In summary, there is a compelling rationale for investigating venetoclax as an intervention to sensitise virus-expressing cells to apoptosis and thereby reduce the size of the latent HIV reservoir. While this concept may ultimately need to be tested in the setting of concomitant latency reversal, the investigators propose to initially establish the safety of venetoclax in PLWH on ART. The investigators will use this study to also investigate effects of venetoclax monotherapy on proapoptotic pathways, immune effector function and HIV persistence in PLWH on ART and through these studies establish the rationale for subsequent studies testing venetoclax in combination with an LRA.
Documented HIV-1 infection
Age 18-65 years, both included
Receiving combination ART for at least 2 years and being on the same ART regimen for at least 4 weeks at the screening visit
HIV-1 plasma RNA <50 copies/mL for >2 years (documented on at least 2 occasions within the 2 years) and <20 copies/mL at screening. Episodes of a single HIV plasma RNA 50-500 copies/mL will not exclude participation if the subsequent HIV plasma RNA was <50 copies/mL
Current or previous use of a BCL-2 antagonist or other pro-apoptotic agent used as cancer therapy
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)
Single group
Venetoclax
DrugIn this study participants will receive venetoclax 200 mg, 400 mg or 600 mg once daily for 14 days in the dose-escalation phase. In the expansion cohort, the selected max-tolerated dose will be given for three cycles, each consisting of venetoclax daily for 14 days followed by 21 days off.
To determine the safety of venetoclax in PLWH on ART
Incidence of treatment-emerging adverse events (AEs) \>=grade 3 probably or definitely related to study treatment. Safety defined as all other treatment-emerging AEs, graded according to severity and assessed as either not related or possibly, probably or definitely related to study treatment.
To determine the effect of venetoclax on HIV persistence in PLWH on ART
The size of the HIV-1 reservoir using the Intact Proviral DNA Assay (IPDA)
To determine the effect of venetoclax on proapoptotic pathways in PLWH on ART
Activation of pro-apoptotic pathways using cytometry by time of flight (CyTOF) and/or single cell RNA sequencing
Click on the lead sponsor to view all of their trials.
University of Aarhus
Lead sponsor
The Peter Doherty Institute for Infection and Immunity
Collaborator
Walter and Eliza Hall Institute of Medical Research
Collaborator
The Alfred
Collaborator
Aarhus University Hospital
Collaborator
