Added value of next generation sequencing in characterizing the evolution of HIV-1 drug resistance in Kenyan youth

Abstract

Drug resistance remains a global challenge in children and adolescents living with HIV(CALWH). Characterizing resistance evolution, specifically using next generation sequencing (NGS)can potentially inform care, but remains understudied, particularly in antiretroviral therapy (ART)-experienced CALWH in resource-limited settings. We conducted reverse-transcriptase NGS andinvestigated short-and long-term resistance evolution and its predicted impact in a well-characterizedcohort of Kenyan CALWH failing 1st-line ART and followed for up to ~8 years. Drug resistancemutation (DRM) evolution types were determined by NGS frequency changes over time, defined asevolving (up-trending and crossing the 20% NGS threshold), reverting (down-trending and crossingthe 20% threshold) or other. Exploratory analyses assessed potential impacts of minority resistancevariants on evolution. Evolution was detected in 93% of 42 participants, including 91% of 22 withshort-term follow-up, 100% of 7 with long-term follow-up without regimen change, and 95% of19 with long-term follow-up with regimen change. Evolving DRMs were identified in 60% andminority resistance variants evolved in 17%, with exploratory analysis suggesting greater rate ofevolution of minority resistance variants under drug selection pressure and higher predicted drugresistance scores in the presence of minority DRMs. Despite high-level pre-existing resistance, NGS-based longitudinal follow-up of this small but unique cohort of Kenyan CALWH demonstratedcontinued DRM evolution, at times including low-level DRMs detected only by NGS, with predictedimpact on care. NGS can inform better understanding of DRM evolution and dynamics and possiblyimprove care. The clinical significance of these findings should be further evaluate