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)

NCT07481175 | Recruiting Phase 1 DMC

• 2 other identifiers: INITIATE-0012025-521841-26-00
• Study Type: interventional
• Target: 38
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

HIV-1

Keywords

venetoclax; bcl-2 inhibitor; anti-apoptotic protein

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• 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

Study Arms (2)

Study participants receive venetoclax 200 mg concurrent with initiating ART

EXPERIMENTAL

Drug: Venetoclax

ART alone

NO INTERVENTION

Interventions

Venetoclax DRUG

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

Study participants receive venetoclax 200 mg concurrent with initiating ART

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (2)

Infectious Diseases, Q Research

Aarhus, 8200, Denmark

RECRUITING

Hospital Universitari Germans Trias I Pujol, Department of Infectious Diseases

Badalona, Spain

RECRUITING

MeSH Terms

Interventions

venetoclax

Central Study Contacts

Thomas A Rasmussen, Associate professor, MD, PhD

CONTACT

004593801394; thomrasm@rm.dk

Jesper D Gunst, MD, PhD

CONTACT

004523886636; jesdam@rm.dk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor, MD, PhD

Study Record Dates

• First Submitted: March 13, 2026
• First Posted: March 18, 2026
• Study Start: April 13, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030
• Last Updated: May 7, 2026

Record last verified: 2026-04

Locations

DK (1); ES (1)