Acquired HIV drug resistance among Nigerian children failing first-line ART: Implications for second-line dolutegravir use

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PROJECT SUMMARY The accumulation of HIV drug resistance (HIVDR) threatens to erode gains in HIV treatment globally. As a result, the World Health Organization (WHO) Global Action Plan on HIVDR has called for increased surveillance. Notably, the 2019 WHO Drug Resistance report included data on the alarming increase in pretreatment HIV drug resistance (PDR) among adults and infants, as well as data on acquired drug resistance (ADR) among adults failing first-line ART. However, data on ADR among children is glaringly absent. As countries begin to implement 2019 WHO guidance to replace lopinavir/ritonavir- with dolutegravir (DTG)- based second-line ART among children, data on ADR is even more pertinent. While DTG holds great promise for improving HIV outcomes and reducing drug resistance given its potency and high barrier to resistance, its use for second-line ART among patients with pre-existing nucleoside reverse transcriptase inhibitor (NRTI) resistance is unknown. Failed studies of DTG monotherapy provide a cautionary message that the NRTI backbone remains important for virologic suppression and preventing integrase resistance. Nigeria is home to more children living with HIV than any other country in the world. In a national survey of PDR among ART-naïve infants ≤18 months of age, high rates of resistance were observed, including to the most widely used NRTI backbone among children (abacavir and lamivudine). However, rates of ADR after first-line failure are expected to be even higher. Since 2004, APIN Public Health Initiatives has provided HIV care and treatment to over 20,000 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 ADR among 400 children in Nigeria failing first-line ART, and will utilize these data to derive a clinical prediction rule (CPR) to identify those most likely to benefit from targeted HIVDR testing and avoid functional DTG monotherapy. Further, rapid point-of-care (POC) HIVDR testing is needed to address feasibility barriers in low income settings. We will therefore evaluate the OLA-Simple POC HIVDR assay, which has equivalent sensitivity to standard sequencing methods, but has not been validated among the unique HIV-1 subtypes prevalent in Nigeria. This combination of studies addresses a critical gap in knowledge regarding ADR among children failing first-line ART, will inform future studies of targeted HIVDR testing prior to second-line switch, and will evaluate a rapid POC HIVDR assay in this setting. This has the potential to impact international guidance on second-line DTG use and HIVDR testing for this vulnerable population of children.