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

An Exploratory Phase 1b, Multicenter, Randomized, Open-Label Study to Investigate the Impact of the Administration of Intravenous VH3810109 With or Without Oral Fostemsavir in Combination With Integrase Inhibitor-Based Antiretroviral Therapy on the Viral Reservoir in Adults Living With HIV-1

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). The study is designed to include the following phases: Randomized Intervention Phase (Step 1), Analytical Treatment Interruption (ATI) Phase (Step 2), and Follow-up Phase (Step 3).

Inclusion Criteria:

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.

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 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:

• 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.
• 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.