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.
Documented HIV-1 infection
Age 18-70 years (both included) at screening
CD4+ T cell count >300/µL at screening
ART naïve at screening
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
Parallel
Venetoclax
DrugVenetoclax 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
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
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)
Impact on viral decay and HIV persistence of venetoclax administration in PLWH at the time of ART initiation
Impact of venetoclax administered at the time of ART initiation on cellular apoptosis pathways in PLWH
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Thomas Aagaard Rasmussen
Lead sponsor
University of Aarhus
Sponsor institution
Germans Trias i Pujol Hospital
Collaborator
Walter and Eliza Hall Institute of Medical Research
Collaborator
The Alfred
Collaborator
Aarhus University Hospital
Collaborator
