The April 2024 update to TAG’s listing features eight changes.
New Additions
Three new studies were added this month. All are protocols being initiated by the U.S. government-funded ACTG Network (formerly known as the AIDS Clinical Trials Group, recently revised to Advancing Clinical Therapeutics Globally).
The Antiretrovirals Combined With Antibodies for HIV-1 Cure In Africa (ACACIA) trial will evaluate a combination of two long-acting broadly neutralizing antibodies (bNAbs), 3BNC117-LS and 10-1074-LS, with infusions given at the time antiretroviral therapy (ART) is initiated. After 24 weeks, eligible participants will have the option to undergo an analytical treatment interruption (ATI) to assess capacity to control HIV viral load in the absence of ART. The study aims to build on evidence that giving bNAbs when ART is first started can accelerate depletion of the HIV reservoir.
According to the listing, the study is pending and not yet open for enrollment. No location information is provided but the ACTG website indicates there are sites in Botswana, Malawi, and South Africa. The trial will enroll 135 participants, making it one of the largest cure-related protocols with an ATI (and the largest on the African continent), second only to an ongoing international study sponsored by the pharmaceutical company AbbVie which plans to recruit 140 people.
The ACTG has also launched a study of a “triple immune regimen” that consists of therapeutic vaccines, bNAbs, and vesatolimod (an immune-modulating toll-like receptor 7 agonist) in people who initiated ART within 28 days of being diagnosed with acute (recently acquired) HIV. The trial similarly involves an ATI to evaluate whether the interventions can enhance immune system control of HIV viral load. Enrollment is open and the intent is to recruit 45 participants at sites in the U.S. and Brazil.
The final addition is an ACTG observational protocol for any participants in these or other network (or related) trials who experience sustained (at least 24 weeks) low viral load levels after receiving a cure-related intervention and undergoing an ATI. The exact definition of low viral load will be based on the criteria used by the studies they were participating in, but the level cannot have risen to over 1,000 copies/ml for four or more consecutive weeks and CD4 T cell counts must be greater than 350.
All three of these studies had been entered into the clinicaltrials.gov registry over the past few months, but a glitch with the search function of the recently overhauled website meant that we failed to identify them in searches of the database for “HIV” because the condition they’re listed under is “HIV-1-infection” and they fail to appear in results. The search function on the old “classic” version of clinicaltrials.gov doesn’t make the same error, which is something to be aware of for anyone who uses the registry to track HIV-related clinical research.
Updates to Enrollment Status
The RHIVIERA-02 study in France is now open for enrollment. The investigators are recruiting people with recently acquired HIV and testing whether giving the long-acting bNAbs 3BNC117-LS and 10-1074-LS at the time of ART initiation can lead to control of viral load during a subsequent ATI (after at least 52 weeks on treatment).
A clinical trial of baricitinib that was temporarily suspended is now open for enrollment at two sites in Atlanta. Baricitinib belongs to a class of drugs called Janus kinase inhibitors and is FDA-approved to treat severe rheumatoid arthritis and several other conditions. The HIV study is sponsored by William Tyor at Emory University, based on findings from laboratory experiments in humanized mice indicating that baricitinib has the potential to cross the blood-brain barrier and reduce viral persistence in the central nervous system. The trial will investigate if similar effects can be obtained in people with HIV, using blood samples, neurocognitive testing, magnetic resonance imaging (MRIs), and lumbar punctures.
Completed Studies
Occasionally research studies only get added to registries after completion, presumably due to an oversight. This is the case for AVIR, an observational study measuring the HIV reservoir in a large cohort of adolescents in Cameroon living with locally prevalent HIV clades. Results were published in the Journal of Virus Eradication on March 30, reporting that earlier ART initiation (within the first year of life) and longer duration of treatment (>9 years) were associated with smaller reservoirs as measured by HIV DNA. The researchers also identified modest correlations between levels of HIV DNA and HIV RNA, with higher viral loads linked to larger reservoirs.
New Links to Study Results
A link was added to another abstract from last month’s Conference on Retroviruses and Opportunistic Infections (CROI): Leah Carrere from the Ragon Institute presented a poster on a participant from the eCLEAR trial who has now maintained post-treatment control of HIV viral load for over five years after interrupting ART (the trial is completed and the primary results were published in Nature Medicine in 2022). Carrere also gave a brief talk during a poster discussion session at the meeting, which is now available for viewing via webcast (all the CROI materials were made publicly available on April 8th).
The study found evidence that cells containing intact, viable copies of HIV potentially capable of causing viral load rebound had been depleted by the individual’s immune responses, leaving behind a viral reservoir constricted in its ability to emerge and replicate. The constriction is a consequence of the HIV genetic code being integrated into areas of the cell’s DNA genome that are largely inactive, preventing the virus from hijacking the cell’s genetic machinery to make new copies of itself. A similar phenomenon has been reported in the two cases of HIV elite controllers who appear to have cleared all viable HIV from their bodies over time (Loreen Willenberg and the Esperanza Patient), and in some studies of people on long-term ART as well as in a small trial of panobinostat and alpha interferon (see also last month’s blog post and Tim Murphy's interview with Marie Armani-Tourret, Ph.D. for TheBody.com).
Results from a study of very early ART initiation being conducted at the University of California San Francisco that were presented at the IAS 2023 conference are now available as a preprint from medRxiv. Preprint means that the report has not yet been reviewed by scientific peers (a full publication in a peer-reviewed journal typically follows). The study documents a faster decline in levels of both intact and defective HIV after very early ART compared to studies of people who started treatment later.
Davey Smith and colleagues from the University of California San Diego have published their findings from a clinical trial that assessed the capacity of influenza and pneumococcal vaccines to essentially act as latency-reversing agents by stimulating the HIV reservoir to produce viral RNA. The analysis revealed that neither vaccine had significant effects on HIV RNA levels.
Lastly, 157 participants in the observational HEATHER (HIV Reservoir targeting with Early Antiretroviral Therapy) cohort study in the United Kingdom contributed samples to an analysis of the prevalence of resistance to the bNAb 10-1074, which is under investigation in multiple cure-related trials (the work was published in the journal Frontiers in Immunology).
The researchers found that HIV samples from around a third of the participants displayed genetic mutations associated with resistance to 10-1074, with evidence that the prevalence is increasing over time. Echoing previous reports, the study also documented that HIV from non-B clades (specifically CRF01-AE) displayed higher levels of resistance to 10-1074. The authors note that predicting resistance to bNAbs based on genetic analyses can be complex, and emphasize that improved tools are needed to screen potential recipients for baseline resistance to bNAbs.
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