For March, April, and May 2025, there were 38 updates to entries in TAG’s listing. The majority involved the addition of links to results presented at the annual Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.
As is covered further below, this period has seen a horrific and unprecedented political attack on scientific research in the US under the regime that assumed power on January 20th. The US National Institutes of Health (NIH) is by far the most significant funder of biomedical research in the world, and that also holds true for HIV cure research. We’ll continue to monitor and respond to developments, and collaborate with allies to try to ensure that this work can continue.
New Additions
One newly registered HIV cure-related clinical trial was added in March. The protocol is investigating chimeric antigen receptor (CAR) T cells, a gene therapy approach that involves equipping T cells with receptors designed to recognize a specific target (in this case, HIV). Several CAR T cell therapies have been approved for the treatment of cancers in recent years. The study is taking place at Tsinghua University in Beijing, China, and has yet to start recruiting participants.
There were two additions in April:
Jun Chen, MD is leading an investigation of a combination of the PD-1 inhibitor sindilizumab with chidamide, a candidate latency-reversing agent from the HDAC inhibitor class. The study plans to enroll 33 participants at the Shanghai Public Health Clinical Center in China and includes an analytical treatment interruption (ATI). Some evidence of PD-1 inhibitors enhancing control of HIV viral load after an ATI have emerged from early-phase studies conducted by the pharmaceutical company AbbVie.
An observational protocol is inviting participants from a large trial of dual broadly neutralizing antibodies (bNAbs) to undergo an ATI. The parent study has been ongoing since 2023, involving the administration of the long-acting bNAbs 3BNC117-LS and 10-1074-LS to around 200 participants with HIV on antiretroviral therapy (ART).
The invitational trial will assess whether receipt of the bNAbs promotes viral load suppression after ART interruption. The research is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), and the registration of this study in late April suggests that some work is proceeding at the NIH despite the ongoing efforts of the current US regime to disrupt and stop taxpayer-supported scientific research (funded with money appropriated by Congress for this purpose and committed to investigators in a peer-reviewed, highly competitive process).
No new HIV cure-related trials were identified in registries for the May update.
Withdrawn
A clinical trial planned by IAVI to investigate potential HIV vaccine components in people with HIV in Africa has been withdrawn from the clinicaltrials.gov registry, with withdrawal of funding given as the reason. IAVI is a vaccine organization that has been affected by the recent malevolent, politically motivated destruction of the United States Agency for International Development (USAID).
Updates to Enrollment Status
Enrollment status has been updated for 13 studies in the listing:
The TatLat observational study in France is now recruiting. The purpose is to collect blood samples from people on ART for use in laboratory assessments of a candidate latency-reversing agent designed to induce HIV production by activating the viral Tat protein.
An investigation of the effects of increased doses of certain antiretrovirals on the HIV reservoir is also now open for enrollment in Madrid, Spain.
The effects of recent attacks on the NIH have manifested in the form of pauses on screening and enrollment for HIV cure-related trials sponsored by the ACTG (Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections). The ACTG and other US government-supported HIV research networks operate on seven year cycles but money is allocated annually in a process that usually proceeds smoothly. This year, the monies that are due have been held up, leaving the networks in a funding crunch.
Part of the reason is an ongoing attempt to stop all US funding to South Africa, including research funding (TAG and MSF issued an analysis of the effects on US-supported HIV and TB research on May 15, see brief and associated press statement). Reporting from the journal Nature now indicates that NIH support for any research outside the US is at risk of imminent termination. The longer the funding is held up, the greater the possibility that the research networks are forced to close (leaving participants stranded in violation of US law), and there are fears this may be a deliberate strategy to try to claw back the unspent money through a process known as rescission.
The paused studies are:
- The recently opened ACACIA, which was intended to be the largest evaluation (n=135) of whether dual bNAbs given at the time of ART initiation can promote post-treatment control of viral load during an ATI. The study is taking place on the African continent, with the majority of enrollment slated to be at South African sites. The registry record is yet to be updated.
- A second trial in Africa named PAUSE which is administering dual bNAbs to people on long-term ART with suppressed viral loads, followed by an ATI (also with multiple South African sites). The registry record is yet to be updated.
- A dual bNAb/ATI protocol recruiting people with acute HIV infection in Brazil, Peru and the US.
- An investigation of a combination of immunotherapies (therapeutic vaccines, bNAbs, and a toll-like receptor 7 agonist) followed by ATI in people who initiated ART soon after HIV acquisition, with sites in Brazil and the US.
Four trials in the listing have now closed to further enrollment:
- An evaluation of arenavirus vaccine vectors as therapeutic HIV vaccines, sponsored by Hookipa Biotech.
- An ACTG study combining N-803, a cytokine-based immunotherapy candidate, with two broadly neutralizing antibodies.
- Another N-803 trial being conducted by the US Military HIV Research Program in people with acute HIV infection in Thailand.
- An investigation of therapeutic vaccination with a trimeric (three-pronged) HIV Envelope protein (trimer 4571).
Three entries have been completed and moved to table 3 in the TAG listing:
- A trial led by Sharon Riddler at the University of Pittsburgh assessing dendritic cell-based therapeutic HIV vaccines.
- An evaluation of chimpanzee adenovirus and modified Vaccinia Ankara strain viral vectors as therapeutic HIV vaccines conducted at the University of North Carolina, Chapel Hill.
- An adoptive immunotherapy trial involving infusion of HIV-specific T cells, preliminary results were covered on the blog in August 2024 and have just been published in the journal Nature Communications.
New Links to Study Results
March and April were particularly busy months for the addition of links to new results because of CROI, which took place in San Francisco from March 9-12. All CROI abstracts and webcasts were made publicly available on April 15, and relevant embedded links are included below. TAG also helped organize and co-sponsor the annual Pre-CROI Community HIV Cure Research Workshop held at the San Francisco AIDS Foundation on March 8th (recordings are available on the TAG website).
Two particularly prominent presentations at CROI covered the first results from trials of bNAbs administered to participants who started ART soon after HIV acquisition. In both cases ATIs were undertaken to assess effects on control of viral load after ART withdrawal.
Thumbi Ndung’u from the Africa Health Research Institute presented results from a study in the FRESH cohort of young women in South Africa sponsored by Gilead Sciences. The protocol was a single arm, open label design administering a combination of two long-acting bNAbs (VRC07-523LS and CAP256V2LS) and the toll-like receptor 7 agonist vesatolimod. The 20 participants had received ART for an average of seven years, after starting a median of just one day after the detection of acute HIV infection. Sensitivity of HIV samples to at least one of the two bNAbs was a requirement for study entry.
Vesatolimod was dosed every other week for ten weeks, the bNAbs were given via infusion on day seven. An ATI was initiated after four weeks. The researchers observed three patterns of viral load rebound: seven early cases while bNAbs were still likely present; another seven during the period bNAb levels were waning, and six participants who restarted ART late or displayed post-treatment control of viral load and remained off ART through 48 weeks.
Unusually, four participants (20%) continued to experience post-treatment control until week 55 and are still off ART post-trial, now for an average of 1.5 years. Krista Dong also discussed the study during the Pre-CROI Community HIV Cure Research Workshop, highlighting that in one case control of viral load has now persisted for more than two years.
Ndung’u noted that only one of the bNAbs (CAP256V2LS) was specific to the prevalent local HIV clade C, leaving open the possibility that better results might be attainable if both components of dual bNAb regimens are targeted to geographically relevant variants.
Sarah Fidler debuted broadly consistent results from the RIO trial, which is larger and includes a comparator placebo arm. A total of 68 cisgender men who began ART during acute HIV infection were evenly randomized to receive infusions of the long-acting bNAbs 3BNC117-LS and 10-1074-LS or placebo, followed by an ATI.
Receipt of the bNAbs was associated with a significantly greater likelihood of maintaining viral load suppression during ATI at multiple timepoints. After 20 weeks, 75% of bNAb recipients were controlling viral load compared to 8.8% of those in the placebo arm, consistent with prior studies demonstrating prolonged activity after a single infusion of long-acting bNAbs.
Participants with suppressed viral load at week 20 were eligible for a second infusion of bNAbs or placebo, and this was associated with high rates of continued control of viral load: 57% at 48 weeks and 39% after 72 weeks. Demonstrating the importance of control arms, there were also two cases of post-treatment control to beyond 72 weeks in the placebo arm (5%).
Fidler pointed out that there were three observed patterns of viral load rebound during ATI, “very similar to the FRESH cohort”: rapid (8/34 participants), delayed (14/29) and post-treatment control (7/29 for >72 weeks). There no safety concerns related to the bNAbs, but several participants experienced high viral load rebounds during ATI to greater than a million copies/ml – the ART restart criteria was a confirmed measurement >100K copies/ml, but in these cases levels continued to ascend while confirmation was pending (see detailed reporting by Simon Collins for HIV i-Base).
Additional information was presented from RIO in the form of two posters. John Frater and colleagues described a participant with extended post-treatment control for two years (and counting), associated with enhanced HIV-specific T cell immune responses and a reduction in the size of the intact HIV reservoir. The second poster, led by Mohammed Altaf, reported that the bNAbs had a “vaccinal effect” by promoting HIV Gag-specific T cell responses that were associated with control of viral load.
Taken together, the FRESH cohort and RIO studies offer encouraging evidence that the proportion of participants who experience post-treatment control can be increased beyond the rare cases reported previously. For both protocols, the rates of post-treatment control were around 20%. Dr. Ole Søgaard gave an excellent plenary talk on HIV cure research at CROI 2025 that delineated factors that likely contribute to control of viral load off ART.
A number of other clinical trials and observational studies in TAG’s listing had preliminary results presented at CROI 2025:
- The biotech company ImmunoCore is developing a soluble bispecific T cell engager called ImmTAV for HIV. The molecule is designed to facilitate recognition and destruction of HIV-infected cells by CD8 T cells regardless of their original specificity (e.g. a CMV-specific CD8 T cell could potentially be brought into action against HIV by ImmTAV). At CROI 2025, Beatriz Mothe presented evidence of safety, a reduction in the active HIV reservoir, and some modulation of viral load rebound in a small phase I trial.
- The PENTA Foundation’s assessment of a therapeutic HIV vaccine combination in adolescents with perinatal HIV in South Africa (the HVRRICANE Study) reported that the regimen induced sustained HIV-specific T cell and B cell responses.
- A trial sponsored by the US Military HIV Research Program (MHRP) investigating the IL-15 superagonist N-803 in people with acute HIV initiating ART in Thailand: One poster described evidence of enhanced CD8 T cell and natural killer cell proliferation, a second poster stated there were transient indications of accelerated viral load decline at the time of N-803 administration. The major adverse event was injection site swelling, which was severe in eight cases but resolved within seven days. Participants are now being given the option of receiving a second N-803 dose followed by ATI.
- A study of two therapeutic vaccine candidates being developed by Gilead Sciences indicated improvements in HIV-specific T cell functionality in some recipients but not breadth (how many different parts of HIV are being targeted).
- Researchers at UCSF assessed the capacity of T cell receptor (TCR) sequencing approaches to identify changes in CD8 T cell immune responses after receipt of the PENNVAX HIV vaccine in a completed therapeutic trial. The analysis demonstrated that it’s possible to document both induction of new CD8 T cell responses and the boosting of pre-existing CD8 T cells targeting HIV.
- AbbVie presented a poster featuring results from a phase I trial of their anti-α4β7 integrin antibody ABBV-382, now given the name trosunilimab. The antibody is intended to facilitate presentation of HIV components to T cells and may also have some capacity to block viral entry into cells. The study recruited both people with HIV and HIV-negative participants, and the antibody was found to be safe and displayed favorable pharmacokinetics. Trosunilimab is now being evaluated by AbbVie in combination with their PD-1 inhibitor budigalimab in a large international phase II trial that includes an ATI.
- Sara Gianella Weibel gave a talk describing potential benefits of the anti-CMV drug letermovir in people with HIV; in an ACTG trial, there was long-term reduction in inflammatory biomarkers and improvements in measures of aging-related physical function. Another study of letermovir in people with HIV on ART has been registered in the UK but isn’t yet listed as open for enrollment.
- A poster by Timothy J. Henrich and colleagues reported results from a small trial of stem cells gene-modified to promote resistance to HIV. The study recruited people with HIV and lymphoma who required a stem cell transplant. The gene-modified cells persisted in recipients and there was evidence of expansion and protection from HIV infection in one individual who underwent ATI, however they met ART restart criteria within eight weeks.
- MHRP investigators preparing for a combination HIV cure-related protocol in Thailand involving bNAbs and therapeutic vaccines have developed “a strategy combining sequence analysis, in silico bnAb sensitivity predictions and neutralization assays to prioritize enrollment of participants with the most sensitive viruses to the bnAbs that will be used in an ATI.” The idea is to try to maximize the benefits to the participants. Notably, HIV samples from only 21.5% of 116 people screened showed sensitivity to both bNAbs (PGDM1400LS and VRC07-523LS).
- Rafick P. Sekaly’s research group conducted a randomized 30-person clinical trial of a gene therapy originally developed by Sangamo to assess for any reductions in the HIV reservoir. The approach involves infusions of CD4 T cells genetically modified to abrogate expression of the CCR5 co-receptor. A poster presentation disclosed that no significant decline in the intact HIV reservoir was detectable after either 48 or 96 weeks of follow up.
- Researchers in France shared two abstracts about a trial of a full-spectrum cannabidiol in people with HIV on ART. Eighty participants were assigned to receive either 1mg/kg twice a day of a full-spectrum, pharmaceutical grade, CBD oil or a placebo medium-chain triglyceride oil for 12 weeks. There were no significant adverse events and a reported diminution of bilirubin levels and a lower median heart rate in male participants. A second poster abstract described potential anti-inflammatory effects that appeared greater in male participants.
- Mauro Garcia used samples from the BEAT-2 clinical trial in Philadelphia to show that when considering the effects of bNAb infusions on time to viral load rebound during ATI, the natural antibody responses of the recipients (autologous neutralizing antibodies or aNAbs) need to be taken into account. The presence of aNAbs against HIV was significantly correlated with delayed time to the reappearance of viral load after ATI.
- Samples from participants in two studies in TAG’s listing, DGVTAF and APRIL, were used by researchers to interrogate research questions not directly related to the primary purpose of the protocols. In the former case, Hunter M. Courtney and colleagues tracked the evolution of aNAbs and HIV in people who started ART very early. Samples from APRIL were utilized to show that the capsid inhibitor lenacapavir can promote the degradation of viral Gag proteins in HIV-infected cells.
- Multiple abstracts were presented from the very large 2000 HIV Human Functional Genomics Partnership Program (2000HIV) observational study in the Netherlands. Findings included:
- A lack of linkage between residual viremia on ART and immune activation/inflammation (but other possible associations of interest);
- Highest levels of PD-1 expression observed in participants with “higher CMV reactivity, higher HIV reservoir size, males, and immunological non-responders”;
- Samples from females with HIV display enhanced IFN pathway gene expression but lower pro-inflammatory IL-1β production upon TLR7 activation compared to males with HIV;
- An association between mitochondrial gene variants and natural immune control of HIV, and lower HIV reservoirs;
- Differential regulation of immune responses to CMV in natural HIV controllers compared to non-controllers;
- Three distinct clusters of HIV reservoir profiles identified by multiomics in people on ART: 1) High total HIV DNA, low intact HIV DNA (n=348), 2) low total HIV DNA, low intact HIV DNA (n=421), and 3) high total HIV DNA, high intact HIV DNA (n=467).
In addition to these studies presented at CROI 2025, links to were added to newly published information from five trials in the listing:
- A social science study that solicited important feedback from participants in an ongoing ATI trial involving members of the SCOPE cohort in San Francisco .
- An evaluation of the anti-HIV effects of the bNAbs VRC01LS and VRC07-523LS in people with HIV who hadn’t yet initiated ART, published in JCI Insight.
- From the HIV Mercuri observational study, an analysis of HIV reservoirs in blood and tissues that found a lack of compartmentalization and further evidence that effective ART completely suppresses viral replication.
- A secondary paper from the previously published Tatelo trial of dual bNAbs for the maintenance of viral load suppression in infants with HIV, which describes biomarkers that predicted efficacy.
- Results from the AELIX-003 trial in Spain that tested therapeutic HIV vaccines and the TLR7 agonist vesatolimod, previously presented at CROI 2023. The regimen was safe and induced T cell responses that were associated with a slightly increased likelihood of remaining off ART during a 24-week ATI, albeit based on maintaining viral load below 10,000 copies/ml.
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