Background: 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.
Methods: 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.
Results: 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).
Conclusions: 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.
Keywords: HIV; PrEP; capsid; lenacapavir; resistance.
© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America.