TAG HIV Basic Science, Vaccines, and Cure Project Blog

By Richard Jefferys, Project Director at Treatment Action Group (TAG).

recent posts

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the December 2025 and January 2026 Updates

    There were 14 updates to the TAG listing for December 2025, and a further eight for January 2026. No new HIV cure-related studies were identified in registries during this period.

    Updates to Enrollment Status

    A clinical trial testing the Janus kinase inhibitor baricitinib in Barcelona that was added to the listing in July 2025 is now open for enrollment. The study will evaluate baricitinib’s safety, tolerability, and effects on CD4 T cells, with secondary endpoints including measurements of the HIV reservoir.

    Four studies have closed to enrollment:

    • A protocol investigating drug interactions between Merck’s candidate TACK molecule MK-4646 and the TB drug (and liver enzyme inducer) rifabutin, which recruited HIV-negative participants.
    • An observational study evaluating two candidate biomarkers that may be associated with HIV DNA levels in people with HIV on antiretroviral therapy (ART).
    • A trial at the National Institutes of Health (NIH) Clinical Center and Rockefeller University investigating dual broadly neutralizing antibodies (bNAbs) in people on antiretroviral therapy (ART). The protocol enrolled 105 people and administered the long-acting bNAbs 3BNC117-LS and 10-1074-LS. Participants are now being offered the opportunity to join a follow up study involving an analytical treatment interruption (ATI).
    • The suspension of a study of an HIV vaccine construct in people with HIV has been lifted, but the protocol is now in follow up and closed to further enrollment. The focus of the research is assessing the potential to promote the development of bNAbs using a protein named 426c.Mod.Core-C4b (delivered with an adjuvant).

    An investigation of immunization with an HIV envelope protein, CH505 TF chTrimer, is now listed as temporarily paused but no reason is given in the registry entry.

    One trial has been completed and moved to table 3: an assessment of whether people with a specific genetic profile who started ART early have an increased potential to achieve posttreatment control of HIV viral load after an ATI. Results are likely to be presented at either CROI or the AIDS 2026 conference in July.

    New Links to Study Results

    Data from several of the studies in the listing provided the basis for two papers and an accompanying commentary published in the journal Nature on December 1st, World AIDS Day. The reported analyses focus on immunological parameters associated with achieving post-intervention control (PIC) of HIV viral load after an ATI.

    Zahra Kiani and colleagues assessed data from 12 participants in four clinical protocols testing candidate therapeutic interventions (primarily bNAbs) that included an ATI (MCA-906, MCA-965, TITAN and eCLEAR). The research identified multiple properties of participant HIV-specific CD8 T cells that were linked to an increased likelihood of controlling viral load after ART interruption, including: baseline proliferative capacity (ability to copy themselves), cellular youthfulness referred to as stemness, and capacity to kill cells displaying HIV fragments in a lab dish (cytotoxicity). The administration of bNAbs was associated with an increase in HIV-specific CD8 T cell stemness, which in turn was related to superior CD8 T cell metabolic fitness, reduced markers of T cell exhaustion, and a greater chance of post-intervention viral load control.

    In a separate paper, Michael Peluso and colleagues from the University of California San Francisco report broadly similar findings from a small, amfAR-funded multi-intervention trial in which the majority of the participants displayed some degree of control viral load after ATI (including some cases of persistently undetectable levels). Factors associated with post-intervention control included robust CD8 T cell expansion (proliferation) in response to HIV viral load rebound and CD8 T cell expression of TCF-1, a marker of cellular stemness.

    In an accompanying commentary, Jonathan Li states:

    “The two studies offer a coherent vision for how ART-free HIV remission might one day be achieved. They underscore three key principles. First, the quality of anti-HIV CD8+ T cells matters, especially the presence of stem- cell-like antiviral CD8+ T cells that are capable of sustained proliferation and cytotoxic responses. Second, bNAbs and T cells might act in synergy, given that effective anti-HIV antibodies can delay or reduce the immediate post-ART viral rebound (or do both) and create an immune environment that is conducive to enhancing effective cellular responses. Third, therapeutic combination approaches that incorporate several branches of the immune response are likely to hold the greatest promise.”

    Links to another eleven new publications were also added during this period:

    In the journal Communications Medicine, Lucia Bailón and colleagues in Spain report that the magnitude of HIV-specific T cell responses at the time of ATI were associated with a greater chance of remaining off ART for a 12-week interruption in trials of a therapeutic vaccine either alone or combined with the TLR7 agonist vesatolimod. The criteria for ART restart in these studies was a single viral load >100,000 copies/ml or >10,000 copies/ml for eight consecutive weeks, meaning that only a relatively minor degree of viral load control was required to stay off ART for the duration of the 12-week ATI.

    A preprint (not yet peer reviewed) article on the ongoing RIO trial in the UK is available on the medRxiv server. Marcilio Fumagalli and colleagues report that receipt of dual bNAbs was associated with an accelerated decrease in the size of the intact HIV reservoir. Susceptibility of viruses in the reservoir to the bNAb 10-1074 and participants’ natural (autologous) antibody responses was significantly correlated with time to viral load rebound after ATI. Rebounding HIV showed evidence of the development of resistance to the bNAb 3BNC117 but not 10-1074; the likely explanation is that the parts of HIV targeted by different bNAbs can have differing capacities to mutate (similar to how HIV develops resistance more easily to some antiretroviral drugs compared to others).

    Three new papers were published over the holiday period describing results from social science studies involving young women participating in an ATI protocol in the FRESH cohort in South Africa:

    • In the journal HIV Research and Clinical Practice, Karine Dubé and colleagues assessed issues related to potential risks of sexual ATI transmission during ATI, revealing the challenges that this can raise for participants. Table 3 in the open access article offers recommendations for improving the promotion of protective behaviors during ATI trials.
    • Krista Dong and colleagues in Frontiers in Public Health report on a socio-behavioral study involving five male partners and five members of the families of ATI trial participants.
    • Ali Ahmed and colleagues investigated the psychological impact of participating in the trial and their findings were posted online in AIDS Research and Human Retroviruses on December 22nd. The ATI was considered generally well tolerated, with anxiety only transiently increasing pre-ATI, but for the subset of participants who achieved extended posttreatment control of HIV viral load the prolonged time off ART was associated with a persistent elevation of anxiety and depression. The authors note that this latter finding was “possibly because worries about viral rebound and HIV transmission persisted.” Similar concerns have previously been reported by Luis Canales, a posttreatment controller in a US-based study .

    The cytokine interleukin-2 (IL-2) was the first intervention suggested to have the capacity to potentially reverse HIV latency and flush out the viral reservoir, back in the late 1990s. However, studies involving ART interruption didn’t demonstrate notable effects on HIV viral load rebound. Results from a recent trial in people on ART conducted at Case Western Reserve University have been published in Scientific Advances, reinforcing that IL-2 can stimulate HIV production by latently infected CD4 T cells but with side effects that caused the protocol to be stopped early. In the discussion section of the paper, the authors cite the development of potentially safer IL-2 variants that they argue may deserve evaluation in the context of HIV cure research.

    A preprint article on a trial testing a doubled dose of the integrase inhibitor dolutegravir has been posted by medRxiv. The authors outline evidence that the increased dose led to reductions in measures of the HIV reservoir and immune activation, suggesting the participants’ previous regimens weren’t fully blocking HIV replication. The results run counter to a considerable amount of prior evidence that standard ART typically fully suppresses HIV, and it may be prudent to wait for the peer reviewed version before considering the possible implications.

    Finally, four newly linked papers focus on gut-related aspects of HIV cure research:

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the November 2025 Update

    There were 10 changes to the TAG listing in the November update. The completed studies table has also been slightly reorganized to separate the previous “antibodies” category into more specific groupings: anti-α4β7 integrin antibodies, broadly neutralizing antibodies, and intravenous immune globulin (IVIG).

    New Additions

    Only one new HIV cure-related trial was added since the previous update: an evaluation of interactions between Merck’s MK-4646 and the TB drug (and liver enzyme inducer) rifabutin in 18 HIV-negative participants. The study is due to be completed by the end of the year. MK-4646 is an experimental candidate in a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) specifically designed to promote the destruction of HIV-infected cells (categorized as Targeted Activator of Cell Kill or TACK molecules, see prior blog coverage for details). A trial of MK-4646 in people with HIV is ongoing in Moldova and Romania.

    Thanks to a poster on Bluesky for alerting us to this study, which wasn’t registered as HIV-related and hence was missed when first posted in clinicaltrials.gov at the end of September.

    Updates to Enrollment Status

    Four trials have been moved to the completed studies table, along with the addition of a past observational protocol relevant to HIV cure research that was previously missing from our listing (the completed CHRONOS study in Australia).

    In three instances, the reason for the move is lack of updates to registry records suggesting the trials are no longer ongoing (in one case, it’s unclear if the protocol ever started). Attempts to ascertain status via emails have been unsuccessful:

    The fourth addition is a therapeutic HIV vaccine trial sponsored by Hookipa Biotech testing arenavírus vectors, which is now listed as “terminated: business decision.”

    New Links to Study Results

    Since the last update in October, scientific papers have been published related to several studies in the listing:

    An article describing the design of AbbVie’s large phase 2 trial of the PD-1 inhibitor budigalimab and the α₄β₇ integrin inhibitor trosunilimab was made available online by the journal Contemporary Clinical Trials on November 9th. The open access paper focuses particularly on how the researchers approached the analytical treatment interruption (ATI) included in the protocol, including drawing on “consensus recommendations, existing interventional studies with ATI, engagement with HIV experts and HIV community members, correspondence with regulatory agencies, phase 1 study results, and the experience of PWH.”

    The authors note that the study is unique in international breadth, involving 90 sites across 12 countries. With 160 participants, it’s also the largest HIV cure-related trial including an ATI conducted to date. However, since the registry entry was initially updated at the end of September to “completed,” the record has been amended again to state: “Terminated Company Decision.” No reason is given but it may be cause to temper hopes regarding the results, which are expected to be presented at CROI 2026.

    Two new papers describe analyses involving 2000HIV cohort study participants in the Netherlands. In EBioMedicine, researchers report on differences in markers of gene activity between people who naturally control HIV viral load and non-controllers. A study published in Frontiers in Immunology also analyzes spontaneous HIV controllers in the cohort, comparing those who maintain low viral loads with elite controllers who are able to suppress HIV replication to undetectable levels. The study explores a wide range of immunological parameters and identifies commonalities and differences between the groups that  may be important for HIV cure research.

    Investigators conducting the Last Gift study have published an analysis of potential links between HIV reservoir measures and gut microbiota across five different segments of the gastrointestinal tract. A number of associations were identified that varied by location, but the work is exploratory and statistical significance wasn’t achieved when the results were adjusted for multiple comparisons. The authors note that the possibility of varying interactions along the GI tract should be considered when attempting to design microbiota-based strategies for modulating the HIV reservoir.

    The CHRONOS observational study ran from 2015-2018 and initially published findings related to the effect of the circadian rhythm on HIV RNA expression in the Journal of Infectious Diseases in 2021. In a newly published paper in the Journal of Virus Eradication, Jared Stern and colleagues report evidence that acute stress can induce the transcription of HIV RNA by reservoir cells containing HIV DNA. There was no indication of changes in the size of the HIV reservoir.

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the October 2025 Update

    For October 2025, there were 29 updates to the TAG listing. We’re very grateful to the employees at the National Center for Biotechnology Information who are continuing to maintain the trial registry clinicaltrials.gov and scientific literature database PubMed during the current US Federal government shutdown (likely without pay).

    New Additions

    Three newly registered HIV cure-related clinical trials were added:

    The DART DELIVER-02 study is evaluating two antibody-based constructs called dual affinity retargeting (DART) molecules. The DART molecules are designed to bind the CD3 molecule expressed on all T cells, in tandem with the HIV envelope protein when it’s expressed on the surface of virus-infected cells. The aim is to endow any T cell with the capacity to recognize and destroy cells containing HIV. The candidates being tested in the study (MGD014 and MGD020) are manufactured by the biotechnology company Macrogenics, with each designed to recognize different parts of the HIV envelope. Both MGD014 and MGD020 have previously been tested in people with HIV, with no apparent safety issues. The new protocol involves a brief antiretroviral therapy (ART) interruption and some participants will also receive the HDAC inhibitor vorinostat. Recruitment has begun at a University of North Carolina site, with additional locations in Kenya listed in the registry entry but not yet open for enrollment.

    The ACTG network is initiating a small trial of the aminobisphosphonate drug alendronate in people with HIV. Better known by the trade name Fosamax, alendronate is an approved treatment for osteoporosis and bone disease that has been reported to potentially exert HIV latency reversal activity. The study aims to assess any effects of alendronate on the size and activity of the HIV reservoir.

    Emory University is launching a second trial of the Janus kinase inhibitor baricitinib in people with HIV on ART (an ongoing protocol at the institution is focused on central nervous system effects of the drug). The design of the new study includes an analytical treatment interruption (ATI) to investigate whether receipt of baricitinib can maintain HIV suppression in the absence of ART.

    Two long-running observational studies were also added to table 2 in the TAG listing, because samples from participants are now being used to advance HIV cure research:

    • The SCOPE cohort at the University of California, San Francisco.
    • A leukapheresis sampling protocol at the National Institutes of Health (NIH) Clinical Center in Bethesda, which collects plasma and lymphocytes for use in studies.

    Updates to Enrollment Status

    Three trials have opened for enrollment since September:

    The release of NIH funding has allowed the ACTG to lift a pause and restart enrollment in several HIV cure-related protocols involving administration of bNAbs and HIV vaccines: NCT06205602, NCT05719441 and NCT06071767.

    Three additions were made to the completed studies table:

    New Links to Study Results

    Findings from the first iteration of the IMPAACT P1115 pediatric HIV cure research study were published in the Lancet HIV in September. Four cases of extended ART-free remission were documented after an ATI, with one of the children experiencing a late HIV viral load rebound after about 1.5 years off ART. The results were first presented by Dr. Deborah Persaud at CROI 2024 (see webcast and coverage by Liz Highleyman for AIDSMap).

    Phase 1 trial results for AbbVie’s PD-1 inhibitor are now available in Nature Medicine, following their presentation by Jean-Pierre Routy at the 2023 European AIDS Conference. The paper reports evidence of enhanced control of HIV viral load after an ATI, but the pending findings from the 163-person phase 2 study will provide a clearer answer as to whether the approach holds promise.

    Two links were added for the Tatelo Study that tested dual bNAbs as a potential ART alternative in children in Botswana. In Clinical Infectious Diseases, the researchers describe the long-term outcomes among participants who underwent an ATI, uncovering no evidence of any negative consequences. A link was also added to an AIDS 2024 abstract previously missed, which reports possible improvements in growth associated with bNAb-mediated HIV suppression (this analysis is as yet unpublished). The primary results from the trial were published in the journal Science Translational Medicine in 2023, and a further assessment of the approach using three different bNAbs is now underway (the Tatelo Plus Study).

    Researchers in the Netherlands published results derived from their very large 2000HIV cohort study and a substudy on innate immunity in the open access journal EBioMedicine. The analyses focus on the profile of natural killer (NK) cell responses in study participants controlling HIV viral load in the absence of ART.  

    An investigation of the comparability of different approaches to measuring the HIV reservoir, reported in the journal AIDS, drew samples from participants in two protocols in the listing: a completed short-term ATI study and an ongoing observational leukapheresis sampling project, both at the NIH Clinical Center in Bethesda.

    Results from a 60-person trial of Bacillus Calmette-Guérin (BCG) vaccination conducted in Zurich were published in Open Forum Infectious Diseases. The purpose was to evaluate safety and any effects on the HIV reservoir (while BCG is primarily known as a partially effective TB vaccine, it has also been shown to modulate innate immunity). The researchers report no serious adverse events, but no detectable alteration in intact HIV reservoir size. Typical BCG local skin reactions and scarring were common.

    Samples from participants in the ACTG network A5321 cohort study were included in an analysis of how levels of intact and defective HIV change in response to ART, published in Open Forum Infectious Diseases.

    The listing entry for the Netherlands Cohort Study on Acute HIV infection (NOVA) saw three new links added. The first is to a poster abstract (eP004) presented at the recent 2025 European AIDS Conference, which describes evidence of proliferative HIV-specific CD8 T cell responses driving virus escape mutations and potentially also promoting viral integration into inhospitable regions of infected CD4 cell genomes that are less likely to allow for HIV to reemerge. In a separate paper in the Journal of Virus Eradication, social scientists report on the perceptions of HIV cure research among 20 cohort members. During in-depth interviews, participants noted limited knowledge of the cure research field. Half were open to participating in studies with short-term ATIs, but only one was open to the idea of extended ATIs with concerns about viral load rebound and risk of onward transmission prominent among the respondents. The third NOVA addition is a link to a historical paper from 2020 in BMJ Open providing background on the study cohort.

    Another link to the abstracts from the 2025 European AIDS Conference was added for the APRIL observational study in France. The abstract (PS07.2) outlines a laboratory analysis of the effects of lenacapavir on the HIV reservoir using participant samples, providing additional evidence that the drug may be capable of enhancing both innate and adaptive immune responses by degrading the integrity of the HIV capsid and essentially rendering viral components more visible.

    Lastly, a link was added to the clinicaltrials.gov results page for a completed study of the DART molecules MGD014 and MGD020. The detailed presentation of participant data in the registry entry format makes interpretation difficult, but it appears that the interventions were safe which has allowed for the initiation of the DELIVER 02 trial mentioned at the beginning of this post.

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the September 2025 Update

    For September 2025, there were 11 updates to the TAG listing.

    Please note that due to the closure of Typepad, we’ve now shifted to WordPress. Email subscriptions have been transferred, but please email (richard.jefferys@treatmentactiongroup.org) if you encounter any issues.

    New Additions

    One new clinical trial was registered over the past month, an investigation of the cytokine interleukin-15 (IL-15) led by Michael Peluso at the University of California San Francisco (UCSF). The protocol will administer N-803, a modified version of IL-15  approved for the treatment of bladder cancer, and involves an analytical treatment interruption (ATI) to assess whether the intervention enhances control of HIV viral load when antiretroviral therapy (ART) is interrupted. Enrollment is by invitation, likely from the large SCOPE Cohort of people on long term ART at UCSF. The study is supported by amfAR.

    Updates to Enrollment Status

    An HIV vaccine study in people with HIV is listed as temporarily closed “to study agents/products” (no details are provided). The protocol is evaluating protein-based candidates designed to spur early steps toward induction of broadly neutralizing antibodies (bNAbs), and investigating the effects of an ATI on vaccine-induced immune responses.

    An ACTG trial investigating dual bNAb therapy at sites in Botswana, Malawi, and South Africa is now closed to enrollment. The protocol included an ATI and recruitment was stopped early after a review indicated that rates of post-treatment control were too low to support continuation.

    Four trials have been completed and moved to table 3 in the listing:

    New Links to Study Results

    Four entries in the listing had links added to newly published papers:

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the August 2025 Update

    For August 2025, there were eight updates to the TAG listing.

    New Additions

    A study sponsored by the ANRS RHIVIERA project in France plans to investigate the JAK1/JAK2 Inhibitor baricitinib and the mTOR Inhibitor sirolimus in people who started antiretroviral therapy (ART) soon after HIV acquisition. Baricitinib is also being tested in several other ongoing studies, spurred by laboratory evidence of potential activity against the HIV reservoir. Sirolimus has been reported to reduce HIV DNA levels in a prior ACTG-sponsored trial.

    The protocol design involves four arms in which participants will receive baricitinib, sirolimus, baricitinib plus sirolimus, or placebos once daily for ten weeks. Participants receiving just one of the drugs will receive a placebo of the other, to ensure assignments are blinded. An analytical treatment interruption (ATI) will be initiated two weeks into the dosing period, meaning that participants will receive the medications (and/or placebos) for eight weeks while off ART unless restart criteria are met. The primary endpoint is time to viral load rebound of sufficient magnitude to trigger ART restart, but information on the exact viral load criteria isn’t provided in the registry entry.

    Updates to Enrollment Status

    A phase I trial in Moldova and Romania assessing Merck’s TACK molecule candidate MK-4646 wasn’t open at the time it was added to the listing last month, but has since begun recruiting. The same is true for ViiV Healthcare’s investigation of the combination of a long-acting broadly neutralizing antibody (bNAb) N6-LS and the CD4 attachment inhibitor fostemsavir, which is now enrolling at sites in Florida and Missouri in the US.

    IAVI have officially announced that enrollment has begun for their C114 protocol assessing a vaccine that uses a Gorilla adenovirus vector to deliver components derived from HIV designed to induce virus-specific T cell responses. The trial will include both people with HIV and an HIV-negative cohort, with sites located in South Africa and Zimbabwe.

    A study of a Gilead Sciences bispecific T cell engager candidate, GS-8588, is now listed as closed to further enrollment on the University of Pennsylvania website. As is often the case with Gilead Sciences, the phase I study hasn’t been registered in clinicaltrials.gov (registration of phase I trials isn’t mandatory under the relevant regulations).

    A PENTA Foundation sponsored trial of therapeutic vaccination in children and youth with HIV, titled HVRRICANE, has been completed (and moved to the completed studies table). Preliminary safety results were presented at CROI 2024, and increases in HIV-specific immunity were described in a poster at CROI 2025.   

    New Links to Study Results

    Results from a combination HIV cure trial in Brazil that was completed in 2020 were published in the Journal of Infectious Diseases on August 14th. In TAG’s recently posted 2025 Research Toward a Cure and Immune-Based Therapies Pipeline Report, we noted that full results from this study hadn’t yet been formally disclosed, which was true at the time of going to press but unfortunately very quickly out of date. Thanks to co-author Andrea Savarino for letting us know about the publication.

    The trial randomly assigned 30 participants into six small groups of five, receiving either:

    1. ART alone
    2. ART intensified with the addition of maraviroc (MVC) and dolutegravir (DTG)
    3. ART + MVC + DTG + nicotinamide (a form of vitamin B3 reported to have HIV latency-reversing potential)
    4. ART + MVC + DTG + auranofin (an antirheumatic drug reported to have potential anti-HIV reservoir activity)
    5. ART + DTG + dendritic cell-based therapeutic vaccine
    6. ART + DTG + nicotinamide + auranofin + dendritic cell-based therapeutic vaccine

    Receipt of the interventions did not lead to any significant safety issues, and 26 of the 30 participants subsequently consented to undergo an ATI. Two participants who’d interrupted ART earlier during the study were excluded, and another two participants declined the ATI.

    Analyses of ATI outcomes found statistical trends toward lower viral load setpoints in the multi-intervention group (group six), when compared to both their pre-ART baselines and participants in the other arms. Additionally, one participant experienced extended posttreatment control of viral load to undetectable levels for 78 weeks prior to rebound, and two additional participants maintained low viral loads for 22 weeks and then reinitiated ART. All three had received nicotinamide, but the numbers were too small to document a robust statistical association.

    The authors are now planning a larger 70-person protocol in hopes of bolstering and validating their preliminary observations. In the new study, ten participants will serve as controls while 60 receive the same regimen as the multi-intervention group in the previous study, with maraviroc added during the first 44 weeks.

    Notably, before the new publication, partial results from this study had been presented in several prior conference presentations and papers (see the links in the first entry in the “combinations” section of the completed studies table). The participant with the most extended period of posttreatment control was reported as a possible long-term remission case at the AIDS 2020 conference, and then posited at CROI 2021 to have potentially acquired a second HIV variant when they later experienced an HIV viral load rebound – this individual is described in the new paper, but the previous explanation offered for the return of viral load isn’t mentioned.

    Several links were also added this month for results reported from the observational Last Gift cohort study. The project represents a novel and carefully considered approach to involving people with HIV reaching the end of life in HIV cure research. Participants consent to donate their bodies for rapid autopsy analyses after death, allowing for detailed investigations of HIV persistence and tissue distribution. The new links include papers in the journals AIDS Care, JAIDS, Life Science Alliance, and AIDS. Community advocates and social scientists are deeply involved in the work, and several have contributed to an article in the Journal of Infectious Diseases advocating for policy revisions to end discriminatory policies relating to anatomical donations from people with HIV and other infectious diseases.

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the July 2025 Update

    The were ten updates to the TAG listing in July 2025.  

    New Additions

    Four newly registered HIV cure-related studies were added:

    Oxford University in the UK is sponsoring AbVax, a phase II combination trial that will administer therapeutic vaccines designed to induce T cell responses against HIV plus two broadly neutralizing antibodies (bNAbs), teropavimab and zinlirvimab (also known as 3BNC117-LS and 10-1074-LS). A novel aspect of the protocol involves the use of a short interruption of antiretroviral therapy (ART) that the researchers are calling treatment interruption induced viremia (TIIV), intended to interact with the combination therapies to potentially bolster immune responses prior to the conduct of a longer analytical treatment interruption (ATI).

    ViiV Healthcare plans to assess whether adding the CD4 attachment inhibitor fostemsavir to the long-acting bNAb N6-LS can reduce the HIV reservoir. Approximately 100 participants will be enrolled, either already receiving a standard of care ART regimen with an integrase inhibitor or naïve to ART and initiating such a regimen on entry. Participants will be randomly assigned to receive either N6-LS, N6-LS and fostemsavir, or just ART (the control group). Primary endpoints include the size and activity of the HIV reservoir measured by cell-associated HIV RNA and levels of intact and defective HIV DNA.

    A new trial of the Janus kinase (JAK) inhibitor baricitinib is being launched in Barcelona, Spain. Laboratory studies indicate baricitinib may have the potential to reduce HIV latency and reactivation. The main objective of the study is to evaluate safety, tolerability and effects on CD4 T cells, with secondary outcomes including measures of the HIV reservoir.

    Merck has initiated a new trial of a candidate targeted activator of cell kill (TACK) molecule, MK-4646, in Moldova. TACK molecules are non-nucleoside reverse transcriptase inhibitors (NNRTIs) that have been optimized to mediate destruction of cells containing HIV via a mechanism that involves recognition of the viral protease enzyme by innate cellular immune sensors (see previous blog post from 2023). The phase I study is open for enrollment with an anticipated completion date of April 2026. The protocol is focused on safety, tolerability and antiretroviral activity in people with HIV who haven’t yet received ART. A small safety study in HIV-negative people was already completed in Belgium last year, but to our knowledge results haven’t yet been publicly presented.

    Updates to Enrollment Status

    A study of the immunomodulatory anti-cancer drug pomalidomide in people on ART that was added to the listing in November 2024 is now open for enrollment in Denmark. Recruitment remains pending at an additional site in Australia. The protocol includes an ATI to evaluate whether receipt of pomalidomide alters HIV viral load rebound.

    New Links to Study Results

    Links were included to five abstracts presented at the recent International AIDS Society Conference on HIV Science in Kigali, Rwanda.

    Marina Caskey debuted preliminary results from a small combination study involving two bNAbs (3BNC117-LS and 10-1074-LS) plus the IL-15 cytokine superagonist N-803. Caskey noted that four participants suppressed HIV viral load to low levels after an ATI, with two experiencing posttreatment control for 72 weeks of follow up. Detailed coverage is available from Liz Highleyman in an article for Aidsmap, who thankfully have been able to maintain their conference coverage and website resources after support from the Terrence Higgins Trust averted a feared complete closure.

    Two IAS 2025 abstracts addressed findings from an HIV cure-related study in the FRESH cohort of young women in South Africa. The primary results were presented at CROI earlier this year by Thumbi Ndung'u (see prior blog post). Principal investigator Krista Dong described lessons learned from conducting the first HIV cure interventional trial in Africa in one presentation, and late-breaking results from the social science component of the protocol in a second abstract. In the latter analysis, ATIs were found to be tolerable psychologically by participants, but there was evidence of increased anxiety and depression associated with extended time off ART. The abstract concludes: “Findings support the inclusion of young women in ATI-inclusive trials but highlight the need for mental health assessments and directed psychosocial support, especially for trials that include prolonged ATIs.”

    Gaspar Canepa from the biotech company American Gene Technologies presented evidence that their gene therapy strategy for protecting and enhancing HIV-specific CD4 T cells may have led to reductions in the size of the intact HIV reservoir in some study participants. The abstract stresses “these results should be interpreted with caution” given the small numbers .

    Euphorbia kansui is a traditional Chinese medicine that has been reported to potentially have HIV latency-reversing activity. Several years ago, Jingna Xun and colleagues conducted a clinical trial in nine men on ART and at IAS 2025 they reported some evidence of cell-associated HIV RNA reductions in four participants and latency reversal (viral load transiently increasing to >50 copies/ml) in two participants, without any serious adverse events. The researchers conclude that the results may be sufficient to “warrant further investigation” of the intervention.

  • HIV Cure Research at IAS 2025

    IAS 2025, the 13th IAS Conference on HIV Science, is taking place in Kigali, Rwanda from July 14-17, with several pre-conference events scheduled on Sunday July 13. In many cases remote access will also be possible for registered attendees, with recordings made publicly available two months after the meeting ends. Links to events and sessions related to HIV cure research are appended below.

    Sunday July 13

    9:00am – 5:45pm local time (US Eastern time: 3:00 – 11:45am)
    Pre-conference session PC01
    Room: MH1
    Co-infections, viral and host factors: Impact on HIV cure strategies
    Organizer: IAS – the International AIDS Society

    Session 1: Opening and setting the scene
    Session 2: Viral synergy: Impact on HIV reservoirs
    Session 3: Impact of bacterial and fungal co-infections on the reservoir
    Session 4: Host factors
    Session 5: The role of HIV diversity in reservoir and response to cure interventions
    Session 6: Lessons learned from clinical trials in diverse populations

    Monday July 14

    11:30am – 12:30pm (US Eastern time: 5:30 – 6:30am)
    Satellite SAT07
    Room: MH2/Hybrid
    Consolidating and advancing African leadership of HIV Cure strategies to accelerate cure research for Africa and the world
    Organizer: HCAAP and Santhe on behalf of Africa Cure Consortium

    Tuesday July 15

    7:30 – 08:30am (US ET: 1:30 – 2:30am)
    Satellite SAT16
    Room: MH1/Hybrid
    Silencing the transcriptionally active HIV reservoir
    Organizer: The HOPE Collaboratory

    9:00 – 10:30am (US ET: 3:00 – 4:30am)
    Plenary session PL01
    Room: Auditorium
    Better meeting the needs of people living with HIV
    Understanding the HIV reservoir: Novel approaches to measure and test HIV-cure strategies
    Xu Yu, Massachusetts General Hospital, United States

    10:45 – 11:45am (US ET: 4:45 – 5:45am)
    Oral abstract session OAA01
    Room: AD12
    Targeting the HIV reservoir: Emerging discoveries and novel interventions

    3:00 – 4:00pm (US ET 9:00 – 10:00am)
    Oral abstract session OAA02
    Room: MH2
    Here to stay: Renewed momentum for bNAbs in HIV treatment and cure studies

    4:30 – 5:30pm (US ET 10:30 – 11:30am)
    Symposium SY06
    Room: MH3
    Innovations in HIV virology: Translating discoveries into novel therapies

    Wednesday July 16

    3:00 – 4:00pm (US ET 9:00 – 10:00am)
    Oral abstract session OAA04
    Room: AD12
    From cells to systems: The power of omics in HIV research

    4:30 – 5:30pm (US ET 10:30 – 11:30am)
    Symposium SY14
    Growing the paediatric response
    Broadly neutralizing antibodies in paediatric HIV: From HIV reservoir dynamics to clinical outcomes
    Mathias Lichterfeld, Harvard Medical School, United States

    Thursday July 17

    10:45 – 11:45am (US ET: 4:45 – 5:45am)
    Symposium SY17
    Room: AD12
    From insight to impact: Advances in understanding and achieving HIV immunological control

    12:15 – 1:15pm (US ET: 6:15 – 7:15am)
    Oral abstract session OAA05
    Room: MH4
    Basic science highlights: Cutting-edge research and implications

    3:15 – 5:00pm (US ET: 9:15 – 11:00am)
    Closing session CL01
    Room: Auditorium
    Rapporteur report-back and closing session

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the June 2025 Update

    The June 2025 update to TAG’s listing features 11 changes.

    New Additions

    Two studies were added:

    The ACTG has registered a new trial of dual broadly neutralizing antibodies (bNAbs), VRC07-523LS and PGT121.414.LS, in people who initiated antiretroviral therapy (ART) during acute HIV infection. The protocol includes an analytical treatment interruption (ATI) to assess whether receipt of the bNAbs is associated with continued suppression of viral load after ART withdrawal. The study isn’t yet recruiting and may be affected by the withholding of National Institutes of Health (NIH) funding for the ACTG by the current US administration. The registry entry lists sites in Brazil and Peru, so plans for the study could also be affected by the current “pause” on provision of NIH grant subawards that fund international clinical trial units.

    Researchers at the Assistance Publique – Hôpitaux de Paris in France are launching a new observational study investigating contributors to the persistence of low level HIV viral load that occurs in a subset of people on ART. Enrollment is pending.

    Updates to Enrollment Status

    A phase I ACTG study of a vaccine intended to promote the development of neutralizing antibody responses against HIV is now listed as open for enrollment. The vaccine consists of a stabilized form of the HIV envelope protein in a natural trimer (three-pronged) structure. The protocol is recruiting adults with HIV on ART with suppressed viral loads at multiples sites in the US.

    A trial sponsored by ViiV Healthcare investigating a bispecific bNAb (capable of recognizing two different targets on HIV’s outer envelope) has reopened for enrollment after briefly being listed as closed. The pause may have been related to the stepwise protocol design which involves multiple sequential cohorts, some initially receiving single doses before multiple doses are evaluated. 

    Two entries in the listing have now closed to enrollment and are in follow up:

    • AlloReSIST, which is testing an adoptive immunotherapy approach involving infusions of HIV-specific T cells in people who’ve received a stem cell transplant.
    • A study being conducted by the IMPAACT Network monitoring treatment outcomes in children who received early ART to potentially identify candidates for participation future HIV cure-related protocols.

    There are three additions to the completed studies table (table 3).

    A trial that recruited people who acquired HIV during the Antibody-Mediated Prevention (AMP) study at sites on the African continent. Investigators assessed whether receipt of the bNAb VRC01 prior to HIV acquisition enhanced the potential to control HIV viral load after an ATI. All participants had initiated ART rapidly after HIV diagnosis. Results were published recently in the Journal of the International AIDS Society, reporting some cases of post-treatment viral load suppression but with no evident impact of prior receipt of VRC01.

    A completed trial in Belgium was identified from the European clinical trials registry: a first-in-human assessment of new type of non-nucleoside reverse transcriptase inhibitor (NNRTI) called a Targeted Activator of Cell Kill (TACK) molecule. These molecules have the potential to not just inhibit HIV replication but also trigger the death of virus-infected cells. The approach is being developed by Merck who’ve reported promising laboratory results. The outcomes from this completed trial of an initial candidate codenamed MK-4646 haven’t been publicly presented to our knowledge.

    A study of a dendritic cell-based therapeutic vaccine registered to take place in Brazil has been moved to the completed table because the clinicaltrials.gov record hasn’t been updated for some time, and the listed contact hasn’t answered email requests for information on the status of the study. It’s not known if the trial ever took place.

    New Links to Study Results

    Links were added to new papers reporting results from two of the trials in the listing:

    • A phase I evaluation of an adoptive immunotherapy strategy involving infusions of HIV-specific T cells, published in Nature Communications. The data were previously described in conference abstracts, indicating that the intervention was safe with some hints of activity against the HIV reservoir.
    • A small phase I trial of N-803, a modified version of the cytokine IL-15, published in JCI Insight. The investigators found some evidence of a reduction in the number of cells containing HIV RNA or DNA in lymph nodes of six participants with available samples, but the decline didn’t reach statistical significance. These reductions were associated with markers of natural killer (NK) cell activity, suggesting N-803 enhanced NK cell function. In terms of safety, there were similar grade 3 injection site reactions to prior studies including reddening of the skin and induration. There were also some cases of transient low estimated glomerular filtration rate (eGFR). Additional studies of N-803 in people with HIV are ongoing (see table 1 in the listing).

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the March, April, and May 2025 Updates

    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:

    Three entries have been completed and moved to table 3 in the TAG listing:

    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:

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the February 2025 Update

    For February 2025, there were eight updates to TAG’s listing.

    New Additions

    Four new protocols were added.

    In Toronto, a trial is underway that aims to assess whether the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz may be able to promote the death of HIV-infected cells.

    The rationale derives from evidence that certain NNRTI molecules can cause the HIV protease enzyme to be produced prematurely during the viral life cycle, which triggers an antiviral signaling cascade leading to the death of the infected cell. As described in detail in a prior blog post, Merck is pursuing the development of new NNRTIs optimized for this activity, which they call Targeted Activators of Cell Kill (TACK) compounds.

    Merck researchers have stated that currently FDA-approved NNRTIs are unlikely to be able to mediate TACK activity, but not all scientists have reached the same conclusion – at least one published study has suggested that efavirenz (EFV) and rilpivirine (RPV) might be exceptions:

    “In NNRTI-treated patients, NNRTI plasma concentrations are in the range of efficient NNRTI-induced PR [HIV protease] cytotoxicity reported here. For example, EFV remains above 3.2 μM (1 μg/mL) and RPV remains above 0.4 μM (400 ng/mL). However, lower penetration of NNRTIs occur in peripheral compartments such as lymphoid tissues, which are primary sites of the HIV-1 reservoir.”

    The trial in Toronto, led by Dr. Mario Ostrowski, is recruiting people on antiretroviral therapy (ART) with a history of low-level detectable HIV viral load (between 20-400 copies/ml). Participants will add a daily dose of 600mg of efavirenz to their regular ART regimen for two months, with various measures of HIV persistence compared before and after the intervention. The hope is that efavirenz might have sufficient TACK activity to deplete the HIV-infected reservoir cells suspected of generating low-level viral load that can’t be suppressed by ART (sometimes referred to as “unsuppressible viremia,” see TAG/HIV i-Base webinar from 2023 for additional background).

    Another new study involving an FDA-approved antiretroviral has been registered but isn’t yet recruiting participants. The researchers plan to add the capsid inhibitor lenacapavir to standard ART and evaluate whether the approach can promote greater reductions in the size of the HIV reservoir. A recently published paper has reported that lenacapavir may enhance natural antiviral mechanisms in HIV-infected cells by disrupting the capsid protein, which typically shields viral DNA from recognition by innate immune sensors.

    The trial is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and scheduled to take place at the National Institutes of Health (NIH) Clinical Center. It’s currently unclear if the egregious, politically motivated disruptions to the conduct of science at NIH might affect these plans.

    A research group led by Dr. Ricardo Diaz at the Federal University of São Paulo in Brazil has registered two HIV cure-related protocols over the past month. The first is a 70-person trial investigating a combination regimen that previously showed some promise in enhancing post-treatment control in a smaller study that first reported results at CROI in 2019, but to our knowledge hasn’t shared the full findings in a journal article yet. The components being added to standard ART include the CCR5 inhibitor maraviroc, the integrase inhibitor dolutegravir, a dendritic cell-based therapeutic vaccine, auranofin, and nicotinamide (a form of vitamin B3). The protocol includes an analytical treatment interruption (ATI).

    The second trial may be a late registration of a study that already had results presented at the HIV Glasgow conference last November. The intervention is a product called Gammora added to ART. The checkered and dubious history of Gammora — sometimes named Codivir — was covered in a prior blog post. The results reported in Glasgow indicated very rapid declines in HIV DNA levels (see abstract P212), but the past actions of the manufacturer leave some uncertainty regarding the extent to which the data can be trusted (at least from TAG’s perspective).  

    Updates to Enrollment Status

    Two studies in the listing updated their enrollment status:

    • Now open for recruitment is ACACIA, a trial sponsored by the ACTG evaluating dual bNAbs and ART that includes an ATI. The aim is to enroll 135 people, making it the largest HIV-cure related study on the African continent so far (current sites include Botswana and South Africa). The US President’s heinous recent decision to dismantle USAID and stop PEPFAR funding could conceivably affect this type of research, because some potential participants may depend on the program for access to ART.
    • The largest international HIV-cure related clinical is being undertaken by the pharmaceutical company AbbVie to assess whether receipt of budigalimab (a PD-1 inhibitor) with or without ABBV-382 (an anti-α₄β₇ integrin antibody) can promote control of viral load during an ATI. The protocol is now closed to new enrollment and in follow up.

    New Links to Study Results

    Links to were added to newly published information from two trials in the listing:

    • Karine Dubé and colleagues published findings from the social science component of a small study investigating a combination of interventions at the University of California, San Francisco (UCSF). The researchers found that overall satisfaction with participation was high, with the altruistic desire to contribute to the scientific development of an HIV cure being a major motivation. Several issues of potential concern were identified, including misestimation of the likelihood of therapeutic benefit, mixed feelings about restarting ART after ATI with some difficulties maintaining adherence, and social harms related to worries about HIV transmission risk and intimacy with partners.
    • A paper published in the Journal of Virology draws on data from a trial involving people who started ART very rapidly after HIV acquisition. The investigators describe evidence of preferential depletion of the intact HIV reservoir, and encouragingly note that: “Our findings suggest the existence of immune responses that act selectively to reduce HIV transcriptional completion and/or preferentially kill cells making completed or intact HIV RNA.”