VIOLA: Study of Viremia on Long-acting Antiretroviral Therapy with Cabotegravir and Rilpivirine

PROJECT SUMMARY/ABSTRACT Long-acting antiretroviral therapy (LA-ART) has the potential to improve viral suppression and accelerate Ending the HIV Epidemic (EHE) goals in the U.S. Cabotegravir (an integrase strand transfer inhibitor, INSTI) and rilpivirine (a non-nucleoside reverse transcriptase inhibitor, NNRTI) (CAB/RPV), an every 4 or 8 week injection, is FDA-approved for maintenance of viral suppression among people with HIV (PWH). Based on data from clinics and the A5359 LATITUDE trial, U.S. HIV guidelines now also recommend CAB/RPV for select PWH with adherence challenges or persistent viremia on oral ART, ushering in an era of expanded use of LA- ART. Although CAB/RPV was highly effective in trials, rare, but significant, cases of virologic failure occurred among participants, resulting in emergence of 2-class (INSTI, NNRTI) resistance and limiting future ART options with preferred regimens, such as bictegravir or dolutegravir. Rare cases of virologic failure on CAB/RPV are being reported in routine clinical care, and early data suggest the risk of virologic failure may be higher among PWH starting CAB/RPV with initial viremia, compared to those switching in the setting of viral suppression on oral ART. With expanded CAB/RPV use in routine care in the U.S., investigation of virologic failure on LA-ART is needed to inform strategies to mitigate the risk of virologic failure and INSTI/NNRTI resistance. This application proposes a short-term, exploratory study investigating virologic failure on LA-ART, leveraging an ongoing study enrolling across the U.S. and established laboratory methods. The proposed aims are: 1) to assess CAB/RPV concentrations among persons with virologic failure on LA-ART and 2) to evaluate viral resistance mutations among PWH with virologic failure on LA-ART using standard and next-generation sequencing (NGS) methods. The proposed exploratory study, made feasible by existing infrastructure from a larger grant, will fill key knowledge gaps on PK and resistance outcomes after virologic failure on LA-ART in routine care across the U.S.