Administration of Venetoclax to Promote Apoptosis of HIV-infected Cells and Reduce the Size of the HIV Reservoir Among People Living With HIV on ART

Inclusion Criteria: * 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 * CD4+ T cell count \>500 cells/yL at screening and at least two CD4+ T cell counts \>500 cells/yL in the 24 months prior to screening * Ability and willingness to provide informed consent and to continue ART throughout the study * For potential study participants who anticipate receiving a SARS-CoV-2 vaccine within the study period, enrolment and commencement of study therapy will be postponed until 4 weeks after completing SARS-CoV-2 vaccination, whereas screening procedures can be initiated before or concurrently with SARS-CoV-2 vaccination. * A female, may be eligible to enter and participate in the study if she: * Is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or, * Is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy: * Complete abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all study medications * Any intrauterine device (IUD) with published data showing that the expected failure rate is \<1% per year * Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject * Approved hormonal contraception (Where other medications to be used in the study (e.g., efavirenz and darunavir) are known, or are likely, to significantly interact with systemic contraceptives, resulting in decreased efficacy of the contraceptive, then alternative methods of non-hormonal contraception are recommended) * Any other method with published data showing that the expected failure rate is \<1% per year * Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of study therapy. * 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 * Heterosexually active male if they are * willing to use an effective method of contraception (anatomical sterility in self that is confirmed prior to study entry) or * agree on the use of an effective method of contraception with an effective failure rate of \< 1% by his partner (hormonal contraception, intra-uterine device (IUD), or anatomical sterility) from the day prior to the first dose and for at least 2 weeks after discontinuation of study drug. Exclusion Criteria: * 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) * Current use of any strong inhibitor of the P-gp drug efflux pump (this includes cobicistat, ritonavir, azithromycin and clarithromycin) * current use of drugs that are P-gp substrates (such as TDF, TAF and dolutegravir) is allowed but will require venetoclax dosing at least 6 hours after intake of those drugs * for study participants receiving TDF or TAF we will perform enhanced renal monitoring by quantifying estimated glomerular filtration rate (eGFR) at each study visit during venetoclax administration * Current use of strong CYP3A4 inducers (such as carbamazepine, phenytoin, rifampicin and St. John's wort); moderate CYP3A4 inducers (such as bosentan, efavirenz, etravirine, 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 significant acute medical illness in the past 4 weeks * 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 or C (Individuals with prior hepatitis C infection that is now cleared are eligible for enrolment) * 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) * Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN) * eGFR \<50 mL/min * Platelet count ≤100 x109/L * Absolute neutrophil count ≤1.5x109/L * Haemoglobin \<10,0 g/dL * Total lymphocyte count \<800 cells/yL * CD4+ T cell count \<500 cells/yL