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Using cell-associated DNA and cell-free RNA of HIV-1, we investigated the role of drug-resistant viral variants that emerged during early antiretroviral therapy (ART) in determining virological outcome. This case-control study compared virologic non-responder children (two viral loads ≥200 copies/ml within two years of ART) and responder children (two VLs <200 copies/ml after six months of ART) infected with HIV-1 initiated on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. The partial reverse transcriptase gene of HIV-1 in cell-associated DNA was genotyped using next-generation sequencing (NGS; Illumina; threshold 0.5%; at baseline and month six of ART) and in cell-free RNA (concurrently and at virological failure; VL >1000 copies/ml at ≥12 months of ART) using the Sanger method. Among 30 non-responders and 37 responders, baseline differences were insignificant while adherence, viral load and drug resistance mutations (DRMs) observed at month six differed significantly (p=>0.05). At month six, NGS estimated a higher number of DRMs compared to Sanger (50% vs. 33%; p=0.001). Among the non-responders carrying a resistant virus (86.6%) at virological failure, 26% harboured clinically-relevant low-frequency DRMs in the cell-associated DNA at month six (0.5 to 20%; K103N, G190A, Y181C, and M184I). Plasma VL of >3 log copies/ml (AOR=30.4, 95%CI=3.3-281, p=0.003) and treatment-relevant DRMs detected in the cell-associated DNA at month six (AOR=24.2, 95%CI=2.6-221, p=0.005) were independently associated with increased risk for early virological failure. Our findings suggest that treatment-relevant DRMs acquired in cell-associated DNA during the first six months of ART can predict virological failure in children initiated on NNRTI-based ART. This article is protected by copyright. All rights reserved.
This article was published in the following journal.
Name: Journal of medical virology
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