The goal of this clinical study is to compare how effective a long-acting injectable treatment of lenacapavir (LEN), teropavimab (TAB), and zinlirvimab (ZAB) versus (CAB) and rilpivirine (RPV) injections given every 8 weeks in adults with HIV-1 whose virus is well controlled on daily oral treatment, after 1 year (52 weeks) of the treatment.

The primary objective of this study are to evaluate the efficacy of switching to the regimen of LEN, TAB, and ZAB versus switching to CAB and RPV in virologically suppressed people with HIV-1 (PWH) as determined by the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 52.

Key Inclusion Criteria:

• Human immunodeficiency virus type 1 (HIV-1) susceptibility results from screening meeting specific criteria:

  1) Proviral phenotypic susceptibility to both TAB and ZAB by the investigational protocol-defined assay at screening.

• At least 1 documented HIV-1 RNA level measured between 6 months and 12 months (+2 months) prior to screening. This and any other HIV-1 RNA measurements documented in this period must be < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL). A single virologic elevation of ≥ 50 copies/mL and < 400 copies/mL (transient detectable viremia or "blips") prior to screening are acceptable if the subsequent plasma HIV-1 RNA level is < 50 copies/mL.

• A plasma HIV-1 RNA test < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) within the last 6 months prior to screening.

  1) If > 1 plasma HIV-1 RNA measurements in the last 6 months prior to screening are available, all must be < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL).

• On a stable oral ARV therapy (ART) for ≥ 6 months prior to screening.

  1. A change in ART regimen ≥ 3 months prior to the screening visit for reasons other than virologic failure (VF) (eg, tolerability, simplification, drug-drug interaction profile) is allowed; individuals with a change in ART regimen ≥ 3 months prior to screening must have been on the regimen for ≥ 3 months prior to screening, and all HIV-1 RNA measurements in that period must be < 50 copies/mL. There are no permitted changes to ART regimens between screening and Day 1.

Key Exclusion Criteria:

• History of an opportunistic infection or illness indicative of Stage 3 HIV disease.

• History of treatment failure.

• Known or suspected resistance to either CAB or RPV.

  1. Resistance to CAB defined as the following mutations: G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R, E138K+Q148K/R, G140C+Q148R, G140S+Q148H/K/R, Y143H+N155H, and Q148R+N155H.
  2. Resistance to RPV defined as the following mutations: K101E and P; E138A, G, K, R, and Q; V179L; Y181C, I, and V; Y188L; H221Y; F227C; M230I and L, and the combination of L100I/K103N.

• Individuals with a dermatologic condition or implanted prothesis overlying the gluteal injection site for CAB + RPV.

• Known hypersensitivity to the study intervention, its metabolites, or formulation excipients.

• Active, serious infections (other than HIV-1) requiring therapy < 30 days prior to randomization.

• Active tuberculosis infection.

• Acute hepatitis of any cause < 30 days before randomization.

• History of, or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or variceal bleeding) or severe hepatic impairment (Child-Pugh Class C).

• Active malignancy requiring acute systemic therapy.

• Have poor venous access that would limit phlebotomy or intravenous (IV) infusion of study drugs.

• Prior use of, or exposure to, LEN or a broadly neutralizing antibody (bNAb) for HIV-1.

• Prior use of, or exposure to, long-acting (LA) injectable CAB or LA injectable RPV.

• Prior use of, or exposure to, ibalizumab, fostemsavir, or maraviroc.

• Baseline regimen consisting of monotherapy with any single antiretroviral (ARV).

• Treatment with immunosuppressant therapies (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies) within 4 weeks of screening (with the exception of a single short course of corticosteroids lasting ≤ 7 days) or have a comorbid condition with an anticipated need ongoing immunosuppressive treatment during the study.

• Hepatitis C virus (HCV) antibody positive and HCV RNA detectable.

• Chronic hepatitis B virus (HBV) infection, as determined by either:

  1. Positive HBV surface antigen and negative HBV surface antibody, regardless of HBV core antibody status, at the screening visit.
  2. Positive HBV core antibody and negative HBV surface antibody, regardless of HBV surface antigen status, at the screening visit.

• Severe renal impairment-estimated glomerular filtration rate < 30 mL/min according to the Cockcroft-Gault formula.

• Abnormal electrocardiogram (ECG) at the screening visit that is clinically significant, as determined by the investigator.

• Any of the following laboratory values at screening:

  1. Alanine aminotransferase > 5 x upper limit of normal (ULN).
  2. Direct bilirubin > 1.5 x ULN.
  3. Platelets < 50,000/mm^3.
  4. Hemoglobin < 8.0 g/dL.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.