HIV-1 infection MedDRA version: 20.1 Level: LLT Classification code 10068341 Term: HIV-1 infection System Organ Class: 100000004862
Conditions
Interventions
Trade Name: Venetoclax
Pharmaceutical Form: Tablet
INN or Proposed INN: Venetoclax
CAS Number: 1257044-40-8
Current Sponsor code: AMB-001
Other descriptive name: AMBER
Concentration unit: mg milligram
Sponsors
Aarhus University Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
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 2 years (documented on at least 2 occasions within the 2 years) and 500 cells/?L at screening and at least two CD4+ T cell counts >500 cells/?L 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: o 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, o 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 ? Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide) ? Any intrauterine device (IUD) with published data showing that the expected failure rate is =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: An individual who meets any of the following criteria will be excluded from participation in this study. Study participants receiving cobicistat or a protease inhibitor may opt to switch their ART regimen away from those drugs to allow study participation if this is deemed reasonable by their treating physician but will need to maintain their new regimen for at least 4 weeks prior to enrolling in the study. • 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 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) o 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 o 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 • Currently pregnant, breastfeeding or unwilling to use barrier contraception • 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 wee
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the safety of venetoclax in PLWH on ART ;Secondary Objective: To determine the effect of venetoclax on HIV persistence in PLWH on ART To determine the effect of venetoclax on proapoptotic pathways in PLWH on ART;Primary end point(s): •Safety defined as treatment-emerging adverse events (AEs) ?grade 3 (as cited as dose limiting toxicities section 4.2) 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;Timepoint(s) of evaluation of this end point: 2Q2025 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • The frequency of peripheral blood CD4+ T cells containing total and intact HIV-DNA using real-time PCR and the Intact Proviral DNA Assay (IPDA) • The proportion of cells containing constitutive and inducible cell-associated multiply spliced HIV RNA (MS HIV-RNA) using the tat/rev induced limiting dilution assay (TILDA) • The level of cell-associated unspliced HIV RNA (CA-US HIV RNA) in peripheral blood CD4+ T cells using real-time PCR • Numbers and proportions of B cells, total lymphocytes, CD8+ T cells and CD4+ T cells including memory subsets • Plasma levels of venetoclax • The maximal tolerated dose of venetoclax as determined in the dose-escalation cohorts A-C;Timepoint(s) of evaluation of this end point: 2Q2025 | — |
Countries
Australia, Denmark
Contacts
Public ContactDanish Inclusion Site
Aarhus University Hospital
Outcome results
None listed