Emergent pan-integrase inhibitor resistance in HIV: first reported case from the Indian subcontinent

Integrase strand transfer inhibitors (INSTIs) are highly valued for their efficacy, safety, and high resistance barrier in antiretroviral therapy (ART). However, reports of emergent INSTI-selected mutations causing resistance are rising. We report the first case of emergent pan-INSTI resistance in an ART-experienced, INSTI-naïve male from the Indian subcontinent. Initially treated with zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP), the patient achieved virological control until poor adherence following a myocardial infarction (MI) in 2017 resulted in viraemia. After switching to a tenofovir (TDF) + 3TC + dolutegravir (DTG) regimen in 2021, the patient experienced virological rebound in May 2024, followed by virological failure (VF) in June 2024. Resistance testing at the time of VF identified major INSTI mutations (G118R, E138K, and L74M), conferring pan-INSTI resistance and necessitating switch to a boosted protease inhibitor (PI)-based regimen. Emergent INSTI resistance in DTG-based regimens is relatively rare. While DTG resistance often follows specific mutational pathways (R263K, G118R, N155H, Q148H/R/K), the G118R mutation, when combined with E138K and L74M, specifically poses a significant challenge, severely reducing the efficacy of all available INSTIs and highlighting the critical impact of such resistance patterns on treatment outcomes. This case highlights the importance of resistance testing, early intervention, and adherence monitoring to prevent the emergence of multidrug-resistant HIV and optimize treatment.