The AIDS Clinical Trials Group (ACTG), a global clinical trials network focused on HIV and other infectious diseases, announced the opening of a phase 1/2a study evaluating the safety and tolerability of a combination regimen including a therapeutic T-cell vaccine, two broadly neutralizing antibodies (bNAbs), and a toll-like receptor 7 (TLR7) agonist (immune booster) among people living with HIV who started treatment shortly after acquiring HIV.
A5374 (Triple Immune Strategy for HIV Remission) is a multi-site, randomized, placebo-controlled trial. The study is a collaboration with the University of Oxford and Gilead and hypothesizes that the triple active therapy of a novel T-cell vaccine, bNAbs, and a TLR7 agonist will result in greater viral control following analytic treatment interruption (a pause in taking HIV medications that is carefully observed by a research team) compared to placebo.
While current medications can manage HIV very well, none of them can remove HIV from the body. Instead, as long as they are being taken, they keep the virus in check so that it cannot multiply and thereby destroy the immune system. The approach being studied in A5374 is an important part of the path toward a functional cure, which aims to improve the HIV immune response in order to control the virus rebound and reduce the HIV reservoir, which will together offer longer periods of time during which a person living with HIV could stop taking daily medication, in the very best scenario indefinitely.
Professor Tomáš Hanke, Professor of Vaccine Immunology at NDM’s Jenner Institute said: ‘Our vaccines are unusual in that they aim to induce killer T cells targeting functionally conserved regions: We target HIV at its Achilles heel.’
Professor Judith Currier, Professor of Medicine at the UCLA Division of Infectious Diseases, Department of Medicine and ACTG Chair said: ‘Achieving a functional cure is likely to require a combination of novel treatments that will stimulate the immune system to control the virus rebound and simultaneously decrease the number of cells harbouring HIV. A5374 is a pivotal trial and we are hopeful that it will provide us with important insights into mechanisms of functional cure for people living with HIV.’
A5374 will enrol 45 participants of whom 30 will receive active study treatment and 15 will receive placebo, aged 18 years and older who started combination antiretroviral therapy (cART) within 28 days of acute HIV diagnosis (when someone tests positive for HIV very shortly after acquiring HIV). The study will last up to approximately two years for each participant.
After enrollment, participants will continue taking their HIV medications and will either receive a series of treatments including a T-cell vaccine regimen [vaccines vectored by replication-deficient chimpanzee adenovirus ChAdOx1 and poxvirus MVA expressing mosaics of functionally conserved HIV Gag and Pol regions], broadly neutralizing antibodies [GS-5423 (3BNC117-LS) and GS-2872 (10-1074-LS)] and vesatolimod (a TLR7 agonist) or placebo. After about 16 months in the study, participants will stop taking their HIV medications.
They will be closely monitored for increases in HIV viral load, decreases in CD4 T-cell counts, and symptoms, and will resume taking their HIV medications when certain criteria that indicate that their HIV is rebounding are met. The study will compare the length of time that participants in the active treatment and placebo groups can control the amount of HIV in their blood while they are off their HIV medications.
Professor Sharon Riddler, Professor of Medicine at the University of Pittsburgh, and A5374 protocol chair said: ‘Our goal with this study is to demonstrate that enhancing immune responses to HIV will lead to sustained suppression of HIV during treatment interruption.’
Carefully monitored analytic treatment interruptions are an important part of HIV cure clinical trials as they can help determine whether a cure-related research intervention can increase immune function or decrease latent HIV.
A5374 will take place at up to 10 sites in the United States and Brazil. It is sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (which also funds the ACTG), under award numbers UM1 AI068636, UM1 AI107716, and UM1 AI068634.
This study is led by Prof Riddler and Dr Cynthia L. Gay, University of North Carolina (Co-vice Chair) and John Mellors, University of Pittsburgh (Co-vice Chair). The ACTG is led by Dr Currier and Joseph J Eron, University of North Carolina (ACTG Co-Chair).
For more information about A5374, please visit clinicaltrials.gov.