The April 2023 update to TAG’s HIV cure-related clinical research listing adds five new studies, two involving interventions and three observational.
Researchers at the University of Sao Paulo General Hospital in Brazil are opening a study of a therapeutic HIV vaccine based on dendritic cells (DCs). DCs are immune system cells tasked with initiating the immune response against pathogens like HIV, and the researchers aim to exploit this aspect of their function to bolster anti-HIV immunity and potentially enhance control of viral load after an antiretroviral therapy (ART) interruption. DCs are sampled from participants, cultured in a laboratory to promote their immune-stimulating function, exposed to HIV protein fragments sampled from the intended recipients, and then infused in large numbers.
The goal is to induce highly functional CD4 and CD8 T cell responses targeting HIV. The approach was tested as part of a combination regimen in a prior trial, with the researchers reporting encouraging preliminary results. The new trial will divide 30 participants into three arms: one will receive placebo (dummy infusion), one will receive dendritic cells (called alpha-type-1 polarizing dendritic cells or aDC1 for short), and the third will receive aDC1 and then undergo an analytical treatment interruption (ATI). Primary outcome measures will be safety and viral load and CD4 counts after ATI.
A trial of dasatinib, a tyrosine kinase inhibitor drug approved for the treatment of certain forms of chronic myelogenous leukemia and acute lymphoblastic leukemia, is being initiated at Hospital Universitari Germans Trias i Pujol in Barcelona, Spain. The rationale is based on previously published evidence that dasatinib therapy for cancer in people with HIV is associated with a smaller HIV reservoir and a reduced ability to reactivate viable HIV from latently infected cells. Proposed mechanisms include enhancement of the activity of an innate antiviral enzyme, SAMHD1 (by preventing phosphorylation of the enzyme), immunomodulatory effects on natural killer cells and T cells, and possibly also a reduction in the proliferation of HIV-infected CD4 T cells.
The main aim of the trial is to investigate safety and effects on SAMHD1 in people with HIV on ART, with secondary outcome measures assessing any impacts on the HIV reservoir. Another clinical study of dasatinib in people with HIV was registered in September 2022 and is also taking place in Spain. The design is slightly different, involving recruitment of people with recent HIV infection who’ve not yet started ART. Participants will receive dasatinib or placebo for a total of 16 weeks, with the first four-week period occurring prior to initiating an ART regimen.
Newly added observational studies are:
- The EARTH study (part of the larger EPIICAL project), which has enrolled children treated with ART within 90 days of birth. The goal is to assess virus and immune system parameters to identify potential participants for cure-related interventional trials. The study is sponsored by the PENTA Foundation and is taking place in South Africa, Mali, and Mozambique. The listed start date is May 2018 and participants are no longer being recruited, suggesting that the registry record has been created somewhat belatedly.
- MERCI (measuring the HIV-1 reservoir during cure interventions studies) is an observational study planned at Ghent University Hospital that will conduct detailed evaluations of the HIV reservoir using blood and tissue sampling (lymph node and colon biopsies) from 30 participants, before and after receipt of cure-related interventions in other (unspecified) trials.
- Similarly, a study at Icahn School of Medicine at Mount Sinai Hospital in New York City is investigating the HIV reservoir and immune system parameters in the gastrointestinal-associated lymphoid tissue (GALT) of eight participants in cure-related interventional trials (again, the specific interventional trials from which the participants are being recruited are not named).
Completed Studies
Multiple entries in the listing were shifted into the “completed studies” table this month. These include a first-in-human trial of a gene therapy approach developed by American Gene Technologies that aims to protect HIV-specific CD4 T cells (the cells responsible for coordinating the immune response against HIV) from infection and disruption by the virus. Preliminary results were published in Frontiers in Medicine in November 2022. Study participants were offered the opportunity to move into a follow up protocol involving an ATI, which remains ongoing.
IMPAACT P1107 was a study that sought to identify donor cells with the CCR5Δ32 mutation for people with HIV requiring stem cell transplants for life-threatening cancer diagnoses. The research project led to the widely publicized fourth case of a likely cure of HIV infection by this method, in a woman of mixed race in New York City. The case was described in detail in a paper published in the journal Cell last month. The paper notes that there was one other participant in P1107, a middle-aged man with HIV who died after a relapse of Hodgkin’s lymphoma within a year of receiving the stem cell transplant.
One observational study — ANRS CO24 OncoVIHAC — was moved to the completed table in error because the registry record hasn’t been updated since January 2018. After reaching out by email to investigators, Dr. Olivier Lambotte kindly replied to let us know that the research is still ongoing. The error will be corrected when the listing is updated again next month.
Two additional studies were moved to the completed table due to out-of-date registry records:
- Albuvirtide + 3BNC117 (registry identifier NCT04819347)
- Euphorbia kansui (registry identifier NCT04503928)
Neither was ever listed as open for enrollment and study contacts haven’t responded to email inquiries, so it’s not known if the trials went ahead as planned. We’ll continue to attempt to find out more information and update the table entries if successful.
Results
Results have been published from a completed study of valproic acid and pyrimethamine as candidate latency-reversing agents. Pyrimethamine is an old, FDA-approved antiparasitic drug used for the treatment of toxoplasmosis that has been shown to inhibit a cellular mechanism involved in maintaining HIV latency (the BAF complex). In an article published in the open access journal Science Advances, the investigators report evidence of “a rapid, modest, and significant increase in [cell-associated unspliced] HIV-1 RNA in response to pyrimethamine exposure.” The finding suggests that the drug could have a role in reactivating latent HIV, although the authors note that there was no evidence of a reduction in the size of the HIV reservoir. Valproic acid did not show any significant effects.
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