The March 2024 revision to TAG’s listing includes 26 updates. The annual Conference on Retroviruses and Opportunistic Infections (CROI) took place in Denver from March 3-6, and the addition of links to results from HIV cure-related studies presented at the meeting typically makes this the busiest month for changes — hence the delay to this blog post.
New Additions
Three new studies were added this month.
Gilead Sciences is one of the few large pharmaceutical companies pursuing an HIV cure research program. As part of this effort, a phase I trial has been initiated of GS-8588, an immune-based therapeutic candidate described as a bispecific T cell engager.
The approach derives at least in part from research conducted with public funding at the National Cancer Institute by Dimiter Dimitrov and Weizao Chen. The scientists developed and patented a protein with two components (bispecific): mD1.22, an element from the human CD4 protein, and m36.4, from a human antibody, each specific for a different vulnerable target on HIV’s outer gp120 envelope protein. The Gilead construct includes a CD3 molecule to engage T cells to kill cells expressing the HIV gp120 protein; all the ingredients included in GS-8588 will be described in a presentation by Nathan D. Thomsen from Gilead at a conference in May of this year.
GS-8588 is an example of how research supported by public funding from the National Institutes of Health (NIH) can be licensed to a private company for potential profit. When the NIH requested public comment on their plan to license the fusion protein to Gilead, Jamie Love’s organization Knowledge Ecology International filed comments highlighting concerns about cost and the lack of any requirements for access and availability if the approach should prove successful:
“The NIH should include terms in the license that protect affordable, equitable access to patients in the US and around the world. Gilead has a track record of pricing its treatments – including HIV products – aggressively, and in the past, the high prices have been a barrier to the deployment of PrEP to prevent HIV infections.”
The response from NIH doesn’t disclose whether any such terms were included.
Gilead hasn’t entered the GS-8588 trial into the clinicaltrials.gov registry (at least so far), taking advantage of the lack of a requirement to register phase I trials. This has been a consistent problem with Gilead’s HIV cure research program, and it runs counter to their public commitments to community engagement in HIV research — it’s not possible for people to engage with a clinical trial if they’re not aware of it. Limited information is available online from individual study sites, such as the entry in the UPenn Medicine website. Gilead also states that GS-8588 is in a phase I trial on their website pipeline page, without providing any additional detail.
Casper Rokx and colleagues at the Erasmus Medical Center in the Netherlands are working to translate findings from laboratory analyses of candidate HIV latency-reversing agents into clinical interventions. Their newest trial (not yet recruiting) plans to investigate the activity of an approved antiepileptic drug, topiramate, in people with HIV on antiretroviral therapy (ART).
The rationale derives from laboratory studies showing that a particular cellular gene — glutamate ionotropic receptor kainate type subunit 5 (GRIK5 for short) — is involved in the maintenance of HIV latency. Topiramate is an inhibitor of GRIK5 and was found to reverse HIV latency in cell line models and in CD4 T cells isolated from people on ART, without inducing immune activation or causing significant toxicity.
The clinical trial will administer a single topiramate dose of 400mg to assess HIV latency-reversing activity, toxicity, and any differences in response related to sex assigned at birth.
The third addition is sponsored by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and involves participants in a cohort of children with HIV treated early with ART in the ANRS Pediacam III cohort in Cameroon. The goal of the study is to better understand the factors that contribute to maintenance of HIV-negative results on antibody tests in a subset of cohort members.
Updates to Enrollment Status
A clinical trial in Spain investigating the tyrosine kinase inhibitor dasatinib in people with HIV is now open for enrollment. The protocol aims to recruit people with recent HIV acquisition (past 3-12 months) and will administer dasatinib (70mg a day) alone for four weeks before ART is initiated. Dasatinib will then be continued as an adjunct to ART for another 12 weeks. Study endpoints include the safety and tolerability of dasatinib both alone and in combination with ART, effects on HIV viral load prior to ART, and measurements of the HIV reservoir.
The impetus for the study (and another recently opened trial in Spain recruiting people on ART for >3 years) comes from evidence that the use of dasatinib to treat cancers in people with HIV is linked to smaller reservoir size and a diminished capacity to reactivate viable HIV from latently infected cells.
A phase I trial in China of ICVAX, a therapeutic vaccine candidate, is now closed to new enrollment. ICVAX takes a novel approach by targeting the PD-1 pathway to try to improve immune responses against the HIV Gag proteins included in the vaccine construct. Preliminary information from the trial was presented at an IAS 2023 pre-conference by Zhiwei Chen (see blog post from August 2023).
Completed Studies
An interesting-looking trial that planned to investigate an off-the-shelf natural kill cell product called FT538 in people with HIV on ART has unfortunately been withdrawn (and deleted from TAG’s listing). The study record provides no information except stating: “Withdrawn, Abandoned.” Fate Therapeutics, the company that produced FT538, no longer lists it in their pipeline suggesting development has been discontinued.
New Links to Study Results
The majority of newly added links to study results derive from CROI 2024. Links are included to the conference abstracts, with PDFs of posters already available but webcast links for oral presentations due to be added to the respective abstract pages and made publicly accessible on April 8, 2024.
The multinational IMPAACT P1115 study is evaluating whether the extended period of remission from detectable HIV viral load that was documented in the Mississippi baby case may be reproducible in other infants with HIV treated very early after birth. At CROI 2024, Dr. Deborah Persaud presented the first study results after analytical treatment interruptions (ATIs), noting that six infants met pre-specified criteria for stopping ART, including absence of detectable HIV DNA. The average age at time of interruption was 5.5 years. Viral load returned quickly in two of the children. In another participant, there was a delay of 80 weeks before viral load rebounded necessitating the reintroduction of ART. The reappearance of viral load was associated with symptoms of acute HIV infection in two of these cases. Three study participants currently remain off ART without viral load rebound after 48, 52 and 64 weeks of ongoing follow up, respectively.
Persaud noted that the study demonstrates that extended remission from detectable viral load is possible in very early-treated infants, but better biomarkers are needed to identify the ideal candidates. A second version of the IMPAACT P1115 protocol is investigating whether the inclusion of an integrase inhibitor and a broadly neutralizing antibody (bNAb) in treatment regimens can improve outcomes. See Liz Highleyman’s report for Aidsmap for detailed coverage. A second IMPAACT P1115 abstract presented as a poster reported results from a detailed analysis of the HIV reservoir among infants in the study, showing that around half of the HIV DNA detected at birth represented intact virus genomes, with levels subsequently declining after ART initiation.
Marie Armani-Tourret from the Ragon Institute described results from a completed clinical trial of the HDAC inhibitor panobinostat combined with interferon-alpha2a in people on ART. The results were also published in the journal Cell shortly before CROI 2024. The researchers found evidence that the interventions altered the makeup of the HIV reservoir, with a trend toward a reduction in the proportion of intact HIV (viable virus that can cause viral load rebound) and an apparent depletion of cells containing virus integrated in places in the cell’s genetic code known to be susceptible to the latency-reversing activity of panobinostat. The authors conclude “these results provide proof-of-principle that the viral reservoir is vulnerable to ‘shock and kill’ interventions.”
Two oral presentations reported on different approaches to combining three bNAbs (see also Gus Cairns’s coverage for Aidsmap). Boris Juelg conducted a study of PGT121, PGDM1400, and VRC07-523LS given as monthly infusions, with ART interrupted after the first infusion. At CROI, Juelg reported that a majority of participants (10 of 12) maintained viral load suppression during bNAb dosing, and several (5 of 12) displayed extended post-treatment control after antibody levels waned. Participants weren’t pre-screened for evidence of baseline resistance to the bNAbs, and the two individuals with early viral load rebound were found to have HIV mutations associated with reduced susceptibility to PGT121 and PGDM1400. A poster from the same study identified inflammatory markers that appeared to increase prior to viral load rebound, suggesting they could have a role as predictors of loss of control of HIV replication.
Athe Tsibris debuted results from an ACTG study of SAR441236, a construct originally developed by Sanofi Pasteur that combines three bNAbs (VRC01, PGDM1400 and 10E8v4) into a single antibody construct. The antibody behaved similarly to other long-acting bNAbs in terms of the levels achieved in the body after administration, but the viral load effect in people not on ART was very weak for reasons that are unclear (0.38 log reduction at the highest dose, compared to declines averaging around 1.5 logs observed previously with single bNAbs). The candidate has been acquired from Sanofi Pasteur by a company called ModeX Therapeutics who issued a modest press release noting only that the safety and pharmacokinetics support further development of multispecific antibody approaches.
Several abstracts presented additional information from the BEAT-2 trial conducted by the BEAT-HIV Martin Delaney Collaboratory. Katherine Bar described evidence that both the bNAbs administered during the trial and the participants' own neutralizing antibody responses against HIV (called autologous neutralizing antibody responses) exerted activity against the virus that led to the selection of mutations associated with resistance. The bNAb infusions were also linked to improvements in the potency of participant autologous neutralizing antibody responses. In two participants who experienced the longest delay in viral load rebound after an ART interruption, autologous neutralizing antibody responses against HIV were already detectable when they first entered the study. The findings imply that autologous neutralizing antibody responses can contribute to post-treatment control of viral load.
A separate poster abstract from BEAT-2 reported an unexpected decrease in antibody-mediated cellular cytotoxicity (ADCC) associated with the interventions. Two additional posters provided information on the development of an experimental home viral load testing device evaluated as part of the protocol, and presented results suggesting that the approach may have utility for home monitoring of viral load rebound during ATIs. The device works by allowing the collection of capillary blood samples at home; the blood dries and is then sent for HIV viral load analysis via mail.
Tim Henrich from the University of California San Francisco (UCSF) gave an update from an ongoing imaging study assessing immune activation in people with HIV using positron emission tomography (PET) scanning. Henrich found that T cell activation was generally elevated in the participants with HIV compared to HIV-negative controls, including in people on ART. An exception was inguinal (groin) lymph nodes, where T cell activation was lower in people with HIV compared to the controls, possibly suggesting a decline in the capacity to activate T cells in these locations linked to the persistent presence of the virus. As an aside, Henrich noted that background levels of T cell activation detectable by this method have increased among all study participants in the post-COVID era, as evinced in a different study investigating long COVID (results are available as a preprint). A poster from Frank Maldarelli’s research group at the National Cancer Institute offered an update on the use of the same technique in a currently open study involving an ATI.
The pharmaceutical company AbbVie provided updates on their HIV cure research program in the form of an oral presentation on biomarkers associated with responses to their PD-1 inhibitor budigalimab and a poster describing the potential ability of a partner antibody targeting the α4β7 integrin (ABBV-382) to both directly inhibit HIV and enhance the presentation of viral antigens to T cells. Results from their phase I budigalimab program were previously covered on the blog. A large multinational phase II trial is now underway which plans to enroll 140 participants and explore the combination of budigalimab and ABBV-382.
Many other CROI 2024 posters featured results from studies in TAG’s listing.
The PENTA Foundation is sponsoring an ongoing trial in adolescents who acquired HIV perinatally, testing two therapeutic HIV vaccine candidates and the Cervarix human papilloma virus (HPV) vaccine (the latter given as an adjuvant because it contains a toll-like receptor 4 agonist). No efficacy data is available yet, but a poster presented information showing that the interventions have demonstrated safety.
Three posters reported analyses of participant samples from the large 2000HIV cohort study in the Netherlands. An investigation into genetic associations with natural control of HIV viral load found evidence to suggest that certain gene variants contribute to an increased capacity to restrict viral replication by modulating the function of natural killer (NK) cells. A separate study conducted the largest assessment of the intact HIV reservoir in different populations of people living with HIV (total = 863), finding that participants with various degrees of natural control of viral load have lower levels of intact HIV DNA compared to those with a more typical pattern of disease progression (designated “normal progressors”). People with suboptimal CD4 T cell recovery despite ART displayed significantly higher levels of intact HIV DNA compared to the normal progressors. Additionally, participants with HIV variants that use the CXCR4 co-receptor to enter cells had higher levels of intact HIV DNA than counterparts with viruses targeting the CCR5 co-receptor. In a novel companion study that also involves HIV-negative family members of participants with HIV, a particular profile of increased responsiveness among innate immune cells called monocytes (referred to as trained immunity) was associated with elite controller status.
Two abstracts covered analyses from a small trial of multiple interventions (therapeutic HIV vaccines, bNAbs and a TLR9 agonist) being led by Michael Peluso at UCSF. Results were presented as a poster at CROI last year indicating viral load rebound after ATI was reduced compared to the typical pattern, with 5 out of the 10 participants controlling viral load to <1,000 copies/ml (there’s no placebo control group in the study). One participant maintained undetectable viral load for 18 months of follow up, which is potentially encouraging albeit a challenging situation for the individual, Luis Canales, as he described in a recent article for Positively Aware. The posters presented at CROI 2024 reported an association between control of viral load and the ability of CD8 T cells to proliferate (copy themselves) in response to the rise in HIV levels after ATI, as well as assessing the impact of bNAb levels and concluding that they likely didn’t directly contribute to the apparent reductions in set point viral load but were linked to the timing of rebound (with higher bNAb levels linked to a longer delay).
Another study at UCSF led by Sulggi Lee is investigating the effects of rapid ART initiation after HIV acquisition on the viral reservoir. Initial results presented at IAS 2023 showed that participants who started ART earliest experienced the most rapid declines of both intact and defective HIV DNA. One poster at CROI 2024 outlined an association between higher levels of the cytokines IL-10 and type I interferons and more rapid declines in intact HIV. A second poster featured an analysis by Steven Yukl and colleagues which found that ART reduced both the proportion of cells in which the HIV life cycle was being completed, and levels of intact HIV RNA (which is transcribed from intact HIV DNA during the viral life cycle).
The SCOPE cohort at UCSF is recruiting participants for an ATI study that restarts ART as soon as viral load is confirmed to have increased to detectable levels (or after around three weeks if viral load remains undetectable). Two poster abstracts at CROI reported initial results from current participants. An analysis by Mauro Garcia and colleagues found an association between time to viral load rebound and the levels of HIV variants in the reservoir that were susceptible to autologous neutralizing antibodies: participants with higher levels of HIV in their reservoir that could be inhibited by their autologous neutralizing antibody responses experienced a longer time to rebound. The results echo those of Katie Bar and add to the evidence that neutralizing antibody responses can play an important role in post-treatment control of HIV. The second poster presentation from Natalia de la Force notes that an increase in levels inflammatory monocytes preceded the rise of viral load to detectable levels.
An ACTG trial of the anti-CMV drug letermovir was stopped early because changes in the levels of certain inflammatory markers didn’t meet criteria prespecified in the protocol as necessary for recruiting additional participants. In a late-breaker poster at CROI, Sara Gianella Weibel described an analysis involving 40 participants after eight weeks. Unexpectedly, there was an increase in one marker of inflammation, soluble tumor necrosis factor receptor 2 (sTNFR2), likely connected to a reduction in levels of an immune-suppressive protein generated by CMV. However, other markers associated with inflammation and cardiovascular disease risk declined, suggesting the approach may deserve further evaluation.
The last of the CROI abstracts so far identified as related to trials in the TAG listing came from the RIVER trial in the UK, which tested therapeutic vaccination in people starting ART early after HIV acquisition. In a subset of 10 participants whose samples were studied in detail, early ART initiation was linked to a shift in the composition of the HIV reservoir suggestive of immune-mediated clearance of cells containing HIV capable of making viral proteins either intermittently or persistently (thereby making the infected cell visible to the immune system). The evidence derived from an increase in the proportion of cells with HIV integrated into locations in the cellular genetic code known to restrict the capacity of the virus to emerge and make new proteins, keeping it hidden. However, these effects on the HIV reservoir were associated with markers of innate immunity and not with receipt of the therapeutic vaccine.
Links to newly published results were added for four studies in the listing:
In the journal Open Forum Infectious Diseases, Cynthia Gay and colleagues reported complete findings from an ACTG trial of the PD-1 inhibitor cemiplimab which was stopped early due to two serious adverse events (already described at the 2020 Pre-CROI Community HIV Cure Research Workshop and in a paper in JAIDS). The new publication notes there was evidence of an increase in HIV-specific T cell responses in one of four recipients studied. Multiple other studies of PD-1 inhibitors in people with HIV (with or without cancer) remain ongoing.
An observational study in people on ART in Rakai, Uganda found evidence of a temporary increase in the size of the replication-competent HIV reservoir after switching to an integrase inhibitor-based ART regimen (primarily from previous NNRTI-based ART). The researchers note there might be possible confounding variables and that it will be important to assess whether a similar phenomenon occurs in other cohorts. The results were published in the open access journal EBioMedicine.
An ongoing observational study in France titled APRIL (Analysis of the Persistence, Reservoir and HIV Latency) presented an analysis of HIV target cells in people with late stage disease in the journal Pathogens & Immunity. The authors report that productively infected cells in people with AIDS were highly differentiated and exhausted — indicating they’d been exposed to multiple rounds of stimulation leading to dysfunction.
Lastly, the researchers conducting the Zurich Primary HIV Infection Study published a description of their cohort in the journal Microorganisms.