Since 2014, TAG has maintained an online listing of HIV cure-related clinical trials and observational studies, drawing information primarily from the clinicaltrials.gov registry. The listing is updated monthly. Studies are included based on the registry descriptions and the outcomes being assessed (study endpoints), with measurements of the HIV reservoir representing the most common reason for inclusion.
The listing contains a large amount of information and can be difficult to follow if you’re not familiar with the field of HIV cure research. To help provide some context, TAG creates an annual summary and explainer in the form of our Research Toward a Cure and Immune-Based Therapies Pipeline Report. Starting this year, we’re aiming to supplement this coverage by providing background information on each monthly update to the listing via this blog.
The January 17, 2023, update includes two newly registered cure-related studies.
The first is an interventional trial in which participants on antiretroviral therapy will receive venetoclax, a drug that is approved for the treatment of blood cell cancers. Venetoclax inhibits or antagonizes BCL-2, a protein involved in promoting the survival of white blood cells by inhibiting apoptosis (a mechanism of cell death).
The rationale for the study is based on evidence from laboratory and animal studies indicating that CD4 T cells containing integrated HIV—the cells that constitute the main HIV reservoir that persists despite ART—have high levels of the BCL-2 protein and are resistant to apoptosis. In both the laboratory dish and the humanized mouse model, venetoclax has been shown to promote the death of HIV-infected CD4 T cells, when HIV is actively making viral proteins.
The human trial is being led by Thomas Rasmussen from Aarhus University in Denmark in collaboration with Sharon Lewin from the Doherty Institute at the University of Melbourne in Australia. The plan is to recruit participants in both locations. Venetoclax will be given daily in 14-day cycles of escalating doses (200mg, 400mg, 800 mg), with each dose increase only proceeding if safety is established at the lower dose.
The primary goal is to evaluate the safety of venetoclax in people with HIV on ART because the drug can cause a range of side effects. Secondary outcome measures include the size of the HIV reservoir and any effects of venetoclax on cell pathways involved in promoting apoptosis.
If the results support further research in people with HIV, the researchers will consider investigating venetoclax in combination with latency-reversing agents. This plan is based on the evidence that venetoclax’s ability to promote the death of HIV-infected cells requires the virus to be actively making viral proteins. Current information on the HIV reservoir in people on ART suggests that some cells actively make viral proteins (at least intermittently) whereas others contain HIV that is completely latent (inactive). The researchers believe that in this latter group of reservoir cells, HIV may need to be awakened by a latency-reversing agent to enable venetoclax to promote cell death.
The second new entry in the listing is an observational study, in which researchers led by Barbara Ensoli at the Istituto Superiore di Sanità in Italy are conducting long-term follow-up of people with HIV who received an experimental therapeutic HIV vaccine in a completed trial conducted in South Africa. The primary aim is to assess the persistence of immune responses against the HIV Tat protein contained in the vaccine more than 10 years after administration. Secondary measures include CD4 T cell counts, HIV viral load, and HIV reservoir size.
An ongoing trial of the anti-cytomegalovirus (CMV) drug letermovir (trade name Prevymis) sponsored by the ACTG has temporarily suspended recruitment - this is not due to any problem but reflects a planned pause to evaluate the effects of the drug on inflammatory markers among the first 40 participants before deciding whether to continue enrollment.
Additional updates to the listing include links to a newly published scientific paper describing the ongoing 2000HIV observational study. Led by researchers at Radboud University in the Netherlands, the study represents an ambitious effort to use the latest multi-omics tools to “comprehensively identify environmental, host genetic and non-genetic pathways and mechanisms that impact HIV-related comorbidities and the size of the viral reservoir.”
Lastly in the January 2023 update, three studies shift into the table for research that has been completed or ended:
- An investigation of the effect of N-803, an enhanced version of the cytokine IL-15, on lymph node B cell follicles in people with HIV on ART. Conducted by Timothy Schacker and colleagues at the University of Minnesota, results are pending.
- A French observational study exploring whether a cell surface protein, CD32a, may help identify CD4 T cells containing HIV has been terminated. The reason cited in the registry entry is: “no interesting results.” The original research suggesting CD32a as a potential marker of the HIV reservoir was controversial, and the premature end of this study may suggest that this line of investigation has not panned out.
- A small Canadian study of cannabinoid capsules in people with HIV has published initial results, reporting mostly good tolerability but safety concerns in two participants. Measures of the HIV reservoir were included in the trial but will be reported in future papers. A larger ongoing study in France is currently investigating the effects of cannabidiol administration on the HIV reservoir, inflammation, and autophagy (a complex mechanism involved in cell survival).
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