For September 2024 there are six updates to TAG’s listing:
New Additions
One new study was registered over the past month, a protocol for conducting analytical treatment interruptions (ATIs) in people with HIV who’ve received successful stem transplants to treat cancers. The criteria require that the stem cell transplants were sourced from donors homozygous for the CCR5Δ32 mutation (as has occurred in the majority of cases of HIV cures achieved under these circumstances). The research is sponsored by the University of Kansas Medical Center and led by principal investigator Dr. Wissam El Atrouni. The study hasn’t yet opened for enrollment but the protocol has been designed for a specific local candidate; the researchers are open to additional recruitment if other potential participants are identified.
Updates to Enrollment Status
An ACTG study of the long-acting broadly neutralizing antibodies (bNAbs) VRC07-523LS and PGT121.414.LS plus antiretroviral therapy (ART) is now open for enrollment. The protocol aims to recruit 48 participants with acute HIV (acquisition <90 days prior to screening) at sites in the United States, Brazil, and Peru. As noted by Katherine Bar in a presentation at this year’s pre-CROI community HIV cure research workshop, an ATI will be conducted after receiving the combination but the scheduling will be based on real-time assessment of how quickly the levels of the bNAbs decline – the minimum duration of treatment prior to ATI will be 48 weeks, but may extend to 60, 72, 84 or 96 weeks. The primary endpoints are safety and time from ART discontinuation to HIV viral load reaching ≥1,000 copies/ml for four consecutive weeks during the ATI.
Researchers and advocates from the ACTG’s Partner Protections Working Group (PPWG) have also just published on their updated toolkit for mitigating HIV transmission risks during ATIs.
New Links to Study Results
At the IAS 2023 conference, Asier Sáez-Cirión presented on a possible case of an HIV cure achieved by a stem cell transplantation administered to treat a life-threatening cancer. Several individuals are considered to have been cured under similar circumstances, however — as mentioned above — in those prior instances the stem cells were sourced from donors homozygous for the CCR5Δ32 mutation, which makes immune cells resistant to most HIV variants.
Romuald, the person described by Sáez-Cirión (who’s since publicly identified himself in interviews), received a stem cell transplant from a donor lacking the CCR5Δ32 mutation (referred to as wild type CCR5). Previously, this type of stem cell transplantation has only led to short term remission from detectable HIV viral load, as in the two “Boston patients.”
Romuald’s case has now been published in the journal Nature Medicine, with a link added to TAG’s listing because he’s part of the IciStem observational cohort of people with HIV who’ve undergone stem cell transplantation during care for other conditions. The reasons for the extended absence of HIV and potential cure are uncertain but may be related to the occurrence of graft-versus-host disease (GVHD), which can involve transplanted immune cells killing the original host immune cells containing HIV. Management of GVHD has also required the administration of the drug ruxolitinib, which has been reported to have activity against the HIV reservoir. At the current time Romuald remains off ART without evidence of detectable HIV and follow up is continuing.
Results from a clinical trial of a triple bNAb combination led by Boris Juelg at the Ragon Institute and sponsored by IAVI were presented at CROI earlier this year and have now been published in Nature Medicine. The bNAb combination, comprising PGT121, PGDM1400, and VRC07-523LS, had previously demonstrated strong but transient suppression of HIV viral load in people with HIV who hadn’t yet started ART. The newer results are from a subsequent protocol administering the bNAbs to people with HIV on ART who underwent an ATI immediately after receiving the first bNAb infusions.
A majority of recipients (10 out of 12) experienced continued viral load suppression for at least 28 weeks, and a subset of five participants maintained control for 38-44 weeks (or more) even after bNAb levels declined to low or undetectable. In two cases viral load rebound occurred rapidly, and this was associated with the detection of resistance to the bNAbs in baseline samples. Participants weren’t screened for bNAb resistance before entering the study, and some researchers and advocates believe this should now be standard (while acknowledging the assays still have limitations).
Findings from a trial that combined a PD-L1 inhibitor (ASC22) with the HDAC inhibitor chidamide (approved to treat several conditions in China) were debuted at IAS 2023 (see prior blog post). The results have now been published in the journal Signal Transduction and Targeted Therapy, providing evidence of some activity and support for further evaluation in the context of ATIs.
The French National Agency for AIDS Research (ANRS) is sponsoring a cohort study for people with HIV receiving immune checkpoint inhibitors to treat cancers. Results relating to effects on T cell responses and the HIV reservoir have previously been presented and published. The latest publication in the Journal for Immunotherapy of Cancer focuses on safety and tolerability, finding that incidence of adverse events was broadly comparable to people without HIV (similar to other independent studies). As the authors note in the discussion section of the paper, there were factors identified that were associated with a greater risk of immune-related adverse events (irAEs):
“The study showed that a low CD4 count, a longer time since HIV diagnosis, a history of cancer surgery and positive CMV serology at the start of ICI [immune checkpoint inhibitor] were risk factors for the development of severe irAEs. These data also suggest that ICI treatment has no impact on HIV control, with no disruption in control of viral replication and no decrease in CD4 T-cell count. The survival benefit for PWH with melanoma and Hodgkin’s disease after ICI is encouraging and reinforces the value of these treatments in this population.”
The PITCH protocol in the United Kingdom evaluated the effects of short-term ATIs in people with HIV on ART, with preliminary results presented at CROI 2022. A new paper in the European Journal of Immunology includes data from the study cohort as part of a larger analysis and offers evidence that the ATI induced new T cell responses to the HIV Gag protein in PITCH participants.
Lastly, for anyone attending the upcoming R4P conference, results from a completed ATI trial in participants who acquired HIV during the Antibody-Mediated Prevention (AMP) trial in Brazil and Peru are being presented by Jorge Gallardo-Cartagena on Tuesday October 8th at 3:30pm local time. A link to the abstract will be added to TAG’s listing for the trial when it becomes publicly available next month.
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