There are ten updates this month: a newly entered therapeutic HIV vaccine trial in China, a new observational study in Belgium, one observational study shifted to the completed studies table, and links added to presented/published results for seven of the studies in the listing.
The therapeutic HIV vaccine trial is testing a novel DNA construct called ICVAX, which encodes a mosaic form of the HIV Gag protein fused to a soluble human PD-1 protein. Mosaic means that the Gag protein consists of elements from multiple different HIV variants, with the aim of inducing T cell responses capable of responding to diverse viruses (in this case the focus is on variants circulating primarily — but not only — in China). The reason for the inclusion of the PD-1 protein is to target the HIV Gag protein to dendritic cells, which are responsible for initiating immune responses. Dendritic cells express molecules called ligands which interact with PD-1, and delivering antigens such as the HIV Gag protein via this pathway is associated with superior induction of CD8 T cell responses.
The approach is being developed by a biotech company, Immuno Cure, and promising results have been reported in both macaque and mouse models. The launch of the phase I trial in Shenzhen was announced in February 2023, but initially we were unable to identify a trial registry entry. We’ve since found a link describing the study and a recent news article indicates results are anticipated soon (however the bulk of the piece is behind a paywall).
In a presentation at the recent IAS HIV Cure & Immunotherapy Forum in Brisbane (see video), Zhiwei Chen from the University of Hong Kong described the vaccine approach and disclosed that the first doses were administered to study participants in March 2023. The study design involves a stepwise assessment of escalating doses, and Chen explained that the lowest dose cohort has been completed with no safety issues identified. The researchers have now initiated a medium dose cohort. An analytical treatment interruption (ATI) will be considered in the future if all goes according to plan.
The new observational study is taking place in Belgium, sponsored by the University Hospital, Ghent. The plan is to recruit two cohorts of people living with HIV on ART: one group will include people who started ART during acute HIV infection a minimum of three years ago but no more than 10 years ago (designated the short-term ART cohort), while the second group will comprise people receiving ART for more than 20 years (long-term ART cohort).
Participants will be selected based on continuous use of ART and maintenance of viral load suppression to undetectable levels. The latter criteria are quite strict, with only one prior viral load blip (that didn’t exceed 200 copies/ml) allowed. Cells will be collected via leukapheresis in order to study the HIV reservoir in each cohort in great detail and test the effect of potential interventions on HIV-infected cells in the laboratory (in vitro). The goal is to generate information that can contribute to the development of curative interventions. The principal investigator is Dr. Linos Vandekerckhove.
The observational study that’s now completed is named DOLUVOIR and involved a detailed assessment of antiretroviral drug levels and the HIV reservoir in men on first line treatment including the integrase inhibitor dolutegravir combined with abacavir/lamivudine or tenofovir/emtricitabine. The aim was to quantify drug levels in multiple body tissues and in semen, in addition to looking for evidence of residual HIV replication in these compartments. The research took place at multiple sites in France and was led by principal investigator Antoine Chéret. To our knowledge, results have not been published or presented as yet.
Five studies in the listing have had links added to results presented during IAS 2023 in July:
Among the most widely publicized news from the conference was Asier Sáez-Cirión’s description of a case of extended HIV remission after stem cell transplantation for cancer in a person who didn’t receive cells from a donor with the HIV-resisting CCR5Δ32 mutation (covered previously on the blog and the subject of detailed reporting by Liz Highleyman for AIDSMap). The individual is being followed as part of the IciStem project (an "International Collaboration to guide and investigate the potential for HIV cure by Stem Cell Transplantation"), which is included in our table of observational studies.
At the pre-conference HIV Cure & Immunotherapy Forum (see video), Monica Reece from Emory University presented an analysis of the effects of ruxolitinib, a Janus kinase inhibitor, on the HIV reservoir in people on antiretroviral therapy (ART) with suppressed viral loads. The information was also shared as a poster at IAS 2023.
The results derive from a randomized, open label trial sponsored by the AIDS Clinical Trial Group (ACTG) that assigned 40 participants to receive ruxolitinib in addition to ART while 20 participants continued on ART alone (information on safety, inflammatory markers and pharmacokinetics has been published previously in Clinical Infectious Diseases and the Journal of Clinical Pharmacology). Ruxolitinib was dosed at 10mg twice a day for the first five weeks and then stopped, with all participants in both arms followed for 12 weeks. The drug was generally well tolerated; three participants prematurely discontinued but in only one case was this due to an adverse event considered related to ruxolitinib (severe elevation of the liver enzyme AST).
Reece’s presentation showed that there was no significant decline in the size of the HIV reservoir (as measured by the intact proviral DNA assay or IPDA) when ruxolitinib recipients were analyzed as a group and compared to the controls. But when the researchers divided the ruxolitinib recipients into three tiers based on the baseline size of their HIV reservoir, those in the top third with the highest baseline levels experienced a statistically significant decline during weeks 5-12 after dosing was stopped. No difference was evident after five weeks.
Reece also described several biomarkers that were associated with this apparent reservoir decline, and used the kinetics of the decay to create a mathematical model suggesting that — in the subset of participants who experienced this decline or people who respond similarly — 99.99% of the HIV reservoir might be cleared after 2.86 years. The data appears somewhat encouraging, but there are some potential caveats to bear in mind:
- The decision to conduct an analysis of HIV reservoir decline by dividing ruxolitinib recipients into different groups based on baseline reservoir size was post hoc, meaning it was not planned in the original trial protocol. Post hoc analyses of subsets of study participants are unfortunately notorious for producing unreliable results.
- The fact that the apparent decline in the size of the HIV reservoir only occurred after ruxolitinib dosing was stopped, combined with the unreliable nature of post hoc subset analyses, raises questions about the wisdom of using the data to make a mathematical model suggesting 99.99% clearance of the HIV reservoir after a little less than three years. The model certainly garnered some publicity, but may be premature given that no decline was seen while ruxolitinib was being administered.
More positively, the biomarkers reported to be associated with a decline in HIV reservoir size were consistent with ruxolitinib’s proposed mechanism of action (inhibiting the survival of virus-infected cells) and, as Reece noted, there’s speculation that ongoing use of the drug may have contributed to the extended case of HIV remission reported at the conference by Asier Sáez-Cirión. The publication of Reece’s results and further investigation into Janus kinase inhibitors in people with HIV will hopefully help clarify the promise of the approach.
Researchers led by Dr. Jun Chen from the Shanghai Public Health Clinical Center at Fudan University are conducting an ongoing clinical trial combining an anti-PD-L1 antibody (ASC22) with chidamide, an HDAC inhibitor licensed for use in China. A prior small study has suggested that chidamide may have HIV latency-reversing activity, and antibodies against PD-L1 aim to restore function to T cell responses that have become exhausted and dysfunctional. An antibody against PD-L1 has previously been tested in people with HIV by the ACTG, generating some evidence of enhanced HIV-specific T cell responses but also reporting a delayed autoimmune adverse event that was potentially linked to the intervention (hypoadrenalism and hypogonadism, which was eventually resolved).
In their IAS 2023 poster abstract, Chen and colleagues describe preliminary results in 15 participants on antiretroviral therapy (ART) who’d maintained viral load suppression for at least a year prior to study entry. Administration of ASC22 and chidamide was associated with transient increases in HIV RNA consistent with latency-reversing activity and an elevation in the proportion of a subset of CD4 and CD8 T cells (effector memory cells) that are known to be important for killing pathogen-infected cells. Some participants also demonstrated evidence of enhanced T cell function.
There were eight adverse events, all of which were grade 1 and resolved on their own. Study follow up was 24 weeks, and additional follow up may be needed to confirm safety because the autoimmune adverse event in the ACTG study occurred 36 weeks after administration of the anti-PD-L1 antibody. The abstract concludes that: “This strategy holds promise for activating and clearing latent HIV reservoirs and deserves further investigation.”
The manufacturer of ASC22, Ascletis Pharmaceuticals, also has a separate ongoing 30-person phase II trial evaluating the safety, tolerability and efficacy of two different doses in people with HIV on ART, which is due to complete at the end of the year.
David Margolis from the University of North Carolina and the Martin Delaney CARE Collaboratory debuted results from a small trial that combined the HDAC inhibitor vorinostat with an adoptive immunotherapy approach (HIV-1 antigen expanded specific T cell therapy or HXTC). The immunotherapy requires extraction of T cells from study participants, expansion of HIV-specific T cells in the laboratory, and reinfusion back into the participant. The combination led to some evidence of a decline in the size of the HIV reservoir measured by the quantitative virus outgrowth assay (QVOA), but Margolis noted that the effect was not large enough to rule out a role of assay variability (based on previous work that defined a six-fold change in QVOA measures as the minimum necessary to indicate a true difference). The poster abstract suggests that more potent interventions are likely needed to achieve more significant effects.
The last of the studies in the listing with results presented at IAS 2023 is an investigation into the effects of oral cannabinoid capsules (with or without THC) on inflammation and HIV reservoir size in people on ART. Led by Cecilia Costiniuk at the McGill University Health Centre in Canada, the study reported evidence of potentially beneficial reductions in some markers of inflammation and T cell exhaustion, but no significant changes in HIV reservoir measurements. The researchers propose that the data support the initiation of larger trials. The results were also published in the journal Cells shortly before the conference got underway.
Links to newly published results were added for two studies in the listing:
An analysis of samples from participants in the completed BCN02 trial, which investigated a combination of a therapeutic HIV vaccine and the HDAC inhibitor romidepsin, found that lower levels of the cell receptor CD33 were associated with partial control of viral load after an ATI (while higher CD33 levels were associated with an absence of control). The researchers note that additional research is needed to confirm the findings and expand to broader populations, because the majority of participants in the trial were men. The results are published in the open access journal eBioMedicine.
A completed observational study investigating the HIV reservoir in people on ART in Uganda has provided samples for an analysis of the timing of reservoir formation, with results published in the journal Virus Evolution. The rationale derived from previously presented evidence that, in many cases, the bulk of the persistent HIV reservoir in people on ART shows evidence of having been formed close to the time ART was started. The suggestion from these findings was that HIV-infected cells may be more prone to die when viral load is high and T cells are more activated and show higher rates of death, whereas suppression of viral replication by ART allows a more favorable environment for some HIV-infected cells to de-activate and create the reservoir from which the virus can reemerge if ART is stopped.
However, the results from men and women on ART in Uganda weren’t consistent with prior findings and indicate that their HIV reservoir formed across an extended period of time before treatment initiation. Only two of 11 participants displayed evidence of HIV reservoirs formed close to the time ART was started. The researchers state that larger studies are needed to better understand variation in the timing of HIV reservoir formation, but the research will likely depend on the availability stored pre-ART samples now that immediate ART initiation is the standard of care. The question is not just academic because there are implications for when candidate anti-reservoir interventions should be given, with some investigators already testing administration at the time that ART is begun (such as the eCLEAR study, which offered support for the idea).
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