Correlates of Dolutegravir Resistance in Low- and Middle-Income Countries: A Combined Analysis of Drug Resistance Surveys in Four Countries.

Abstract

Dolutegravir (DTG)-based regimens (DBR) account for >97% of antiretroviral drugs dispensed through President's Emergency Plan for AIDS Relief. Understanding factors associated with DTG drug resistance (DR) is critical to safeguarding its long-term efficacy. We included adults on DBR from cohorts in Malawi, Mozambique, Uganda and Ukraine (2020-2022) with successful genotypes. DTG DR was defined as Stanford HIV Drug Resistance Database genotypic susceptibility score >15. Logistic regression assessed associations between DTG DR and clinical/sociodemographic factors, reporting odds ratios (ORs) and 95% confidence intervals (CIs). Median age was 36.2 years; 59% were female; 89% transitioned to DTG from a prior regimen. In a multivariable analyses including findings from genotype test, male sex (OR 2.02, 95% CI 1.10-3.73), any NRTI resistance (OR 31.17, 95% CI 12.93-75.14), and any NNRTI resistance (OR 2.56, 95% CI 1.12-5.88) were associated with DTG DR. After excluding genotype-derived variables, male sex remained associated with DTG DR (OR 2.13, 95% CI 1.28-3.54), while participants receiving zidovudine-containing backbones had higher odds of DTG DR compared with those receiving tenofovir-containing backbones (OR 5.87, 95% CI 2.45-14.07). Among individuals with DTG DR, G118R was the most frequent major mutation. M184V demonstrated high sensitivity (83%) and specificity (91%) for detecting DTG resistance. These findings identify key clinical correlates of DTG resistance, including concurrent NRTI/NNRTI resistance and zidovudine-containing regimens, which may serve as proxies for prior viral non-suppression and help inform more targeted drug resistance testing and regimen optimization in settings where genotypic testing is not readily available.