid A. Beck, Molly Levine, Christine J. McGrath, Steve Bii, Ross Milne, James Munyao Kingoo, Isaac So, Nina Andersen, Sandra Dross, Robert W. Coombs, James Kiarie, Bhavna Chohan, Samah R. Sakr, Michael H. Chung, Lisa M. Frenkel
Abstract
BackgroundPre-treatment HIV-drug-resistance (PDR) to WHO-recommended 1st-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral treatment (ART) is increasing in low-resource communities. We evaluated the risk of PDR on treatment failure if detected at single or multiple codons, at minority (2–9%) or higher (≥10%) frequencies during efavirenz- vs. nevirapine-ART.MethodsWe conducted a pooled analysis across three cohorts of Kenyans initiating 1st-line NNRTI-ART between 2006 and 2014. Mutations K103N, Y181C, G190A, M184V and K65R were detected by an oligonucleotide ligation assay (OLA) and confirmed by Sanger and next-generation sequencing (NGS). PDR was defined as detection of any mutation by OLA when confirmed by NGS. Treatment failure, defined as plasma HIV RNA ≥400 copies/mL at month-12 of ART, was compared by PDR genotypes.FindingsPDR was detected in 59/1231 (4·8%) participants. Compared to wild-type genotypes, PDR in participants prescribed nevirapine-ART was associated with increased treatment failure [PDR 69·2% (27/39) vs. wild-type 10·4% (70/674); p = 0·0001], whether detected as minority [66·7% (4/6)] or higher [69·7% (23/33)] frequencies in an individual's HIV quasispecies (p = 0·002 and p < 0·0001, respectively), or mutations at single [50·0% (12/24)] or multiple [100·0% (15/15)] codons (p < 0·0001). During efavirenz-ART, PDR was also associated with increased virologic failure [PDR 25·0% (5/20) vs. wild-type 5·0% (25/498); p = 0·005], but only if detected at multiple drug-resistant codons [50·0% (3/6); p = 0·003] or high frequencies PDR [33·3% (5/15); p = 0·001].InterpretationThe risk that PDR confers for treatment failure varies by number of mutant codons and their frequency in the quasispecies, with a lower risk for efavirenz- compared to nevirapine-based regimens. PDR detection and management could extend the effective use of efavirenz-ART in low-resource settings.FundingNIH, PEPFAR.