Short-term Addition of Efavirenz to Induce CARD8-mediated Reduction of Persistent Nonsuppressible HIV Viremia in People with High Adherence to ART.
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.
• 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