Resistance profiles in HIV-1 positive patients failing protease inhibitor- and dolutegravir-based treatment in the South African public sector

Abstract

INTRODUCTION: South African antiretroviral therapy (ART) guidelines recommend dolutegravir (DTG)-based regimens, though some individuals remain on protease inhibitor (PI)-based ART during the transition. We evaluated resistance profiles for people living with HIV (PLWH) failing PI- or DTG-based regimens. Additionally, we assessed plasma DTG (pDTG) drug-exposure (DE) testing for predicting DTG resistance and investigated nanopore sequencing for HIV drug resistance (HIVDR) testing. METHODS: HIV sequences from PLWH who failed PI regimens in 2022 and DTG regimens from 2019–2022 were analysed. Nanopore sequencing using the SQK-NBD114.96 kit and pDTG DE testing through liquid chromatography tandem mass spectrometry were performed on DTG cohort specimens. RESULTS: In the PI cohort (n=1244), the LPV/r group showed higher cross-resistance to DRV/r compared to the ATV/r group (14.5% vs 8.9%, p=0.013). In the DTG cohort (n=97), 19.5% had DTG resistance, with 8.5% developing resistance within 24 months. Undetectable pDTG (54.6%) accurately predicted the absence of DTG resistance (negative predictive value: 94.2%, 95% CI: 85.1-97.9). Sanger and nanopore sequencing demonstrated 99.6% (range: 88.9- 100.0) and 97.9% (range: 75.6-100.0) identity for integrase and protease-reverse transcriptase regions, respectively. DISCUSSION: Our findings support ATV/r as the preferred PI in the South African public sector. DTG resistance in 19.5% of failures underscores the need for early identification of PLWH at risk for resistance. pDTG DE testing can reduce HIVDR testing costs by triaging samples for HIVDR testing. As DTG resistance developed within 24 months, earlier resistance testing may be warranted. Nanopore sequencing is a reliable alternative to Sanger sequencing for HIVDR testing.