Resistance Analysis of Low-Level Virologic Rebound During HIV-1 Treatment With Lenacapavir and Broadly Neutralizing Antibodies Teropavimab and Zinlirvimab.

Abstract

High rates of virologic suppression were observed in the Phase 1b study (NCT04811040) investigating lenacapavir and two broadly neutralizing antibodies (bNAb), teropavimab (30 mg/kg) and zinlirvimab (10 or 30 mg/kg), in virologically suppressed people with HIV-1 susceptible (IC90 ≤ 2 μg/mL) to both (primary cohort, n = 20) or either (pilot cohort, n = 10) bNAb. We describe resistance analyses through Week (W) 26. Post-baseline resistance analyses were conducted at virologic failure, and exploratory resistance analyses performed for participants with virologic rebound. Low copy number genotyping methods for capsid and a 1 kb stretch of gp120 from rebound virus were developed, and phenotypic susceptibility assessed. Virologic failure was observed in 1/30 participants. This primary cohort participant had HIV RNA 155 copies/mL at W16 and developed Q67H in capsid (lenacapavir fold-change 4.7), without resistance to bNAbs; the participant resuppressed on oral antiretrovirals. Two pilot cohort participants, experienced virologic rebound at W26 (55 and 72 copies/mL) and restarted oral antiretrovirals. In exploratory analyses, neither had emergent lenacapavir resistance or altered bNAb susceptibility. Lenacapavir, teropavimab, and zinlirvimab maintained a high rate of virologic suppression through W26, with rare emergent lenacapavir resistance and no bNAb resistance, supporting further Phase 2 evaluation.