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)

Prior treatment

• 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 strong inhibitor of the P-gp drug efflux pump (this includes cobicistat, ritonavir, azithromycin and clarithromycin)
• 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
• 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
• 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)

Other illness

• Evidence of or strong suspicion that HIV infection was acquired during active PrEP use
• Current use of any HIV protease inhibitor (due to CYP3A4 inhibition)
• Known hypersensitivity to the components of venetoclax or its analogues
• Any evidence of an active AIDS-defining opportunistic infection
• History of malignancy or transplantation, excluding adequately treated basal cell carcinoma
• For individuals with isolated anti-HBcAb (cleared hepatitis B), the chosen ART regimen must include TDF or TAF
• Severe hepatic impairment (Class C) as determined by Child-Pugh classification
• Significant cardiac dysfunction

Lab values

• Impaired liver function with AST or ALT \>3 times upper limit of normal
• Impaired renal function with estimated creatinine clearance (eGFR) \<50 mL/min
• 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

Other

• An individual who meets any of the following criteria will be excluded from participation in this study.
• 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
• Individuals who intend to modify their ART regimen within the study period
• Unable or unwilling to adhere to protocol procedures
• 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

• 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