Predictors of treatment-emergent resistance to dolutegravir

Abstract

Integrase strand transfer inhibitor (INSTI)-based regimens became a first-line treatment for HIV worldwide in 2018, with 93% of people with HIV who are on antiretroviral therapy (ART) estimated to be taking dolutegravir-based regimens as of 2023. Since the genetic barrier to resistance of dolutegravir is not impenetrable, rising rates of dolutegravir resistance among those with virological failure on this drug regimen have been reported. Risk factors for dolutegravir resistance include treatment experience, having background resistance to the nucleoside reverse transcriptase inhibitors in the regimen, switching to tenofovir, lamivudine, and dolutegravir when viraemic on a former regimen, previous experience with first-generation INSTIs, and being on dolutegravir monotherapy or dual therapy, with rates higher in children than in adults. HIV drug resistance does not emerge if selective drug pressure is not present, so some exposure to the ART regimen with virological failure is associated with higher rates of resistance than complete non-adherence. Detectable objective metrics of adherence (eg, ART drug concentrations in urine, plasma, dried blood spots, and hair) have been associated with high levels of viral resistance and can be used to triage who needs resistance testing the most.