Quantifying integrase resistance among Nigerian children failing dolutegravir to inform rapid diagnostic development in partnership with Nigerian scientists

PROJECT SUMMARY Dolutegravir is widely used for HIV treatment globally, yet glaringly little data on integrase resistance after dolutegravir failure among children are available. While dolutegravir is associated with improved efficacy and decreased resistance compared to other antiretroviral therapy (ART) regimens, a recent study from Malawi found that integrase resistance was present in 30% of select adults failing dolutegravir. While this may be an overestimate, children have multiple risk factors that increase the risk of developing integrase resistance including greater reuse and resistance to companion antiretroviral drugs, lower rates of viral suppression, higher viral load at failure, and more severe immunocompromise. To address this knowledge gap we will quantify integrase resistance in a population of children failing dolutegravir in Nigeria and utilize this resistance data to develop and validate a rapid diagnostic in collaboration with colleagues there. The 2021 World Health Organization HIV Drug Resistance Report specifically calls for surveys of integrase resistance in order to provide early signals of emerging dolutegravir resistance. Our population of highly treatment-experienced children who were rapidly transitioned to dolutegravir ART, of which 12% have detectable viremia, represents such a clinical population at increased risk of developing integrase resistance, and will inform nationally representative surveys of drug resistance. Nigeria is home to more children living with HIV than any other country in the world. A national survey of pre- treatment drug resistance among ART-naïve infants ≤18 months of age (2016) shows high rates of resistance, including to the most widely used companion drugs among children: abacavir and lamivudine. Such resistance may predispose children to develop integrase resistance. Since 2004, APIN Public Health Initiatives has provided HIV care and treatment to over 22,000 children in Nigeria, and thus is uniquely positioned to provide critical drug resistance data from multiple pediatric sites/regions across Nigeria. We propose to evaluate integrase resistance among 500 children in Nigeria failing dolutegravir-ART at two different time points to provide critical data on the evolution of integrase resistance. We will further utilize these data to develop rapid diagnostics to detect specific integrase resistance mutations with the goal of making dolutegravir resistance testing accessible globally via rapid, low-cost assays. These studies address a critical gap in knowledge regarding integrase resistance among children failing dolutegravir ART, will inform future surveys of drug resistance, and will support the development and validation of a rapid integrase resistance assay in this setting. This has the potential to impact international guidance on dolutegravir use and resistance testing for this vulnerable population of children.