A Study to Investigate the Use of VH3810109 With or Without Fostemsavir (FTR) to Reduce the Size and Activity of the Viral Reservoir in People Living With HIV

Prior treatment

• CONCURRENT MEDICAL CONDITIONS \& MEDICAL HISTORY
• History of clinically relevant hepatitis in the 6 months prior to Screening.
• Two or more plasma HIV-1 RNA results \>=50 c/mL in the 18 months prior to Screening.
  • INFECTIOUS DISEASES
• Known history of active Mycobacterium TB disease (regardless of treatment status).
  • ANTIRETROVIRAL RESISTANCE • Known major resistance-associated mutations to second-generation INSTIs or to antiretroviral (ARV) agents from 2 or more drug classes.
  • PRIOR AND CONCOMITANT MEDICATIONS
• Prior use of any of the following agents:
  • \- long-acting ARVs (any dose in the past 24 months or within 5 half-lives \[whichever is longer\])
  • \- FTR (any lifetime use)
  • \- HIV-1 immunotherapeutic vaccines or prophylactic vaccines (any lifetime use)
  • \- HIV-1 monoclonal antibody therapy (any lifetime use).
• Prior receipt of any approved or experimental non-HIV vaccination within 2 weeks prior to study enrolment.
• History of systemic corticosteroids, immunosuppressive anti-cancer, interleukins, systemic interferons, or systemic chemotherapy, within 6 months prior to Screening.
• Participant has received an experimental drug or experimental vaccine within either 30 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent (whichever is longer), prior to enrolment.
• Treatment with any of the following agents within 30 days of enrolment:
  • \- radiation therapy
  • cytotoxic chemotherapeutic agents
  • anti-tuberculosis therapy
  • immunomodulators that alter immune responses such as chronic systemic corticosteroids, interleukins, or interferons.
• Participant is receiving any protocol-defined prohibited medication and is unwilling or unable to switch to an alternate medication. Prohibited medications must be stopped within 7 days (or 14 days if the drug is a potential CYP3A4 enzyme inducer) or 5 half-lives (whichever is longer), prior to enrolment.
  • Population 1 only:

Other illness

• Participant has documented diagnosis of HIV-2 infection.
• Participant is known to have acquired HIV via perinatal transmission.
• Any evidence of a current or known past Center for Disease Control and Prevention (CDC) Stage 3 disease.
• Any ongoing malignancy or history of systemic cancers, such as Kaposi's sarcoma and lymphoma, or other virus-associated malignancies.
• Current HIV-related kidney disease.
• History of or active HIV-associated dementia or progressive multifocal leukoencephalopathy.
  • CARDIAC \& CARDIOVASCULAR CONDITIONS
• Participants who are at clinically significant risk of cardiovascular disease.
• Ongoing or any lifetime history of clinically significant cardiovascular or cardiac disease.
• Confirmed QTcF value outside normal range at Screening or Day 1.
  • HEPATIC CONDITIONS
• Participants with severe hepatic impairment.
• Unstable liver disease.
• Participants who are experiencing (Population 1) or are known to have initiated ART during (Population 2) acute HIV infection.
• Active hepatitis B virus (HBV) co-infection.
• Active hepatitis C virus (HCV) co-infection.
• Known use of PrEP or PEP within \<30 days (for oral agents) or \<52 weeks (for LA parenteral agents) of HIV-1 diagnosis. Participants with a documented seronegative result \>=30 days after the last dose of oral PrEP or PEP (or \>=52 weeks after the last dose of LA PrEP) are not excluded.
  • Population 2 only:
• History or presence of allergy or intolerance to the study drugs or their components or drugs of their class, or a history of drug or other allergy that contraindicates study participation.
• Any condition which may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to receive study drugs.
• Any pre-existing physical or mental condition (including substance use disorder) which, may interfere with the participant's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant.
• Participant is known or suspected to be an HIV long-term non-progressor or elite controller, based on historical off-treatment plasma HIV-1 RNA results.

Lab values

• History of liver cirrhosis with or without hepatitis viral co-infection.
  • NEUROPSYCHIATRIC CONDITIONS • Participants who pose a significant suicide risk.
  • LABORATORY DIAGNOSTIC ASSESSMENTS
• Any verified Grade 4 laboratory abnormality at Screening, excluding asymptomatic elevations of lipids or CPK.
• Alanine transferase (ALT) \>=3 times the upper limit of normal (ULN) at Screening.
• Estimated glomerular filtration rate (eGFR) of \<60 mL/min/1.73 m\^2.
• Hemoglobin \>=Grade 2 at Screening.
• Platelets \>=Grade 2 at Screening.
• Absolute Neutrophil Count (ANC) ≥Grade 2 at Screening.

Other

• Participant is pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study.
• Ongoing or clinically relevant pancreatitis.
• Advanced MAFLD and advanced non-alcoholic steatohepatitis, if evidence for substantial fibrosis (fibrosis score ≥F2) or evidence of cirrhosis.
• Any acute abnormality at Screening, which, in the opinion of the investigator, would preclude the participant's inclusion in an interventional clinical study.
  • Population 2 only:
• Participant has untreated syphilis before enrolment.
• Current use of NNRTI-containing ART.
  • OTHER EXCLUSIONS
• Participant is currently participating in, or anticipates being selected for, any other interventional study.

• AGE
• Age between 18 years and 70 years old at the time of obtaining informed consent.
  • SEX AND GENDER • Persons of any sex or gender are eligible. Note: Participants of childbearing potential (POCBP) are eligible to participate if not pregnant, not lactating, and agreeing to adhere to study requirements for use of contraception and pregnancy avoidance.
  • PARTICIPANT KEY CHARACTERISTICS • Participant has a documented diagnosis of HIV-1 infection. Note: Participants in Population 1 must have a documented positive HIV antibody result available for Screening.
  • Population 1 only:
• Plasma HIV-1 RNA \>=2000 copies/milliliter (c/mL) at Screening.
• CD4+ T cell count \>=300 cells/microliter (μL) at Screening.
• Antiretroviral treatment naïve, defined as no exposure to ART after a diagnosis of HIV-1 infection, prior to enrollment.
  • Population 2 only:
• Participant is stably virologically suppressed (plasma HIV-1 RNA \<50 c/mL).
• Documented evidence of uninterrupted treatment with oral non-boosted INSTI-based ART for at least 6 months prior to Screening, as well as uninterrupted treatment with ART (any guideline-recommended oral regimen) for at least 24 months prior to Screening.
• CD4+ T cell count \>=450 cells/μL at Screening.
  • WEIGHT
• Body weight \>=50 kg to \<=115 kg.
  • INFORMED CONSENT • Participant is capable of giving written informed consent, which includes adherence to the requirements and restrictions listed in the consent form and in the protocol.