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RECRUITING

NCT06823596

The T Cell Activator of Cell Killing ("TACK") IT ON" STUDY

Sponsor: University of Toronto

View on ClinicalTrials.gov

Summary

Antiretroviral therapy or ART blocks HIV replication reducing plasma viral loads to undetectable levels but has no effect on persistently infected cells in the body, called the virus reservoir. These cells carry infectious HIV capable of restarting HIV replication if therapy is stopped. The reservoir is so stable forcing people to adhere life-long ART. Over 5% of ART adherent individuals continue to have residual non-suppressive viremia (NSV) detected by clinical assays (40-400 copies/ml). Residual viremia reflects a more persistent reservoir and has the potential for increased morbidity. For eg., persistent expression of HIV proteins contributes to inflammation, and can lead to comorbidities. Recently, a novel way to target this reservoir called "TACK" or "Targeted activator of cell killing" is proposed. TACK compounds only target HIV infected cells and directly kill them by inducing a natural killing program (called the inflammasome). Recently the HIV drug, Efavirenz (EFV), which was used to suppress HIV replication for decades, has now been shown to also be a TACK compound. This pilot study will evaluate the impact of Efavirenz (EFV) in reducing HIV persistence by its ability to be a TACK molecule. So in addition to blocking HIV growth, this compound when added to a current ART regimen can kill HIV infected cells in the test tube. We aim to harness this effect to determine whether the addition of EFV to the current ART regimen in people with NSV can suppress the viremia to undetectable levels by killing those cells. NSV represents the "the tip of the iceberg" of those with bigger reservoirs and represents a challenging clinical scenario in dire need of new diagnostic and therapeutic options. This pilot study will spark larger clinical trials to advance HIV cure strategies, and will provide new tools to improve the clinical management of people living with HIV.

Official title: Short-term Addition of Efavirenz to Induce CARD8-mediated Reduction of Persistent Nonsuppressible HIV Viremia in People With High Adherence to ART.

Key Details

Gender

All

Age Range

18 Years - 89 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2025-01-14

Completion Date

2028-11-15

Last Updated

2026-03-17

Healthy Volunteers

Conditions

Hiv

Interventions

DRUG

Efavirenz 600mg

Efavirenz induces pyroptosis of HIV expressing cells via the CARD8 inflammasome. In contrast to most ART drugs, and in addition to its anti-retroviral effect, EFV also induces intracellular Gag-Pol dimerization and premature HIV protease activation, causing cleavage of the inflammasome protein CARD8. CARD8 activation results in the production of effector molecules that rapidly kill virus-infected cells by pyroptosis. This effect of EFV has been called "TACK" or "T cell activator of cell killing". We aim to harness this effect to reduce residual nonsuppresible viremia (NSV) in people on stable antiretroviral therapy (ART). Participants in this study will receive EFV in addition to their stable ART regimen for two months, during and after which we will monitor plasma HIV RNA and markers of viral persistence and immune activation.

Inclusion criteria for participants are: * Ability to provide signed written informed consent; age \>18 years * Documented HIV diagnosis * Continuous antiretroviral therapy for \> 4 years with no issues of adherence * Taking a stable ART regimen, without the inclusion of a protease inhibitor * At least 4 HIV viral loads \>20 and \< 400 copies/ml over the past two years * No documented resistance to EFV in history, no PI including ritonavir in current ART regimen or during study period * No evidence of EFV resistance by plasma virus sequencing at screening visit * Non-pregnant throughout the study period, if female sex * Good general health as shown by medical history and screening laboratory tests at the screening visit: * Hemoglobin ≥ 85 g/L, white blood cell count (WBC) \> 3,000 cells/mm3 * Total lymphocyte count .750 X109/L * Platelets = 50 to 550 X109/L * Chemistry panel: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase \< 5 times the institutional upper limit of normal (ULN); * Willing to undergo either leukapheresis or blood draw at visits 2 and 7 (participants will be given the option to undergo blood draws rather than leukapheresis) * Ability to add efavirenz to their current ART HIV medication re: avoid drug to drug interactions Exclusion criteria There will be no exclusion criteria based on gender/gender identity, ethnoracial composition, language, socioeconomic status, mode of HIV acquisition or sexual orientation/identity. Any participant who requires language interpretation can and will be accommodated for by the participation of translators, either at the patient's choice and/or with the assistance of the translator services provided by local ASO organizations. Exclusion criteria for participants include the following: * Participants who would have difficulty participating in a trial due to non-compliance * No active medications / illicit drugs that could adversely affect study compliance * Currently prescribed and using EFV as part of ongoing ART treatment regimen for HIV suppression * Currently prescribed a protease inhibitor or pharmacologic booster (cobisistat) as part of current ART regimen * History of major psychiatric condition that would be adversely affected by efavirenz * Diagnosed severe cognitive impairment or of strong concern in the judgement of investigators that efavirenz would adversely affect participant * Documented or suspected history of resistance to any NNRTI including efavirenz, nevirapine or rilpivirine * History of severe intolerance or documented allergy to efavirenz * Participants with any of the following abnormal laboratory results at the screening visit: * Hemoglobin \< 85 g/L * Lymphocyte count \< .750 X109/L * Platelet count \< 50 X109/L or \> 550 X109/L * AST or ALT \> 5X the upper limit of normal * Creatinine \> 250 µmol/L * Participants with a malignancy or undergoing chemotherapy * Participants with other significant underlying disease (non-HIV-1) that might impinge upon disease progression or death * Any concurrent condition requiring the continued use of immunoglobulin, antineoplastic agents, glucocorticoids (other than corticosteroid nasal spray for allergic rhinitis; topical or ophthalmic corticosteroids for acute, uncomplicated dermatitis or conjunctivitis; over the counter medications for acute, uncomplicated dermatitis for treatment period not longer than 14 days) or other immunomodulator medications (other than NSAIDS which will be allowed for any length of time) * Active drug or alcohol use/dependence that, in the opinion of the investigator, would interfere with adherence to study requirements * Any illness or conditions including acute illnesses that, in the opinion of the investigator, may affect the safety of the participant or the evaluation of any study endpoints * Any other conditions judged by the investigator that would limit the evaluation of a participant * Any confirmed or suspected immunosuppressive or immunodeficient state (except HIV infection for Group-3), asplenia, recurrent severe infections and chronic use (more than 14 days) immunosuppressant medication within the past six months (topical steroids are allowed)

Locations (2)

Unity Health Toronto -St. Michael's Hospital

Toronto, Ontario, Canada

Maple Leaf Medical Clinic