Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1 ( ISLEND-2 )

Prior treatment

• Prior virologic failure.
• HBV infection, as determined below at the screening visit: a) Positive HBV surface antigen OR b) Positive HBV core antibody and negative HBV surface antibody. Note: Participants found to be susceptible to HBV infection (eg, negative hepatitis B surface antibody at the screening visit, regardless of prior HBV vaccination history) should be recommended to receive HBV vaccination
• Active hepatitis C virus (HCV) coinfection, defined as detectable HCV RNA. Note: particpants with prior/inactive HCV infection (defined as undetectable HCV RNA) may be enrolled.
• Participation or planned participation in any other clinical study (including observational studies) without prior approval from the sponsor.
• Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study or unable to comply with dosing requirements.
• Requirement for ongoing therapy or use of any prohibited medications listed in Section 5.3 within 30 days prior to screening through the last dose of study drug.
• Treatment < 3 months prior to screening or anticipated treatment during the study period with immunosuppressant therapies, hydroxyurea, foscarnet, radiation, or cytotoxic chemotherapeutic agents without approval from sponsor prior to randomization. Agents disallowed in Section 5.3 may not be considered for sponsor approval. (See Appendix 11.8.2 for United Kingdom [UK]-specific requirements for this criterion).
• Prior use of, or exposure to, ISL or LEN.
• Active, serious infections requiring parenteral therapy within 30 days before randomization.
• Acute hepatitis within 30 days before randomization.

Other illness

• Known hypersensitivity to any of the study drugs, their metabolites, or formulation excipients.
• History of or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or variceal bleeding).
• Active malignancy requiring acute systemic therapy.
• Active tuberculosis infection.

Lab values

• Any of the following laboratory values at screening: 1. Creatinine clearance (CLcr) ≤ 30 mL/min according to the Cockcroft-Gault formula 2. Alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN) 3. Direct bilirubin > 1.5 x ULN 4. Platelets < 50,000/μL 5. Hemoglobin < 8.0 g/dL
• Participants of childbearing potential (as defined in Appendix 11.5) who have a positive serum pregnancy test at screening or positive urine and serum pregnancy tests at Day 1 prior to study drug administration.

Other

• Participants who plan to continue breastfeeding during the study.
• Abnormal electrocardiogram (ECG) at the screening visit that is clinically significant as determined by the investigator.

• Participants 18 years of age or older at screening and able to understand and give written informed consent.
• HIV-1 RNA < 50 copies/mL for ≥ 6 months before screening, as documented by: a) One HIV-1 RNA < 50 copies/mL immediately preceding the 24 week period prior to screening. b) Within 24 weeks prior to screening, if HIV-1 RNA results are available, all levels must be < 50 copies/mL. c) During the 6 to 12 months period prior to screening, transient detectable viremia ≥ 50 copies/mL is acceptable (“blip”), as long as it is not confirmed on 2 consecutive visits.
• Plasma HIV-1 RNA levels < 50 copies/mL at screening.
• Are receiving guideline-recommended standard of care treatment such as International Antiviral Society (IAS), Department of Health and Human Services (DHHS), European AIDS Clinical Society (EACS) consisting of 2 or 3 ARVs for ≥ 6 months prior to screening and willing to continue until Day 1. Participants in Treatment Group 2 must also be willing to continue their standard of care through at least Week 96. a) INSTI combined with 1 or 2 NRTIs (B/F/TAF, DTG/ABC/3TC, DTG+TXF/FTC, DTG/TDF/3TC, DTG/3TC, RAL+TXF/FTC, RAL+TDF/3TC, EVG/c/TXF/FTC), or b) Boosted PI combined with 2 NRTIs (D/C/F/TAF, boosted DRV+TXF/FTC, boosted DRV+TDF/3TC), or c) NNRTI combined with 2 NRTIs (DOR/TDF/3TC, DOR+TXF/FTC, DOR+TDF/3TC, RPV/TXF/FTC, RPV+TXF/FTC, RPV+TDF/3TC). Notes: RAL can be taken either once or twice daily; all other agents are to be taken once daily, including and single tablet regimen. TXF = TAF or TDF. Boosted PI taken once daily with cobicistat or ritonavir.
• Participants assigned female at birth and of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified methods of contraception as described in Appendix 11.5.