Plasma dolutegravir exposure testing to identify people with HIV at highest risk for dolutegravir resistance (ITREMA-2): a two-centre, prospective implementation study in South Africa.

Abstract

Dolutegravir resistance is increasingly reported in treatment-experienced people with HIV in low-income and middle-income countries. Resistance testing resources are sparse, and viral rebound often reflects adherence lapses rather than resistance. Efficient strategies are needed to target testing to individuals at highest risk. We evaluated a reflex laboratory approach using plasma dolutegravir exposure to guide resistance testing in routine care. In this prospective implementation study at two public-sector clinics in Johannesburg, South Africa, we analysed adults (aged ≥18 years) on dolutegravir-based antiretroviral therapy (ART) with viral rebound of 400 copies per mL or higher. From May 18, 2023, to Jan 10, 2025, we tested residual routine viral load samples for dolutegravir exposure using an enzyme immunoassay. If dolutegravir was detectable (≥20 ng/mL), we did reflex resistance testing on the same specimen; retrospective sequencing was done at study end for dolutegravir-undetectable samples. We modelled costs comparing the reflex approach with standard of care. We analysed 400 samples from 288 individuals; 160 (56%) were female and 128 (44%) male, the median age was 44 years (IQR 35-50), and 240 (83%) had previous non-dolutegravir ART exposure. Plasma dolutegravir was detectable in 108 (38%) participants. Among those with successful sequencing, dolutegravir resistance occurred in 13 (13%) of 102 participants with detectable dolutegravir and three (2%) of 138 with undetectable dolutegravir, yielding an overall prevalence of 6·7% dolutegravir resistance and a negative predictive value for absence of dolutegravir resistance of 97·8% (95% CI 93·5-99·5). Dolutegravir resistance was associated with detectable dolutegravir (odds ratio [OR] 3 [95% CI 1-9], p=0·031), nucleoside reverse transcriptase inhibitor mutations (OR 33 [4-264], p=0·0009), non-nucleoside reverse transcriptase inhibitor mutations (OR 17 [2-135], p=0·0068), or M184V (OR 20 [4-92], p=0·0002). Cost modelling showed a 23% reduction in monitoring cost per person using the reflex strategy after confirmed viraemia versus current national guidelines. Laboratory-initiated reflex plasma dolutegravir exposure testing provides an objective, cost-efficient strategy to predict the absence of dolutegravir resistance and supports adherence management, enabling timely, individualised treatment decisions. Reflex dolutegravir exposure testing could enhance clinical decision making, improve treatment outcomes, and strengthen HIV treatment and resistance monitoring algorithms in programmatic settings. The Amsterdam Dinner Foundation and Aidsfonds, the Netherlands Organisation for Scientific Research, ZonMw, and WOTRO.