Impact of next-generation sequencing defined human immunodeficiency virus pretreatment drug resistance on virological outcomes in the ANRS 12249 treatment-as-prevention trial

Derache, Anne, Iwuji, Collins C, Baisley, Kathy, Danaviah, Siva, Marcelin, Anne-Geneviève, Calvez, Vincent, de Oliveria, Tulio, Dabis, François, Porter, Kholoud and Pillay, Deenan (2019) Impact of next-generation sequencing defined human immunodeficiency virus pretreatment drug resistance on virological outcomes in the ANRS 12249 treatment-as-prevention trial. Clinical Infectious Diseases, 69 (2). pp. 207-214. ISSN 1537-6591

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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.

Item Type: Article
Keywords: HIV, pretreatment drug resistance, antiretroviral therapy, next-generation sequencing, virological response, sub-Saharan Africa
Schools and Departments: Brighton and Sussex Medical School > Global Health and Infection
Subjects: R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine > RA0643 Communicable diseases and public health > RA0644 Individual diseases or groups of diseases, A-Z > RA0644.A25 AIDS. HIV infections
Depositing User: Deborah Miller
Date Deposited: 25 Oct 2018 14:47
Last Modified: 16 Mar 2021 18:28
URI: http://sro.sussex.ac.uk/id/eprint/79672

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