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

NCT06823596 | Recruiting

• 1 other identifier: 46646
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Hiv

Keywords

Tack it on

Outcome Measures

Primary Outcomes (1)

• Change in plasma viremia (viral copies/ml)

  The change in plasma HIV viremia will be compared at baseline (visit 2) versus after 8 weeks of EFV. (visit 7)

  The change in plasma HIV viremia will be compared at baseline (visit 2) versus after 8 weeks of EFV. (visit 7)

Secondary Outcomes (1)

• The change in plasma HIV viremia will be compared at baseline (visit 2) after 8 weeks of EFV. (visit 7) and after EFV is discontinued (Visits 8 to 10).

  compared at baseline and 8 weeks

Study Arms (1)

Addition of Efavirenz in people with high adherence to ART.

OTHER

Single arm - Participants will be prescribed Efavirenz 600 mg q hs x 2 months starting at baseline visit (visit 2)

Drug: Efavirenz 600mg

Interventions

Efavirenz 600mg DRUG

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.

Also known as: Sustiva, Teva-Efavirenz, Mylan-Efavirenz, Jamp-Efavirenz, Auro-Efavirenz

Addition of Efavirenz in people with high adherence to ART.

Eligibility Criteria

• Age: 18 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to provide signed written informed consent; age \>18 years
• Documented HIV diagnosis
• Continuous antiretroviral therapy for \> 4 years with no issues of adherence
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Toronto: lead
• Ontario HIV Treatment Network: collaborator
• Maple Leaf Research: collaborator
• Unity Health Toronto: collaborator

Study Sites (2)

Unity Health Toronto -St. Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

RECRUITING

Maple Leaf Medical Clinic

Toronto, Ontario, M5G 1K2, Canada

RECRUITING

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

efavirenz

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Mario Ostrowski, MD

  University of Toronto

  PRINCIPAL INVESTIGATOR

• Colin Kovacs, MD

  University of Toronto

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andy Mok, RN

CONTACT

416-465-3532; amok@mlmedical.com

Colin Kovacs, MD

CONTACT

416-465-3252; ckovacs@mlmedical.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Depts. of Medicine, Immunology. University of Toronto

Model Details: Pilot study of an already approved HIV drug (Efavirenz), as an addition to current HIV treatment regimen

Study Record Dates

• First Submitted: December 3, 2024
• First Posted: February 12, 2025
• Study Start: January 14, 2025
• Primary Completion (Estimated): November 15, 2027
• Study Completion (Estimated): November 15, 2028
• Last Updated: March 17, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2)