There were 14 updates to TAG’s listing for October 2024.
New Additions
Two new clinical trials were identified in registries, neither yet open for enrollment:
Researchers in the UK are initiating a study of the anti-CMV drug letermovir primarily to assess effects on T cell activation in people with HIV on antiretroviral therapy (ART). Markers of HIV persistence will also be measured as secondary endpoints. The trial appears similar to a previous pilot protocol conducted by Peter Hunt and colleagues, which reported evidence of modulation of inflammatory pathways but didn’t document changes of sufficient magnitude to meet pre-specified criteria for expanding the number of participants (see prior blog post from March 2024).
IAVI has registered a new trial that plans to investigate an HIV vaccine candidate based on an adenovirus variant derived from gorillas. The study will recruit people with HIV on ART and a cohort of HIV-negative participants. The modified gorilla adenovirus serves as a vector for delivering selected HIV components known to induce CD8 T cell responses. The main outcome measures will be safety and levels of vaccine-induced HIV-specific T cells. For the cohort of people with HIV, individuals with past CD4 nadirs (lowest ever values) less than 200 are excluded, presumably based on concerns that immune responses to the vaccine might be diminished.
Updates to Enrollment Status
A multi-site protocol investigating infusions of HIV-specific T cells for people undergoing autologous stem cell transplantation to treat HIV-associated lymphoma is now closed to further recruitment. The research is sponsored by Dr. Catherine Bollard at the National Heart, Lung, and Blood Institute (NHLBI) and has an estimated final completion date of June 2026.
A study of the immune checkpoint inhibitors nivolumab and ipilimumab in people with HIV and relapsed or refractory cancers has been stopped, with the reason given as “inadequate accrual rate.” The trial was sponsored by the AIDS Malignancy Consortium and recruited enough participants to publish several conference abstracts and papers reporting on safety and effects on the HIV reservoir (see table entry for registry # NCT02408861 for complete links).
New Links to Study Results
Results from two trials in the listing were presented at the recent HIVR4P conference in Lima, Peru:
Jorge Gallardo-Cartagena described findings from a study involving participants who acquired HIV during the Antibody-Mediated Prevention (AMP) trial at sites in Peru. A total of 18 participants who started ART early and maintained viral load suppression for at least a year were enrolled. The demographics reflected the diversity of participants in the parent AMP trial and included 14 men who have sex with men, three transgender women, and one gender non-conforming individual.
All participants underwent an analytical treatment interruption (ATI) to assess whether receipt of the broadly neutralizing antibody VRC01 prior to HIV acquisition delayed or reduced viral load rebound after an ATI. Gallardo-Cartagena reported that the average time to viral load rebound above 200 copies/ml was 4.1 weeks, and the average time to reaching ART restart criteria was 7.9 weeks. There were no significant differences between participants who received VRC01 in the AMP trial and those who were in the placebo arm.
There was one adverse event related to the ATI, an acute retroviral syndrome associated with a rapid rise in viral load from 1,450 to 679,000 copies/ml which prompted immediate reinitiation of ART. There were four cases of participants resuming ART at their request and one due to clinician request, although biomarker criteria for restarting hadn’t been met. This represents a higher proportion of participants returning to ART by request than has typically been the case historically in ATI studies and this may be an issue to pay attention to as this type of protocol expands into new geographic locations where there may be less familiarity with HIV cure-related research.
Aljawharah Alrubayyi from the Ragon Institute of Mass General, MIT and Harvard presented a new analysis of results from a therapeutic HIV DNA vaccine study conducted at the University of California San Francisco (UCSF). Alrubayyi reported that the PENNVAX construct induced new CD8 T cell responses targeting conserved HIV proteins in a small subset of participants (11%). This type of CD8 T cell response has previously been associated with immune control of HIV, suggesting that additional research could help shed light on both the anti-HIV efficacy of the vaccine-induced CD8 T cells and strategies for increasing the rate of the response among vaccine recipients.
Links to published results were added for nine studies in the TAG listing:
Anastasia Korolkova and colleagues evaluated how participants in an HIV cure-related ATI study at UCSF recalled and appraised the risks, benefits, and purpose of the protocol. The investigators found a high level of recall and highlighted the important role of the study staff in communicating key information about participation. There was no evidence that participants had mistaken expectations about being cured as a result of joining the study (referred to as therapeutic misconception). The results were published in the journal AIDS and Behavior.
In the journal Cell Reports Medicine, Tim Henrich and colleagues shared results from an ACTG trial of sirolimus in people with HIV on ART. Sirolimus belongs to a class of drugs called mTOR inhibitors which are known to suppress T cell proliferation, and is most commonly used to prevent organ transplant rejection. There were two serious adverse events among 30 participants who received at least one dose: stomatitis and elevated fasting glucose. Additionally, one participant experienced a decrease in CD4 T cell counts to below 300 cells.
A total of 16 participants completed the full planned 20 weeks of sirolimus dosing, experiencing an average decline of 118 CD4 T cells but also an average reduction in HIV DNA levels of 31%. Immune-modulating effects included reduced CD4 T cell proliferation and decreased expression of the immune checkpoint PD-1 on CD8 T cells. The researchers note that the side effect profile is problematic, but suggest that lower doses in combination with other approaches might still have a role to play in HIV cure research.
A belated link addition for four trials in the listing is a paper published in Clinical Infectious Diseases back in 2020. The research analyzed the central nervous system (CNS) safety of ATIs among participants in four different studies conducted in Thailand. By most measures there were no apparent adverse effects in terms of inflammation in the CNS or cognitive performance, but magnetic resonance spectroscopy (MRS) did reveal evidence of mild cell membrane damage in the basal ganglia. Due to lack of extended of follow up, the researchers weren’t able to investigate whether this resolved with additional time on ART after the ATI. The abstract concludes: “Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.”
A French study of twice-daily cannabidiol full-spectrum oil in people with HIV on ART has published results from a quality of life analysis showing limited effects. The protocol included measurements of the HIV reservoir and immunological parameters as secondary endpoints, but the initial paper doesn’t include information addressing those outcomes.
The final addition to mention is a link to Rachel Presti’s AIDS 2024 conference presentation of results from the first clinical trial of EBT-101, a CRISPR approach targeting the HIV reservoir. The outcomes were reported in our August 2024 update, and a recording is now available on the conference website.
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