HIV-1 subtype-specific drug resistance on dolutegravir-based antiretroviral therapy: protocol for a multicentre study (DTG RESIST)

Abstract

Introduction: HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the WHO in 2019 for first-line, second-line and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance.

Methods and analysis: Nested within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST is a multicentre study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virological failure on dolutegravir-based ART. At the time of virological failure, whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (1) individuals who experienced virological failure on dolutegravir and (2) those who started or switched to such a regimen and were at risk of virological failure. For population (1), the outcome will be any InSTI drug resistance mutations, and for population (2) virological failure is defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virological failure and limited power for analysing factors associated with individual InSTI drug resistance mutations.

Ethics and dissemination: The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in International epidemiology Databases to Evaluate AIDS and have obtained ethics approval from their local ethics committee to collect additional data.

Trial registration number: NCT06285110.

Keywords: HIV & AIDS; adolescent; drug utilization; international health services; public health.

Figure 1. Schematic representation of enrolment, specimen collection and sequencing. DBS, dried blood spot; VL, viral load.

Figure 2. Countries with sites participating in DTG RESIST with the dominant HIV-1 subtypes and circulating recombinant forms. The colours represent the six IeDEA regions. IeDEA, International epidemiology Databases to Evaluate AIDS.

Figure 3. Power versus exposure prevalence (%N) and OR for 84 (red) and 157 (green) patients developing InSTI DRMs. InSTI, integrase strand transfer inhibitor; DRMs, drug-resistance mutations.