Lenacapavir with Teropavimab and Zinlirvimab (twice‑yearly) versus Cabotegravir/Rilpivirine in virologically suppressed adults with HIV‑1

The primary objective is to assess efficacy of switching to a long‑acting regimen comprising lenacapavir, teropavimab and zinlirvimab versus switching to cabotegravir plus rilpivirine in virologically suppressed adults with HIV-1, as measured by the proportion of participants with HIV‑1 RNA ≥ 50 copies/mL at Week 52.

• Evaluate efficacy by HIV‑1 RNA levels and CD4+ T‑cell counts at Weeks 52 and 92.
• Assess safety and tolerability of the two study regimens.
• Determine pharmacokinetic parameters of lenacapavir, teropavimab and zinlirvimab.
• Investigate immunogenicity of teropavimab and zinlirvimab.

The trial enrolled 407 participants diagnosed with HIV-1 who were virologically suppressed on a stable oral antiretroviral regimen for at least six months. Eligible individuals were adults aged 18 years or older, of any gender, with a body weight of ≥ 35 kg. All participants had plasma HIV‑1 RNA levels consistently below 50 copies/mL during the 12‑month period preceding screening, including at least one measurement within the six months prior to enrollment. Inclusion required documented phenotypic susceptibility to both the investigational agents TAB (IC90 ≤ 2 µg/mL) and ZAB (IC90 ≤ 2 µg/mL). Female participants of childbearing potential were required to use protocol‑specified contraception and to have a negative pregnancy test at screening and before dosing. The population represented generally healthy individuals on stable therapy, without recent virologic failure or changes in antiretroviral regimen other than for non‑failure reasons.

The study is a Phase 3, randomized, open‑label, controlled trial evaluating a long‑acting antiretroviral regimen that combines the capsid inhibitor lenacapavir with the broadly neutralizing antibodies teropavimab and zinlirvimab versus a regimen of cabotegravir and rilpivirine in virologically suppressed adults with HIV-1. Participants are screened for eligibility, including confirmation of plasma HIV‑1 RNA < 50 copies/mL and susceptibility to the monoclonal antibodies, after which they are randomized 1:1 to receive either the test regimen (subcutaneous lenacapavir 600 mg and intravenous teropavimab 3400 mg plus zinlirvimab 3400 mg administered twice yearly) or the comparator regimen (intramuscular cabotegravir 3400 mg and rilpivirine 900 mg administered every eight weeks). The study schedule includes a screening visit, a baseline (Day 1) visit for randomization and first dosing, subsequent dosing visits at weeks 24 and 48 for the test arm, and dosing visits at weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96 and 104 for the comparator arm, with safety and efficacy assessments performed at each visit. Follow‑up assessments continue through an end‑of‑study visit at week 104, resulting in a total participant involvement of approximately two years. Early termination may occur if a participant experiences confirmed virologic failure (HIV‑1 RNA ≥ 200 copies/mL), a serious adverse event related to study drugs, pregnancy, or withdrawal of consent or inability to adhere to protocol requirements.

The test arm includes zinlirvimab supplied as GS‑2872, a sterile solution for infusion. Each dose contains 3400 mg and is administered intravenously over a defined infusion period. Dosing occurs twice yearly in accordance with the study schedule, and infusion parameters are recorded to verify compliance.

lenacapavir is provided in two formulations. Sunlenca 464 mg solution for injection delivers a 600 mg subcutaneous dose and is given twice yearly. Sunlenca 300 mg film‑coated tablets contain a 600 mg oral dose taken daily. Both routes are documented in the dosing log, and tablet adherence is assessed by pill counts and patient diaries.

teropavimab is supplied as GS‑5423, a solution for infusion. The preparation contains 3400 mg and is administered intravenously. Dosing follows the same twice‑yearly schedule as the other test agents, with infusion records maintained for each administration.

cabotegravir is administered as Vocabria prolonged‑release suspension for intramuscular injection. Both the 400 mg and 600 mg presentations contain a total of 3400 mg per injection. Injections are given every 8 weeks. Injection sites and dates are recorded to ensure protocol adherence.

rilpivirine is provided as REKAMBYS prolonged‑release suspension for intramuscular injection. The 900 mg and 600 mg formulations each deliver a total of 3400 mg per dose. Administration occurs every 8 weeks, with injection details captured in the study database for compliance monitoring.

The primary efficacy endpoint is the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 52, assessed according to the US FDA snapshot algorithm. Secondary efficacy endpoints include the proportion with HIV-1 RNA ≥ 50 copies/mL at Week 92, the proportion with HIV-1 RNA < 50 copies/mL at Weeks 52 and 92, changes from baseline in CD4+ T-cell counts at Weeks 52 and 92, the proportion of participants experiencing treatment‑emergent adverse events, premature discontinuations due to adverse events, trough concentrations of the study drugs at Weeks 26, 52, and 104, and the incidence of anti‑drug antibodies (ADAs) and neutralizing antibodies (NAbs) for the monoclonal antibodies.

Viral load assessments are performed using the FDA snapshot algorithm at the specified weekly time points. CD4+ T-cell counts are measured at baseline and at Weeks 52 and 92. Pharmacokinetic sampling for trough concentrations of the long‑acting agents occurs at Weeks 26, 52, and 104. Immunogenicity evaluations for ADAs and NAbs are conducted throughout the study period according to the protocol schedule. All efficacy parameters are analyzed using predefined statistical methods consistent with regulatory guidance.