Last month’s revision to TAG’s listing included ten updates.
New Additions
There was only one new HIV cure-related trial identified in registries. The protocol, named Tatelo Plus, represents a follow up to a prior smaller evaluation of dual broadly neutralizing antibodies (bNAbs) in children with HIV in Botswana (the Tatelo study). The research project is primarily testing bNAbs as an alternative to antiretroviral therapy (ART) for maintaining HIV viral load suppression, but straddles the boundary with cure research by including detailed investigations of effects on the HIV reservoir (and using reservoir measurements as part of the criteria for deciding whether to interrupt ART).
In the original Tatelo study, 11 of 25 infants (44%) who received the bNAbs 10–1074 and VRC01-LS maintained undetectable viral loads during a 24 week ART interruption. The new trial, which is under the aegis of the IMPAACT network, will administer three long-acting bNAbs: PGDM1400LS, VRC07-523LS, and PGT121.414.LS.
Based on information gleaned from Tatelo, the protocol includes additional criteria for determining whether a participant will be able to enter the ART interruption phase. These criteria include undetectable levels of HIV DNA using a qualitative test and, for the first time, results from sophisticated analyses of where HIV has integrated its genetic code into the genome of infected cells. Specifically, the protocol requires that >80% of intact HIV proviruses detected with these assays are located in inhospitable regions of the cell’s genome that are less likely to allow the virus to reactivate and replicate.
To recycle a metaphor used previously on the blog: if you think of a cell’s genome as a factory for producing all the proteins the cell needs to go about its daily business, HIV DNA tends to integrate in machinery that gets switched on regularly. This gives the virus opportunities to hijack that machinery to make more HIV proteins (and potentially more copies of infectious HIV). But HIV DNA can also land in the genomic equivalent of a darkened factory storage room nobody goes into (sometimes referred to as a “gene desert”) — in that case, the virus can become locked in, and unable to reactivate. Marcus Lichterfeld, one the pioneers of this area of research along with Xu Yu, recently presented on a community webinar to explain and share current knowledge about the phenomenon.
Analyses of the Tatelo study presented at CROI 2023 suggest that HIV viral load rebound during ART interruption was associated with an HIV reservoir primarily located in regions of the genome that allow for virus reemergence. These findings led to the new eligibility criteria for undergoing ART interruption in Tatelo Plus, with the goal of trying to select participants with the best chance of maintaining HIV viral load suppression.
Updates to Enrollment Status
- A study in Canada testing whether fecal microbiota transplantation (FMT) can reduce inflammation in people with HIV on ART is now open for enrollment at the McGill University Health Centre in Montreal.
- A protocol for people who acquired HIV during the Antibody-Mediated Prevention (AMP) study that took place on the African continent is now closed to further recruitment. The study is investigating whether receipt of the broadly neutralizing antibody (bNAb) VRC01 prior to HIV acquisition can promote control of viral load during an analytical treatment interruption (ATI) among participants who started ART rapidly after diagnosis. Shelly Karuna from the HIV Vaccine Trials Network (HVTN) shared background information and some data snapshots at the 2023 Pre-CROI Community HIV Cure Research Workshop. Videos in multiple languages designed to help potential participants understand the protocol and ATIs have also been made publicly available on HVTN’s Vimeo channel.
Completed Studies
- A second AMP study that took place at sites in Brazil and Peru also included a follow on ATI protocol for participants who acquired HIV and started ART. This study is now completed, but to our knowledge results haven’t been publicly presented yet.
- A completed evaluation of the PD-1 inhibitor pembrolizumab to treat cancers in people with HIV, which also included exploratory analyses of effects on the HIV reservoir. Multiple reports of results have been published and presented, see highlighted entry in the completed studies table under trial registration # NCT02595866.
- An observational study of a particular immunological pathway involving the cytokine interleukin-33 in people with HIV. The registry entry hasn’t been updated for some time and the protocol was due to end last year, hence the move to the completed studies table (email inquiries about the status weren’t answered).
New Links to Study Results
Results from several studies in the listing were presented at the International AIDS Conference (AIDS 2024) in Munich in July.
Among the most significant news was a presentation by Dr. Rachel Presti describing results from the first human trial of a CRISPR-based gene editing strategy named EBT-101, designed to excise HIV’s genetic code from infected cells. Unfortunately there’s no abstract associated with the talk and hence we’re unable to add a link to the entry in our listing until video of the presentation becomes publicly available in October.
As noted in the previous blog post, three EBT-101 recipients underwent an ATI but only one experienced a delay in HIV viral load rebound of 16 weeks, which appeared to be associated with a slight but statistically significant decline in the size of their intact HIV reservoir after EBT-101 administration. The results may in part highlight the challenge of trying to use CRISPR against a highly mutable virus — the gene editing tool needs to recognize conserved genetic sequences in order to work, and several study participant samples displayed evidence of variation at the HIV sites targeted by EBT-101. While some of the media reporting of the results has been pessimistic, there could yet be potential for improving both the targeting and the delivery of the approach.
Immuno Cure BioTech is developing a novel therapeutic HIV vaccine that combines conserved parts of the viral Gag protein with a PD-1 protein intended to promote uptake by dendritic cells (key immune cells for initiating immune responses). A poster presentation of results from a 45-person phase I trial featured at AIDS 2024, reporting that the approach was safe and deserving of further evaluation. Future plans include conducting ATIs to measure any effects on viral load rebound. For additional background see blog post from August 2023.
Researchers from the AIDS Malignancy Consortium presented information on immune responses to PD-1 inhibitor therapy in people with HIV and cancers. The analysis focused on the CD8 T cell repertoire, a measure of the ability of a person’s CD8 T cells to recognize a broad variety of targets. The investigation discovered that participants with a more diverse CD8 T cell repertoire at baseline generated new CD8 T cell responses rapidly in response to a single dose of the PD-1 inhibitor, whereas those with more limited CD8 T cell diversity required multiple doses to achieve similar effects.
An analysis of 21 participants in the Zurich Primary HIV Infection Study compared the evolution of the viral reservoir in people with detectable low level viral load (50-500 copies/ml) compared to those with viral loads consistently below 50 copies/ml. All had started ART soon after HIV acquisition with high levels of adherence. The researchers didn’t find any evidence that low level viral load was associated with ongoing HIV replication or the development of drug resistance. The results suggest that the phenomenon of “unsuppressible” HIV viral load generated by the reservoir (but not indicative of ongoing viral replication) that’s been described in chronic HIV infection can also occur in people who started ART very early.
Italian researcher Barbara Ensoli continues to evaluate the long-term effects of a novel therapeutic vaccine candidate designed to induce immune responses against the HIV Tat protein. At AIDS 2024, Ensoli reported on extended observational follow up of two trial cohorts in Italy and South Africa, respectively, showing evidence that the vaccine was safe and induced sustained immune responses against the Tat protein. Positive changes in immune cell subsets and reductions in the HIV reservoir were also noted, with a manuscript said to be in preparation. The vaccine has been the subject of past controversy and it’s unclear at this time whether further development is likely to occur.
A link to an article in the Journal of Personalized Medicine was added for a completed trial of oral cannabinoids in people with HIV on ART. Preliminary results have already been published and the new paper focuses on the overall feasibility of the research and lessons learned.
Finally there was one AIDS 2024 poster presentation on GS-8588, a new bispecific T-cell engager being developed by Gilead that recently entered clinical testing. However a link wasn’t added to our listing because the poster describes initial encouraging laboratory findings rather than results from the ongoing phase I trial. Encouragingly, the preclinical laboratory testing demonstrated efficient killing of HIV-infected cells sampled from people on ART.
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