For December 2024, there were seven updates to TAG’s listing.
New Additions
The lone addition this month is a clinical trial sponsored by the ACTG investigating the capacity of a therapeutic vaccine to promote neutralizing antibody responses against HIV. The vaccine contains a stabilized part of the outer HIV envelope designed to mimic the natural conformation of the protein, delivered with an Alum adjuvant. The construct, called a stabilized CH505 TF chTrimer, has previously been reported to show promise as a preventive vaccine in the SHIV/macaque model. The study isn’t yet open for enrollment, there will be multiple sites in California, Colorado, Georgia, Illinois, Maryland, Massachusetts, Missouri, New Jersey, New York, North Carolina, Ohio, Pennsylvania, Tennessee, Texas, and Washington (see registry entry for location details).
Updates to Enrollment Status
Five studies changed their enrollment status:
- The Tatelo Plus trial in Botswana evaluating dual broadly neutralizing antibodies (bNAbs) in infants, added to the listing in August, is now open and recruiting.
- A ViiV Healthcare-sponsored study of a bispecific bNAb codenamed VH4527079 is closed to further enrollment, the estimated completion date is June 2026.
- A therapeutic vaccine trial at the University of North Carolina has also closed to enrollment. The research is assessing the safety and immunogenicity (ability to induce T cell responses against HIV) of vaccines based on chimpanzee adenovirus (ChAd) and modified Vaccinia Ankara strain (MVA) in people with HIV on antiretroviral therapy (ART). Estimated completion date is February 2025.
- A widely publicized first-in-human study of a CRISPR-based approach to excising HIV from reservoir cells is now completed. Results were presented at the AIDS 2024 conference in July (video is available on the website, see "session recording" link) and reported in a blog post in August.
- A trial of the PD-1 inhibitor ASC22 in China is also now completed; to our knowledge results have yet to be presented. There has been a published report from a separate study combining ASC22 with the HDAC inhibitor chidamide in people with HIV on ART, which suggests that it was relatively well tolerated albeit with some immune-mediated adverse events that are known to be associated with PD-1 inhibitors.
New Links to Study Results
The only new links to results this month are for a paper published in the Journal of Infectious Diseases that draws information from two studies in the listing: the Zurich primary HIV infection cohort and ACTG 5345, a completed assessment of biomarkers that might predict time to viral load rebound in people interrupting ART.
The study authors identify several factors that were associated with shorter time to viral load rebound among study participants, including later ART initiation, higher pre-ART viral load, higher total HIV DNA levels, and increased amounts of HIV transcription (the virus translating DNA into RNA). Immunological factors included lower CD4 T cell counts at the time of ART interruption and higher proportions of short-lived effector T cells and T cells showing evidence of exhaustion and terminal differentiation (no longer able to proliferate and respond as well). These immunological factors only showed significant associations with shorter time to viral load rebound in people who’d started ART early after HIV acquisition, not in individuals treated later.
There were also differences identified based on sex, with greater genetic diversity of HIV in the reservoir associated with shorter time to viral load rebound only in men. The authors note that this may be related to previously described immunological sex differences: “hormonal differences, genetic factors, and variations in immune system functioning could contribute to these discrepancies.” For example, female sex has been associated with higher levels of production of naïve T cells from the thymus across the lifespan, which could conceivably convey a superior ability to mount an immune response to diverse HIV variants.
Studies of cisgender people and transgender people receiving gender-affirming care have the potential to shed light on the role of hormones compared to chromosomal factors in shaping sex-based immunological differences (e.g. see the recent paper on the immunological effects of gender-affirming hormone therapy in transgender men). But the current politically motivated bigoted attacks on the dignity, humanity, and healthcare needs of transgender people are profoundly damaging to efforts to conduct this important research, harming both transgender and cisgender people.
When the study authors constructed a multivariable model based on their results, the two parameters that emerged as most significantly predictive of shorter time to viral load rebound were levels of HIV DNA and terminally differentiated CD8 T cells. They conclude by stating:
“In summary, our findings collectively highlight the complex interplay between virologic and immunologic factors in determining HIV rebound dynamics especially in participants who started ART during chronic HIV, emphasizing the importance of early ART initiation. Further, it will be important to considered demographic (e.g., sex at birth) and immune profiles (e.g., minimize T cell activation and exhaustion) to optimize treatment outcomes and inform strategies towards achieving sustained viral suppression or eradication.”
Toward the end of 2024 there were two meetings on the topic of HIV cure research: the Joint Meeting of the Martin Delaney Collaboratories (MDCs) in November and the HIV Persistence Workshop in December. The agenda and abstracts are available for the MDC meeting, along with video of each day (day 1, day 2, day 3). Abstracts from the HIV Persistence Workshop have been published as a supplement to the Journal of Virus Eradication – links to any abstracts reporting on studies in TAG’s listing will be added next month.
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