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Minority and majority pretreatment HIV-1 drug resistance associated with failure of first-line nonnucleoside reverse-transcriptase inhibitor antiretroviral therapy in Kenyan women

Milne, Ross S.a; Silverman, Rachel A.b,c; Beck, Ingrid A.a; Mckernan-Mullin, Jennifera; Deng, Wenjied; Sibley, Thomas R.d; Dross, Sandrae; Kiarie, James N.h; Sakr, Samah R.i; Coombs, Robert W.e,f; Chung, Michael H.b,c,f; Frenkel, Lisa M.a,c,e,f,g

doi: 10.1097/QAD.0000000000002134
BASIC SCIENCE
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Objectives: Among women initiating first-line nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based-ART with and without a history of single-dose nevirapine (sdNVP) with or without zidovudine with or without lamivudine (ZDV with and without 3TC) for prevention of mother-to-child HIV transmission (PMTCT), we hypothesized that pre-ART HIV-drug resistance would be associated with virologic failure

Design/methods: In a prospectively enrolled study, three genotypic drug-resistance assays [oligonucleotide-ligation-assay (OLA), consensus sequencing, and next-generation sequencing by Illumina] were retrospectively performed to detect pre-ART drug resistance. Minority or majority drug-resistant variants identified in pre-ART RNA and/or DNA, a history of antiretrovirals for PMTCT, and other risk factors were assessed for association with virologic failure.

Results: Failure occurred in 38/169 (22.5%) women, and was associated with pre-ART drug resistance detected by any assay (OLA of plasma or PBMC, consensus sequencing of PBMC and/or plasma, and next-generation sequencing of PBMC at frequencies of at least 10% and as minority variants; all P < 0.0001). Failure was also associated with PMTCT using sdNVP and ZDV with or without 3TC, but not sdNVP only; however, the longer time-interval between PMTCT and ART initiation observed for sdNVP-only women showed no interaction with failure. Viral loads and OLA of PBMC in longitudinal specimens demonstrated rapid failure and emergence of drug resistance, particularly among sdNVP and ZDV with or without 3TC-experienced women with pre-ART drug-resistant minority variants by next-generation sequencing but without drug resistance by OLA or consensus sequencing.

Conclusion: Pre-ART drug resistance was detected similarly by OLA of PBMC or plasma and by consensus sequencing, and was associated with virologic failure soon after initiation of first-line NVP-based ART. A history of sdNVP and ZDV with or without 3TC for PMTCT or minority variants detected by next-generation sequencing identified additional women with failure. These findings emphasize the value of assessing individual antiretroviral history, particularly nonsuppressive antiretrovirals with at least two drug classes, and testing for pre-ART drug resistance, including minority variants.

aSeattle Children's Research Institute

bDepartment of Epidemiology

cDepartment of Global Health

dDepartment of Microbiology

eDepartment of Laboratory Medicine

fDepartment of Medicine

gDepartment of Pediatrics, University of Washington, Seattle, USA

hDepartment of Obstetrics and Gynaecology, University of Nairobi

iCoptic Hospital, Nairobi, Kenya.

Correspondence to Lisa M. Frenkel, 307 Westlake Avenue, Seattle, WA 98109, USA. Tel: +1 206 987 5140; fax: +1 206 884 7311; e-mail: lfrenkel@uw.edu

Received 8 August, 2018

Revised 13 December, 2018

Accepted 15 December, 2018

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