DTG Resist: HIV-1 subtype-specific drug resistance in people with virological failure on dolutegravir-containing antiretroviral therapy

The delivery of antiretroviral therapy to people living with HIV has been one of the most successful public health interventions in history, but the emergence and spread of HIV drug resistance is a major barrier to ending the HIV epidemic. The next phase of the global HIV response is heavily reliant on integrase strand transfer inhibitors (InSTIs), particularly dolutegravir, a potent antiretroviral with a high genetic barrier to resistance. Dolutegravir is recommended for use in all lines of treatment (first-line, second-line and third-line) by the World Health Organization, and drugs from the same class (e.g. cabotegravir) are in the advanced stages of development for use as pre-exposure prophylaxis and treatment. There is currently limited understanding of the spectrum of dolutegravir-selected mutations and their effects on phenotypic susceptibility in non-B subtype viruses, and of the extent to which mutations outside of the integrase gene contribute to drug resistance. It is therefore critical that we establish robust systems for early detection of emergent InSTI resistance in HIV treatment programs across the world, and develop an understanding of where and how resistance to dolutegravir occurs in real world cohorts.We will do this within the framework of the NIH-funded International epidemiology Databases to Evaluate AIDS (IeDEA) consortium, with the involvement of 43 treatment cohorts across 22 countries in six regions (Central, Southern and West Africa, Asia-Pacific, North America, and the Caribbean, Central and South America).The aims of this project are: i) to determine the patterns and spectrum of InSTI drug resistance mutations in adults with virologic failure on dolutegravir-based antiretroviral therapy by regimen and HIV-1 subtype; ii) to identify risk factors for virologic failure and drug resistance in adolescents and adults on dolutegravir-based antiretroviral therapy; and iii) to investigate correlations between novel resistance genotypes and phenotypic InSTI resistance across HIV-1 subtypes. We will include adults (>=18 years) and adolescents (10-17 years) with virologic failure (viral load >=1000 copies/mL) on dolutegravir-based ART (first-line, second-line and third-line) at the 43 treatment sites. We will perform next-generation sequencing to detect integrase mutations and mutations outside integrase (e.g. in the 3' polypurine tract (PPT) region of the nef gene). By combining these cross-sectional data with the harmonized clinical and programmatic IeDEA data, we will identify predictors of virologic failure and drug resistance. Finally, we will characterize the phenotypic effect of novel resistance genotypes by performing phenotypic testing on selected specimens across the range of HIV-1 subtypes.Our overarching goals are to characterize the dolutegravir resistance pathways in different HIV-1 subtypes and understand the specific contexts in which dolutegravir resistance emerges, as well as more broadly to establish IeDEA as an early detection system for the emergence of HIVDR to help safeguard the long-term sustainability of the global HIV response.