Blocking BCL-2 when starting HIV treatment to help infected cells die (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)

This trial will try giving the BCL-2 blocker venetoclax to people with newly diagnosed HIV who are starting ART to see if it helps infected cells die and reduces the hidden HIV reservoir.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 38 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: University of Aarhus (Academic / other)
• Locations: 2 sites (Aarhus and 1 other locations)
• Trial ID: NCT07481175 on ClinicalTrials.gov

What this trial studies

INITIATE is a phase 1 interventional trial that gives the BCL-2 inhibitor venetoclax at the time ART is initiated in ART‑naïve adults. The approach aims to promote apoptosis of HIV-infected cells and limit the seeding of the long-lived viral reservoir by combining a pro-apoptotic drug with standard antiretroviral therapy. Eligible participants are adults 18–70 with documented HIV‑1 infection and CD4 counts above 300/µL who agree to start and continue ART and follow contraception and condom requirements. The trial will focus on safety and tolerability while measuring reservoir size and viral markers over follow-up.

Who should consider this trial

Good fit: Ideal candidates are ART‑naïve adults aged 18–70 with documented HIV‑1 infection, CD4 counts >300/µL, and willingness to start and remain on ART and comply with contraception and condom requirements.

Not a fit: People already on ART, those with CD4 counts ≤300/µL, pregnant or planning conception, or anyone with prior use of BCL‑2 antagonists or certain pro‑apoptotic cancer therapies are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, this approach could reduce the pool of long‑lived HIV‑infected cells formed at ART initiation and move the field closer to strategies that might allow stopping lifelong ART.

How similar studies have performed: Latency‑reversal strategies to date have not achieved durable reservoir reduction in humans, and while BCL‑2 inhibition has supportive preclinical data, clinical evidence in people with HIV is very limited.

Eligibility criteria

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

Where this trial is running

Aarhus and 1 other locations

• Infectious Diseases, Q Research — Aarhus, Denmark (Recruiting)
• Hospital Universitari Germans Trias I Pujol, Department of Infectious Diseases — Badalona, Spain (Recruiting)

Study contacts

• Study coordinator: Thomas A Rasmussen, Associate professor, MD, PhD

Conditions HIV-1; venetoclax; bcl-2 inhibitor; anti-apoptotic protein