Pharmacogenomic variability in adolescents and youth with virologic rebound while receiving injectable...

Long-acting injectable cabotegravir and rilpivirine (LAI-CAB/RPV) has transformed human immunodeficiency virus (HIV) treatment by providing durable viral suppression without daily oral antiretroviral therapy (ART). Although clinical trials have demonstrated excellent efficacy, real-world experience has identified rare cases of viral blips, persistent low-level viremia and virologic rebound, with underlying mechanisms remaining unclear.

We conducted a retrospective case series of 10 adolescents and young adults with HIV who developed virologic abnormalities after transitioning from suppressive oral ART to LAI-CAB/RPV. Among 76 patients receiving LAI-CAB/RPV during the study period, 11 developed virologic abnormalities and 10 underwent pharmacogenomic (PGx) testing. Clinical, virologic and PGx findings were reviewed.

All patients experienced viral suppression before initiating LAI-CAB/RPV. Following the transition, all experienced viral blips, six developed persistent low-level viremia and one progressed to virologic failure. Eight patients had CYP2B6 intermediate or poor metabolizer phenotypes, seven had clinically relevant CYP2C19 variants, and nine had CYP3A5 variants. All patients demonstrated at least one non-normal metabolizer phenotype, and most exhibited variability across multiple metabolic pathways.

This case series identifies clustering of multiple pharmacogenomic variants among patients experiencing virologic abnormalities while receiving LAI-CAB/RPV. Although these variants are relatively common individually, their combined occurrence warrants further investigation. Prospective pharmacokinetic and pharmacogenomic studies are needed to determine whether host genetic variability contributes to long-acting ART outcomes.