Resistance Analyses of Lenacapavir, Emtricitabine/Tenofovir Alafenamide and Emtricitabine/Tenofovir Disoproxil Fumarate in the PURPOSE 1 and 2 Studies.

Abstract

Lenacapavir (LEN) is an HIV-1 capsid inhibitor being evaluated for pre-exposure prophylaxis (PrEP). The PURPOSE trials assessed the efficacy of LEN and emtricitabine/tenofovir disoproxil fumarate (F/TDF) in cisgender women (PURPOSE 1; P1) and in cisgender men, transgender women, transgender men and gender non-binary persons (PURPOSE 2; P2). Emtricitabine/tenofovir alafenamide (F/TAF) was also assessed in P1. Both studies demonstrated the superiority of LEN to F/TDF. We describe resistance analyses from P1 and P2, which provide the first data regarding emergent drug resistance in the context of LEN for PrEP. HIV testing was performed at screening, baseline, and every study visit. Participants who acquired HIV-1 with a viral load of ≥200 copies/mL were evaluated for resistance by genotyping of the HIV-1 capsid, protease, reverse transcriptase and integrase genes at HIV diagnosis. Adherence in the F/TDF and F/TAF groups was measured by dried blood spot. Resistance to LEN was detected in 0 of 2134 participants (P1) and 2 of 2179 participants (P2); both developed N74D. Four participants in each study receiving LEN were found to have unrecognized HIV-1 at baseline; 4/8 participants developed N74D. In P1, 2/37 participants analyzed for resistance in the F/TAF group had M184I ± K65R. In the F/TDF groups, M184M/I/V was detected in 1/16 participants (P1) and 1/9 participants (P2). Acquisition of HIV while receiving LEN and resistance to LEN in the context of unrecognized HIV was rare but associated with the emergence of the N74D LEN resistance-associated substitution in this population.