Inhibiting the Anti-apoptotic Factor, BCL-2, at the Time of ART Initiation to Promote Apoptosis of HIV-infected Cells and Restrict the Seeding of the HIV Reservoir (The INITIATE Study) (INITIATE)

Inhibiting the Anti-apoptotic Factor, BCL-2, at the Time of ART Initiation to Promote Apoptosis of HIV-infected Cells and Restrict the Seeding of the HIV Reservoir: An Investigator-initiated Randomised, Controlled, Open-label Clinical Trial (The INITIATE Study)

Combination therapy with antiretroviral medication (ART) has proven effective in keeping HIV suppressed and restoring the immune system, but it cannot cure the infection. Therefore, lifelong treatment is necessary. The reason for this is a reservoir of inactive virus that remains hidden in long-lived cells and cannot be eliminated by either HIV treatment or the immune system. This reservoir is the primary barrier to a cure for HIV and must be minimized or eliminated in order to make it possible to discontinue lifelong ART treatment.

Several studies have been conducted with the aim of reducing the reservoir of inactive virus. The drugs used have been able to activate the virus in resting infected cells, thereby making the virus visible to the immune system. Unfortunately, this type of experimental treatment has not been sufficient to reduce the reservoir of inactive HIV in long-lived cells, possibly because these cells do not undergo cell death to a sufficient degree due to specific alterations in the mechanisms of cell death signaling.

The drug venetoclax (Venclyxto) is an inhibitor of BCL-2 (B Cell Lymphoma-2), a key factor involved in the regulation of programmed cell death. Studies have shown increased BCL-2 activity in long-lived cells infected with HIV. In laboratory experiments, we have demonstrated that treating cells with venetoclax while simultaneously activating HIV can lead to the elimination of HIV-infected cells. In experiments with HIV-infected humanized mice receiving ART, we further found that treatment with venetoclax delayed viral rebound after interruption of ART compared with mice that were not treated with venetoclax.

The purpose of this study is to investigate whether treatment with venetoclax in people with HIV who are initiating HIV therapy can promote the death of latently infected cells and thereby lead to a reduction in the latent HIV reservoir. The study will examine the safety and the effect of venetoclax.

Study Overview

• Status: Recruiting
• Conditions: HIV-1
• Intervention / Treatment: Drug: Venetoclax

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Thomas A Rasmussen, Associate professor, MD, PhD; Phone Number: 004593801394; Email: thomrasm@rm.dk
• Study Contact Backup: Name: Jesper D Gunst, MD, PhD; Phone Number: 004523886636; Email: jesdam@rm.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Recruiting
    • Infectious Diseases, Q Research
    • Contact: Thomas A Rasmussen, Associate Professor, MD, PhD; Phone Number: +4593801394; Email: thomrasm@rm.dk
    • Contact: Jesper D Gunst, MD, PhD; Phone Number: +4523886636; Email: jesdam@rm.dk
• Spain
  • Badalona, Spain
    • Recruiting
    • Hospital Universitari Germans Trias I Pujol, Department of Infectious Diseases
    • Contact: José M Marhuenda, MD, PhD; Phone Number: +34934657897; Email: jmolto@lluita.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documented HIV-1 infection
• Age 18-70 years (both included) at screening
• CD4+ T cell count >300/µL at screening
• ART naïve at screening
• Able to give informed consent
• Ability and willingness to provide informed consent and to continue ART throughout the study
• All participants must agree to use condoms during all sexual intercourse in situations where HIV transmission may still occur, i.e. until fully suppressed on ART (plasma HIV-1 RNA <50 copies/mL)
• All participants must agree not to participate in a conception process (e.g. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, egg donation) during the study

Exclusion Criteria:

• An individual who meets any of the following criteria will be excluded from participation in this study.
• Current or previous use of a BCL-2 antagonist or other pro-apoptotic agent used as cancer therapy
• Evidence of or strong suspicion that HIV infection was acquired during active PrEP use
• Any concomitant disease where venetoclax treatment is indicated
• Current use of any moderate or strong CYP3A4 inhibitors (such as ketoconazole, voriconazole, posaconazole, itraconazole, ritonavir, cobicistat and clarithromycin)
• Current use of any HIV protease inhibitor (due to CYP3A4 inhibition)
• Current use of any strong inhibitor of the P-gp drug efflux pump (this includes cobicistat, ritonavir, azithromycin and clarithromycin)
• Current use of P-gp substrates with narrow therapeutic index (such as such as digoxin, tacrolimus, cyclosporine, sirolimus, dabigatran, colchicine, loperamide)
• Current use of strong or moderate CYP3A4 inducers (such as carbamazepine, phenytoin, rifampicin, St. John's wort, bosentan, efavirenz and etravirine); intermittent use of moderate CYP3A4 inducers such as modafinil and nafcillin may be used but should be avoided as much as possible
• Receipt of immunomodulating agents (excluding immunisation) or systemic chemotherapeutic agents within 28 days prior to study entry
• Any other current or prior therapy which, in the opinion of the investigators, would make the individual unsuitable for the study or influence the results of the study
• Known hypersensitivity to the components of venetoclax or its analogues
• Any evidence of an active AIDS-defining opportunistic infection
• Individuals who intend to modify their ART regimen within the study period
• Current or recent gastrointestinal disease or gastrointestinal surgery that may impact the absorption of the investigational drug
• Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy or procedures
• Unable or unwilling to adhere to protocol procedures
• History of malignancy or transplantation, excluding adequately treated basal cell carcinoma
• Co-infection with hepatitis B defined as HBsAg-positive or Hepatitis C defined as HCV-RNA positive (Individuals with prior hepatitis B or C infection that is now cleared are eligible for enrolment)
• For individuals with isolated anti-HBcAb (cleared hepatitis B), the chosen ART regimen must include TDF or TAF
• Impaired liver function with AST or ALT >3 times upper limit of normal
• Severe hepatic impairment (Class C) as determined by Child-Pugh classification
• Impaired renal function with estimated creatinine clearance (eGFR) <50 mL/min
• Significant cardiac dysfunction
• Women who are pregnant or breastfeeding or Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy as specified in the inclusion criteria
• The following laboratory values at screening (lab tests may be repeated, as clinically indicated, to obtain acceptable values before failure at screening is concluded but supportive therapies are not to be administered within the week prior to screening tests): Platelet count ≤100 x109/L, Absolute neutrophil count ≤1.0x109/L, Haemoglobin <10,0 g/dL, CD4+ T cell count <300 cells/uL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study participants receive venetoclax 200 mg concurrent with initiating ART	Drug: Venetoclax; Venetoclax 200 mg will be given daily on days 0-14, days 35-49 and days 70-84. Study visits and blood draws will be done at days 0, 7, 14, 35, 49, 70, 84, 126, 252 and 365
No Intervention: ART alone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety endpoint: Determine the safety of venetoclax administration in PLWH at the time of ART initiation	Safety defined as treatment-emerging adverse events (AEs) related to study treatment	Day 0 to Day 365
Effect endpoint: The frequency of peripheral blood CD4+ T cells containing intact HIV-DNA	The frequency of peripheral blood CD4+ T cells containing intact HIV-DNA using the Cross-Subtype Intact Proviral DNA Assay (IPDA)	Day 365

Secondary Outcome Measures

Outcome Measure	Time Frame
Impact on viral decay and HIV persistence of venetoclax administration in PLWH at the time of ART initiation	Day 0 to Day 365
Impact of venetoclax administered at the time of ART initiation on cellular apoptosis pathways in PLWH	Day 0 to Day 365

Collaborators and Investigators

• Sponsor: Thomas Aagaard Rasmussen
• Collaborators: Aarhus University Hospital; The Alfred; Germans Trias i Pujol Hospital; Walter and Eliza Hall Institute of Medical Research

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: March 13, 2026
• First Submitted That Met QC Criteria: March 13, 2026
• First Posted (Actual): March 18, 2026

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: venetoclax; bcl-2 inhibitor; anti-apoptotic protein
• Additional Relevant MeSH Terms: venetoclax
• Other Study ID Numbers: INITIATE-001; 2025-521841-26-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No