Minority and majority pre-treatment HIV-1 drug resistance associated with failure of 1st-line NNRTI ART in Kenyan women.

OBJECTIVES: Among women initiating 1-line non-nucleoside-reverse-transcriptase-inhibitor-(NNRTI)-based-ART with-and-without a history of single-dose-nevirapine-(sdNVP)±zidovudine±lamivudine (ZDV±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 ≥10% and as minority variants; all P < 0.0001). Failure was also associated with PMTCT using sdNVP+ZDV±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+ZDV±3TC-experienced women with pre-ART drug-resistant minority variants by next-generation-sequencing but without drug-resistance by OLA or consensus sequencing.

SUMMARY/CONCLUSIONS: 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 1-line NVP-based ART. A history of sdNVP+ZDV±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 non-suppressive antiretrovirals with ≥2 drug classes, and testing for pre-ART drug-resistance, including minority variants.