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

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.

Inclusion Criteria:Documented HIV-1 infectionAge 18-65 years, both includedReceiving combination ART for at least 2 years and being on the same ART regimen for at least 4 weeks at the screening visitHIV-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/mLCD4+ 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 screeningAbility and willingness to provide informed consent and to continue ART throughout the studyFor 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 medicationsAny intrauterine device (IUD) with published data showing that the expected failure rate is <1% per yearMale partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subjectApproved 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 yearAny 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 studyHeterosexually active male if they arewilling to use an effective method of contraception (anatomical sterility in self that is confirmed prior to study entry) oragree 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 therapyAny concomitant disease where venetoclax treatment is indicatedCurrent 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 drugsfor 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 administrationCurrent 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 possibleReceipt of immunomodulating agents (excluding immunisation) or systemic chemotherapeutic agents within 28 days prior to study entryAny 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 studyKnown hypersensitivity to the components of venetoclax or its analoguesAny significant acute medical illness in the past 4 weeksAny evidence of an active AIDS-defining opportunistic infectionIndividuals who intend to modify their ART regimen within the study periodCurrent or recent gastrointestinal disease or gastrointestinal surgery that may impact the absorption of the investigational drugActive alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy or proceduresUnable or unwilling to adhere to protocol proceduresHistory of malignancy or transplantation, excluding adequately treated basal cell carcinomaCo-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 normalSevere hepatic impairment (Class C) as determined by Child-Pugh classificationImpaired renal function with estimated creatinine clearance (eGFR) <50 mL/minSignificant cardiac dysfunctionWomen 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 criteriaThe 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/minPlatelet count ≤100 x109/LAbsolute neutrophil count ≤1.5x109/LHaemoglobin <10,0 g/dLTotal lymphocyte count <800 cells/yLCD4+ T cell count <500 cells/yL