Overview

This study investigates the use of VH3810109 with or without FTR to reduce the size and activity of the HIV viral reservoir in two sub-populations of people living with HIV: treatment-naïve adults (Population 1) and treatment-experienced adults currently taking a standard of care (SOC) integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) regimen (Population 2).

Eligibility

Inclusion Criteria:

• Age between 18 years and 70 years old at the time of obtaining informed consent.
• 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 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.
• Body weight >=50 kg to <=115 kg.
• 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.

Exclusion Criteria:

CONCURRENT MEDICAL CONDITIONS & MEDICAL HISTORY

• Participant is pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study.
• 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.
• Ongoing or clinically relevant pancreatitis.
• 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

• History of clinically relevant hepatitis in the 6 months prior to Screening.

• Participants with severe hepatic impairment.
• Advanced MAFLD and advanced non-alcoholic steatohepatitis, if evidence for substantial fibrosis (fibrosis score ≥F2) or evidence of cirrhosis.
• Unstable liver disease.
• History of liver cirrhosis with or without hepatitis viral co-infection.

NEUROPSYCHIATRIC CONDITIONS

• Participants who pose a significant suicide risk.

LABORATORY DIAGNOSTIC ASSESSMENTS

• Participants who are experiencing (Population 1) or are known to have initiated ART during (Population 2) acute HIV infection.
• 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.
• 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 • Two or more plasma HIV-1 RNA results >=50 c/mL in the 18 months prior to Screening.

INFECTIOUS DISEASES

• Active hepatitis B virus (HBV) co-infection.
• Active hepatitis C virus (HCV) co-infection.
• Participant has untreated syphilis before enrolment.
• Known current untreated or incompletely treated active Mycobacterium TB infection.

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 • 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

• Current use of NNRTI-containing ART.

OTHER EXCLUSIONS

• 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 currently participating in, or anticipates being selected for, any other interventional study.