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)

Thomas Aagaard Rasmussen

Status and phase

Not yet enrolling

Phase 1

Conditions

HIV-1

Treatments

Drug: Venetoclax

Study type

Interventional

Funder types

Other

Identifiers

NCT07481175

INITIATE-001

2025-521841-26-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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.

Enrollment

38 estimated patients

Sex

All

Ages

18 to 70 years old

Volunteers

No Healthy Volunteers

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