Phase 3 Randomized Open‑Label Study of Switching to Lenacapavir Combined with Teropavimab and Zinlirvimab in Virologically Suppressed Adults with HIV‑1

The primary objective is to assess the efficacy of switching virologically suppressed adults with HIV-1 from a stable oral regimen to a combination of lenacapavir, teropavimab, and zinlirvimab, as measured by the proportion of participants with HIV‑1 RNA ≥ 50 copies/mL at Week 52, thereby evaluating maintenance of viral suppression. Secondary objectives are to: – evaluate antiviral efficacy by HIV‑1 RNA levels and CD4⁺ T‑cell counts at Weeks 52 and 92; – assess safety and tolerability of the investigational regimen versus the oral standard‑of‑care; – characterize the pharmacokinetic profile of lenacapavir, teropavimab, and zinlirvimab; and – determine the immunogenicity of the administered antibodies.

The trial enrolled 407 participants diagnosed with HIV-1 infection who were virologically suppressed on a stable oral antiretroviral regimen for at least six months. Eligible individuals were 18 years of age or older, of any gender, and had a body weight of at least 35 kg. All participants demonstrated plasma HIV‑1 RNA levels below 50 copies/mL at screening and had documented undetectable viral loads in the preceding 6–12 months, with any transient “blips” meeting predefined limits. Inclusion required phenotypic susceptibility to both TAB and ZAB based on specific IC90 thresholds, and for females of childbearing potential, a negative pregnancy test and agreement to use protocol‑specified contraception were mandatory. The population therefore comprised adults in good general health, maintained on a consistent oral ART regimen, without recent virologic failure or major changes in therapy.

The study is a Phase 3, randomized, open‑label, controlled trial evaluating the efficacy and safety of switching virologically suppressed adults with HIV-1 from a stable oral regimen to a regimen consisting of the capsid inhibitor lenacapavir administered twice yearly in combination with the broadly neutralizing antibodies teropavimab and zinlirvimab, compared with continuation of the current oral regimen. Participants are screened to confirm eligibility, including documented HIV‑1 RNA < 50 copies/mL and susceptibility to the antibodies; eligible individuals are randomized on Day 1 and receive the first dose of lenacapavir and the intravenous infusions of teropavimab and zinlirvimab. Follow‑up visits are scheduled at weeks 26, 52, 92 and 104 for safety assessments, laboratory monitoring, CD4⁺ T‑cell counts, drug trough levels and immunogenicity testing, with an end‑of‑study visit at week 104. The overall participant involvement spans approximately two years from randomization to the final visit. Early termination may occur due to confirmed virologic failure (HIV‑1 RNA ≥ 50 copies/mL), emergence of a serious adverse event, pregnancy, withdrawal of consent, or significant protocol non‑compliance. The primary endpoint is the proportion of participants with HIV‑1 RNA ≥ 50 copies/mL at week 52, assessed by the FDA snapshot algorithm.

Lenacapavir is administered as Sunlenca 300 mg film‑coated tablets. Each tablet contains 600 mg of the active substance. The medication is taken orally and is scheduled to be administered twice yearly in accordance with the study protocol.

Sunlenca 464 mg solution for injection contains 600 mg of lenacapavir in a liquid formulation. The solution is taken orally as a single dose and is also administered twice yearly as part of the investigational regimen.

GS‑5423 is supplied as a 3400 mg solution for infusion. The active monoclonal antibody teropavimab is delivered intravenously over a prescribed infusion period. Dosing intervals follow the study schedule.

GS‑2872 is provided as a 3400 mg solution for infusion. The active monoclonal antibody zinlirvimab is administered intravenously according to the protocol‑defined schedule.

Genvoya 90 mg/90 mg/120 mg/6 mg film‑coated tablets combine emtricitabine, tenofovir alafenamide, cobicistat and elvitegravir. The tablet is taken orally once daily as per the approved label and serves as a standard‑of‑care comparator.

REZOLSTA 800 mg/150 mg film‑coated tablets contain darunavir and cobicistat. The tablet is administered orally once daily according to the prescribing information.

ISENTRESS 400 mg film‑coated tablets contain raltegravir and are taken orally once daily.

Norvir 100 mg powder for oral suspension contains ritonavir and is administered orally once daily.

Aptivus 250 mg soft capsules contain tipranavir and are taken orally once daily.

Tivicay 50 mg film‑coated tablets contain dolutegravir and are administered orally once daily.

Epivir 150 mg film‑coated tablets contain lamivudine and are taken orally once daily.

Emtriva 200 mg hard capsules contain emtricitabine and are administered orally once daily.

EFAVIRENZ VIATRIS 600 mg film‑coated tablets contain efavirenz and are taken orally once daily.

Viread 123 mg film‑coated tablets contain tenofovir disoproxil and are administered orally once daily.

Ziagen 300 mg film‑coated tablets contain abacavir and are taken orally once daily.

Pifeltro 100 mg film‑coated tablets contain doravirine and are administered orally once daily.

Tybost 150 mg film‑coated tablets contain cobicistat and are taken orally once daily.

REYATAZ 200 mg hard capsules contain atazanavir and are administered orally once daily.

REKAMBYS 600 mg prolonged‑release suspension for injection contains rilpivirine and is taken orally once daily.

INTELENCE 200 mg tablets contain etravirine and are administered orally once daily.

Compliance with oral regimens is monitored through pill counts, patient diaries, and periodic drug accountability assessments conducted at study visits.

Efficacy will be evaluated primarily by the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 52, assessed using the United States Food and Drug Administration (US FDA) snapshot algorithm. Blood samples for viral load will be collected at baseline and at Week 52, and quantitative polymerase chain reaction (qPCR) will be performed in a central laboratory following validated procedures.

Key secondary efficacy assessments include the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 92, the proportion with HIV-1 RNA < 50 copies/mL at Weeks 52 and 92 (both using the US FDA snapshot algorithm), and changes from baseline in CD4+ T‑cell counts at Weeks 52 and 92. CD4+ T‑cell counts will be measured by flow cytometry on blood samples obtained at the specified visits. Additional secondary endpoints comprise plasma trough concentrations of lenacapavir, teropavimab, and zinlirvimab at Weeks 26, 52, and 104, which will be quantified using validated bioanalytical assays, and the incidence of anti‑drug antibodies (ADAs) and neutralizing antibodies (NAbs) against teropavimab and zinlirvimab, assessed by standardized immunogenicity tests.