There are ten updates in the May 2024 revision to TAG’s listing. No new HIV cure-related clinical trials or observational studies were identified in registries this month, and one protocol was withdrawn: a combination study codenamed RV582 sponsored by the US Military HIV Research Program (MHRP). No explanation for the withdrawal is provided in the registry entry except “protocol was changed during development.”
Updates to Enrollment Status
A clinical trial investigating the approved anti-cancer drug venetoclax in people with HIV on antiretroviral therapy (ART) is now open for enrollment. The background to the research was covered on the blog in January of 2023 when the trial was first entered into clinicaltrials.gov; the aim is to evaluate whether venetoclax can promote the death of HIV-infected cells. At the moment the only listed study location is the University of Aarhus in Denmark, but as noted by Dr. Jillian Lau in a presentation at the recent Pre-CROI Community HIV Cure Research Workshop the plan is to add a site in Melbourne Australia.
Several studies in the listing have closed to new enrollment:
- The MHRP HVRRICANE trial in South Africa, which is investigating the effects of therapeutic HIV vaccines on the HIV reservoir in children and adolescents nine years and above. Preliminary safety results were presented at CROI earlier this year.
- A MacroGenics study of two dual-affinity re-targeting (DART) proteins (MGD020 and MGD014) designed to recognize and promote clearance of HIV-infected cells.
- The phase I first-in-human trial of EBT-101, a CRISPR/Cas9 gene editing tool intended to target and disable or remove HIV DNA from infected cells. This research has attracted considerable publicity, with very limited safety information on the first two participants presented last year. The original estimated enrollment target was nine participants, but the study has closed to new enrollment with six participants according to the registry entry. The principal investigator Rachel Presti is giving a presentation about the trial at the upcoming AIDS 2024 conference during a session on the use of gene therapy in HIV cure research on July 25th.
Additionally, an observational study at Mount Sinai in New York City has switched to enrolling by invitation; the research appears to be recruiting specifically from ongoing local interventional trials that are administering experimental broadly neutralizing antibodies (bNAbs). The goal is to assess effects specifically on gut-associated lymphoid tissue (GALT).
New Links to Study Results
Links to newly published results were added for five studies in the listing.
Researchers in China investigated the combination of chimeric antigen receptor (CAR) T cells (a gene therapy approach) and the candidate HIV latency-reversing agent chidamide (an HDAC inhibitor approved for the treatment of certain cancers in China). Their paper, published in the journal Cell Discovery, reports that administration of CAR T cells targeting HIV appeared to reduce the amount of HIV RNA generated by the repeated administration of chidamide. These results may be encouraging but it’s important to appreciate that this method of analyzing the activity of CAR T cells against HIV is novel and may have limitations – the amount of HIV RNA generated by receipt of HDAC inhibitors can be variable even in the absence of other interventions. In a separate analysis, measurements of the HIV reservoir using cell-associated HIV RNA showed evidence of a decline between baseline and the end of the study in a subset of ten participants (a little more than half the study cohort).
An analysis of neutralizing antibody responses targeting HIV after early ART has been published by Gregory Whitehill and colleagues in the Journal of Clinical Investigation. Participants were drawn from a study investigating rapid ART initiation after HIV acquisition at the University of California San Francisco (UCSF) led by Sulggi Lee. The researchers found that people who started ART very early (less than 60 days after HIV acquisition) didn't develop antibody responses capable of neutralizing HIV from their samples (called autologous neutralizing antibody responses). In contrast, most participants who initiated ART a little later – between 60 and 128 days after HIV acquisition – did develop autologous neutralizing antibody responses. In discussing their findings, the authors note that there appears to be a threshold of exposure to HIV viral load required to generate neutralizing antibodies and raise the possibility of using therapeutic vaccines to promote and accelerate the process.
A new publication in the journal AIDS from the ACTG’s large study of early ART initiation confirms that levels of the HIV reservoir (measured by a very sensitive test for HIV DNA) are reduced but not eliminated even in those starting earliest (at the Fiebig I stage). The authors note: “These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods.”
Finally a paper in the European Journal of Immunology reports on analyses of gut bacteria in people with HIV receiving the toll-like receptor 7 agonist vesatolimod in two clinical trials (NCT03060447 and NCT02858401). The investigators state that vesatolimod appeared to beneficially modulate the presence of different gut bacteria in samples from people who were naturally controlling HIV. Additionally, the presence of certain bacteria was associated with HIV viral load rebound in study participants who underwent an analytical ART interruption. Further research will be needed to validate and better understand these results.
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