Lenacapavir Intensification to Disrupt HIV Reservoirs in Virologically Suppressed People With HIV Receiving Antiretroviral Therapy

STUDY DESCRIPTION: This is a treatment intensification study designed to ascertain the effects of lenacapavir intensification in people with HIV (PWH) with viral suppression on effective antiretroviral therapy (ART). Participants who fulfill the inclusion and exclusion criteria will be randomized in a 2:1 ratio to either continue their ART plus lenacapavir or continue their ART alone. Up to 24 participants will receive lenacapavir at 927 mg by subcutaneous (SC) injection (2x1.5 mL injections) on day 0 and 600 mg orally (2x300 mg tablets) on days 0 and 1, followed by 927 mg by subcutaneous injection (2x1.5 mL injections) at weeks 24 and 48. Participants in the lenacapavir arm will be followed for 48 weeks following the final injection. Up to 12 participants will remain on their prescribed ART regimens only. The size and rate of decay of intact HIV DNA reservoirs will be longitudinally monitored in each study group. All participants will undergo leukapheresis at baseline (prior to the first lenacapavir injection, if applicable) and at weeks 12, 24, 48, 72, and 96. OBJECTIVES: Primary Objective: -To investigate the effect of the presence or absence of lenacapavir on intact HIV proviral DNA reservoirs in PWH who had been receiving virologically suppressive (\<40 copies/mL) ART for greater than 3 years. Secondary Objectives: -To investigate the effect of the presence or absence of lenacapavir on residual plasma viremia (\<40 copies/mL) in PWH who have been receiving virologically suppressive ART for greater than 3 years. Exploratory Objectives: * To investigate the effect of the presence or absence of lenacapavir on frequencies of CD4+ T cells carrying a) cell-associated HIV RNA, b) inducible HIV, and c) replication-competent virus. * To investigate phenotypic changes on B, T, and natural killer cell markers. * To investigate levels of HIV-specific T cells. * To examine biomarkers in plasma. ENDPOINTS: Primary Endpoint: -Changes in the intact HIV proviral reservoir size, measured by intact HIV proviral DNA assay (IPDA) in the blood CD4+ T-cell compartment from baseline to weeks 12, 24, 48, 72, and 96. Secondary Endpoint: -Changes in the residual HIV plasma viremia (1-39 copies/mL) from baseline to weeks 12, 24, 48, 72, and 96 (weeks 1, 2, 4, and 8 are optional). Exploratory Endpoints: * Frequencies of CD4+ T cells carrying cell-associated HIV RNA, inducible virion-associated HIV RNA, and replication-competent virus before, during, and after ART intensification with lenacapavir. * Immunophenotyping of B, T, and natural killer cells using highdimensional flow cytometry before, during, and after ART intensification with lenacapavir. * Measurements of the frequency of HIV-specific CD4+ and CD8+ T cells using overlapping HIV Gag peptides before, during, and after ART intensification with lenacapavir. * Measurements of plasma biomarkers of immune activation and inflammation before, during, and after ART intensification with lenacapavir.