TAG HIV Basic Science, Vaccines, and Cure Project Blog

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:

• 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.

TAG’s HIV Cure-Related Clinical Research Listing: Background on the December 2024 Update

For December 2024, there were seven updates to TAG’s listing.

New Additions

The lone addition this month is a clinical trial sponsored by the ACTG investigating the capacity of a therapeutic vaccine to promote neutralizing antibody responses against HIV. The vaccine contains a stabilized part of the outer HIV envelope designed to mimic the natural conformation of the protein, delivered with an Alum adjuvant. The construct, called a stabilized CH505 TF chTrimer, has previously been reported to show promise as a preventive vaccine in the SHIV/macaque model. The study isn’t yet open for enrollment, there will be multiple sites in California, Colorado, Georgia, Illinois, Maryland, Massachusetts, Missouri, New Jersey, New York, North Carolina, Ohio, Pennsylvania, Tennessee, Texas, and Washington (see registry entry for location details).

Updates to Enrollment Status

Five studies changed their enrollment status:

• The Tatelo Plus trial in Botswana evaluating dual broadly neutralizing antibodies (bNAbs) in infants, added to the listing in August, is now open and recruiting.
• A ViiV Healthcare-sponsored study of a bispecific bNAb codenamed VH4527079 is closed to further enrollment, the estimated completion date is June 2026.
• A therapeutic vaccine trial at the University of North Carolina has also closed to enrollment. The research is assessing the safety and immunogenicity (ability to induce T cell responses against HIV) of vaccines based on chimpanzee adenovirus (ChAd) and modified Vaccinia Ankara strain (MVA) in people with HIV on antiretroviral therapy (ART). Estimated completion date is February 2025.
• A widely publicized first-in-human study of a CRISPR-based approach to excising HIV from reservoir cells is now completed. Results were presented at the AIDS 2024 conference in July (video is available on the website, see "session recording" link) and reported in a blog post in August.
• A trial of the PD-1 inhibitor ASC22 in China is also now completed; to our knowledge results have yet to be presented. There has been a published report from a separate study combining ASC22 with the HDAC inhibitor chidamide in people with HIV on ART, which suggests that it was relatively well tolerated albeit with some immune-mediated adverse events that are known to be associated with PD-1 inhibitors.

New Links to Study Results

The only new links to results this month are for a paper published in the Journal of Infectious Diseases that draws information from two studies in the listing: the Zurich primary HIV infection cohort and ACTG 5345, a completed assessment of biomarkers that might predict time to viral load rebound in people interrupting ART.

The study authors identify several factors that were associated with shorter time to viral load rebound among study participants, including later ART initiation, higher pre-ART viral load, higher total HIV DNA levels, and increased amounts of HIV transcription (the virus translating DNA into RNA). Immunological factors included lower CD4 T cell counts at the time of ART interruption and higher proportions of short-lived effector T cells and T cells showing evidence of exhaustion and terminal differentiation (no longer able to proliferate and respond as well). These immunological factors only showed significant associations with shorter time to viral load rebound in people who’d started ART early after HIV acquisition, not in individuals treated later.

There were also differences identified based on sex, with greater genetic diversity of HIV in the reservoir associated with shorter time to viral load rebound only in men. The authors note that this may be related to previously described immunological sex differences: “hormonal differences, genetic factors, and variations in immune system functioning could contribute to these discrepancies.” For example, female sex has been associated with higher levels of production of naïve T cells from the thymus across the lifespan, which could conceivably convey a superior ability to mount an immune response to diverse HIV variants.

Studies of cisgender people and transgender people receiving gender-affirming care have the potential to shed light on the role of hormones compared to chromosomal factors in shaping sex-based immunological differences (e.g. see the recent paper on the immunological effects of gender-affirming hormone therapy in transgender men). But the current politically motivated bigoted attacks on the dignity, humanity, and healthcare needs of transgender people are profoundly damaging to efforts to conduct this important research, harming both transgender and cisgender people.

When the study authors constructed a multivariable model based on their results, the two parameters that emerged as most significantly predictive of shorter time to viral load rebound were levels of HIV DNA and terminally differentiated CD8 T cells. They conclude by stating:

“In summary, our findings collectively highlight the complex interplay between virologic and immunologic factors in determining HIV rebound dynamics especially in participants who started ART during chronic HIV, emphasizing the importance of early ART initiation. Further, it will be important to considered demographic (e.g., sex at birth) and immune profiles (e.g., minimize T cell activation and exhaustion) to optimize treatment outcomes and inform strategies towards achieving sustained viral suppression or eradication.”

Toward the end of 2024 there were two meetings on the topic of HIV cure research: the Joint Meeting of the Martin Delaney Collaboratories (MDCs) in November and the HIV Persistence Workshop in December. The agenda and abstracts are available for the MDC meeting, along with video of each day (day 1, day 2, day 3). Abstracts from the HIV Persistence Workshop have been published as a supplement to the Journal of Virus Eradication – links to any abstracts reporting on studies in TAG’s listing will be added next month.

TAG’s HIV Cure-Related Clinical Research Listing: Background on the September 2024 Update

For September 2024 there are six updates to TAG’s listing:

New Additions

One new study was registered over the past month, a protocol for conducting analytical treatment interruptions (ATIs) in people with HIV who’ve received successful stem transplants to treat cancers. The criteria require that the stem cell transplants were sourced from donors homozygous for the CCR5Δ32 mutation (as has occurred in the majority of cases of HIV cures achieved under these circumstances). The research is sponsored by the University of Kansas Medical Center and led by principal investigator Dr. Wissam El Atrouni. The study hasn’t yet opened for enrollment but the protocol has been designed for a specific local candidate; the researchers are open to additional recruitment if other potential participants are identified. 

Updates to Enrollment Status

An ACTG study of the long-acting broadly neutralizing antibodies (bNAbs) VRC07-523LS and PGT121.414.LS plus antiretroviral therapy (ART) is now open for enrollment. The protocol aims to recruit 48 participants with acute HIV (acquisition <90 days prior to screening) at sites in the United States, Brazil, and Peru. As noted by Katherine Bar in a presentation at this year’s pre-CROI community HIV cure research workshop, an ATI will be conducted after receiving the combination but the scheduling will be based on real-time assessment of how quickly the levels of the bNAbs decline – the minimum duration of treatment prior to ATI will be 48 weeks, but may extend to 60, 72, 84 or 96 weeks. The primary endpoints are safety and time from ART discontinuation to HIV viral load reaching  ≥1,000 copies/ml for four consecutive weeks during the ATI.

Researchers and advocates from the ACTG’s Partner Protections Working Group (PPWG) have also just published on their updated toolkit for mitigating HIV transmission risks during ATIs.

New Links to Study Results

At the IAS 2023 conference, Asier Sáez-Cirión presented on a possible case of an HIV cure achieved by a stem cell transplantation administered to treat a life-threatening cancer. Several individuals are considered to have been cured under similar circumstances, however — as mentioned above — in those prior instances the stem cells were sourced from donors homozygous for the CCR5Δ32 mutation, which makes immune cells resistant to most HIV variants.

Romuald, the person described by Sáez-Cirión (who’s since publicly identified himself in interviews), received a stem cell transplant from a donor lacking the CCR5Δ32 mutation (referred to as wild type CCR5). Previously, this type of stem cell transplantation has only led to short term remission from detectable HIV viral load, as in the two “Boston patients.”

Romuald’s case has now been published in the journal Nature Medicine, with a link added to TAG’s listing because he’s part of the IciStem observational cohort of people with HIV who’ve undergone stem cell transplantation during care for other conditions. The reasons for the extended absence of HIV and potential cure are uncertain but may be related to the occurrence of graft-versus-host disease (GVHD), which can involve transplanted immune cells killing the original host immune cells containing HIV. Management of GVHD has also required the administration of the drug ruxolitinib, which has been reported to have activity against the HIV reservoir. At the current time Romuald remains off ART without evidence of detectable HIV and follow up is continuing.

Results from a clinical trial of a triple bNAb combination led by Boris Juelg at the Ragon Institute and sponsored by IAVI were presented at CROI earlier this year and have now been published in Nature Medicine. The bNAb combination, comprising PGT121, PGDM1400, and VRC07-523LS, had previously demonstrated strong but transient suppression of HIV viral load in people with HIV who hadn’t yet started ART. The newer results are from a subsequent protocol administering the bNAbs to people with HIV on ART who underwent an ATI immediately after receiving the first bNAb infusions.

A majority of recipients (10 out of 12) experienced continued viral load suppression for at least 28 weeks, and a subset of five participants maintained control for 38-44 weeks (or more) even after bNAb levels declined to low or undetectable. In two cases viral load rebound occurred rapidly, and this was associated with the detection of resistance to the bNAbs in baseline samples. Participants weren’t screened for bNAb resistance before entering the study, and some researchers and advocates believe this should now be standard (while acknowledging the assays still have limitations).  

Findings from a trial that combined a PD-L1 inhibitor (ASC22) with the HDAC inhibitor chidamide (approved to treat several conditions in China) were debuted at IAS 2023 (see prior blog post). The results have now been published in the journal Signal Transduction and Targeted Therapy, providing evidence of some activity and support for further evaluation in the context of ATIs.

The French National Agency for AIDS Research (ANRS) is sponsoring a cohort study for people with HIV receiving immune checkpoint inhibitors to treat cancers. Results relating to effects on T cell responses and the HIV reservoir have previously been presented and published. The latest publication in the Journal for Immunotherapy of Cancer focuses on safety and tolerability, finding that incidence of adverse events was broadly comparable to people without HIV (similar to other independent studies). As the authors note in the discussion section of the paper, there were factors identified that were associated with a greater risk of immune-related adverse events (irAEs):

“The study showed that a low CD4 count, a longer time since HIV diagnosis, a history of cancer surgery and positive CMV serology at the start of ICI [immune checkpoint inhibitor] were risk factors for the development of severe irAEs. These data also suggest that ICI treatment has no impact on HIV control, with no disruption in control of viral replication and no decrease in CD4 T-cell count. The survival benefit for PWH with melanoma and Hodgkin’s disease after ICI is encouraging and reinforces the value of these treatments in this population.”

The PITCH protocol in the United Kingdom evaluated the effects of short-term ATIs in people with HIV on ART, with preliminary results presented at CROI 2022. A new paper in the European Journal of Immunology includes data from the study cohort as part of a larger analysis and offers evidence that the ATI induced new T cell responses to the HIV Gag protein in PITCH participants.

Lastly, for anyone attending the upcoming R4P conference, results from a completed ATI trial in participants who acquired HIV during the Antibody-Mediated Prevention (AMP) trial in Brazil and Peru are being presented by Jorge Gallardo-Cartagena on Tuesday October 8th at 3:30pm local time. A link to the abstract will be added to TAG’s listing for the trial when it becomes publicly available next month.

TAG’s HIV Cure-Related Clinical Research Listing: Background on the August 2024 Update

Last month’s revision to TAG’s listing included ten updates.

New Additions

There was only one new HIV cure-related trial identified in registries. The protocol, named Tatelo Plus, represents a follow up to a prior smaller evaluation of dual broadly neutralizing antibodies (bNAbs) in children with HIV in Botswana (the Tatelo study). The research project is primarily testing bNAbs as an alternative to antiretroviral therapy (ART) for maintaining HIV viral load suppression, but straddles the boundary with cure research by including detailed investigations of effects on the HIV reservoir (and using reservoir measurements as part of the criteria for deciding whether to interrupt ART).

In the original Tatelo study, 11 of 25 infants (44%) who received the bNAbs 10–1074 and VRC01-LS maintained undetectable viral loads during a 24 week ART interruption. The new trial, which is under the aegis of the IMPAACT network, will administer three long-acting bNAbs: PGDM1400LS, VRC07-523LS, and PGT121.414.LS.

Based on information gleaned from Tatelo, the protocol includes additional criteria for determining whether a participant will be able to enter the ART interruption phase. These criteria include undetectable levels of HIV DNA using a qualitative test and, for the first time, results from sophisticated analyses of where HIV has integrated its genetic code into the genome of infected cells. Specifically, the protocol requires that >80% of intact HIV proviruses detected with these assays are located in inhospitable regions of the cell’s genome that are less likely to allow the virus to reactivate and replicate.

To recycle a metaphor used previously on the blog: if you think of a cell’s genome as a factory for producing all the proteins the cell needs to go about its daily business, HIV DNA tends to integrate in machinery that gets switched on regularly. This gives the virus opportunities to hijack that machinery to make more HIV proteins (and potentially more copies of infectious HIV). But HIV DNA can also land in the genomic equivalent of a darkened factory storage room nobody goes into (sometimes referred to as a “gene desert”) — in that case, the virus can become locked in, and unable to reactivate. Marcus Lichterfeld, one the pioneers of this area of research along with Xu Yu, recently presented on a community webinar to explain and share current knowledge about the phenomenon.

Analyses of the Tatelo study presented at CROI 2023 suggest that HIV viral load rebound during ART interruption was associated with an HIV reservoir primarily located in regions of the genome that allow for virus reemergence. These findings led to the new eligibility criteria for undergoing ART interruption in Tatelo Plus, with the goal of trying to select participants with the best chance of maintaining HIV viral load suppression.

Updates to Enrollment Status

• A study in Canada testing whether fecal microbiota transplantation (FMT) can reduce inflammation in people with HIV on ART is now open for enrollment at the McGill University Health Centre in Montreal.
• A protocol for people who acquired HIV during the Antibody-Mediated Prevention (AMP) study that took place on the African continent is now closed to further recruitment. The study is investigating whether receipt of the broadly neutralizing antibody (bNAb) VRC01 prior to HIV acquisition can promote control of viral load during an analytical treatment interruption (ATI) among participants who started ART rapidly after diagnosis. Shelly Karuna from the HIV Vaccine Trials Network (HVTN) shared background information and some data snapshots at the 2023 Pre-CROI Community HIV Cure Research Workshop. Videos in multiple languages designed to help potential participants understand the protocol and ATIs have also been made publicly available on HVTN’s Vimeo channel.

Completed Studies 

• A second AMP study that took place at sites in Brazil and Peru also included a follow on ATI protocol for participants who acquired HIV and started ART. This study is now completed, but to our knowledge results haven’t been publicly presented yet.
• A completed evaluation of the PD-1 inhibitor pembrolizumab to treat cancers in people with HIV, which also included exploratory analyses of effects on the HIV reservoir. Multiple reports of results have been published and presented, see highlighted entry in the completed studies table under trial registration # NCT02595866.
• An observational study of a particular immunological pathway involving the cytokine interleukin-33 in people with HIV. The registry entry hasn’t been updated for some time and the protocol was due to end last year, hence the move to the completed studies table (email inquiries about the status weren’t answered).

New Links to Study Results

Results from several studies in the listing were presented at the International AIDS Conference (AIDS 2024) in Munich in July.

Among the most significant news was a presentation by Dr. Rachel Presti describing results from the first human trial of a CRISPR-based gene editing strategy named EBT-101, designed to excise HIV’s genetic code from infected cells. Unfortunately there’s no abstract associated with the talk and hence we’re unable to add a link to the entry in our listing until video of the presentation becomes publicly available in October.

As noted in the previous blog post, three EBT-101 recipients underwent an ATI but only one experienced a delay in HIV viral load rebound of 16 weeks, which appeared to be associated with a slight but statistically significant decline in the size of their intact HIV reservoir after EBT-101 administration. The results may in part highlight the challenge of trying to use CRISPR against a highly mutable virus — the gene editing tool needs to recognize conserved genetic sequences in order to work, and several study participant samples displayed evidence of variation at the HIV sites targeted by EBT-101. While some of the media reporting of the results has been pessimistic, there could yet be potential for improving both the targeting and the delivery of the approach.

Immuno Cure BioTech is developing a novel therapeutic HIV vaccine that combines conserved parts of the viral Gag protein with a PD-1 protein intended to promote uptake by dendritic cells (key immune cells for initiating immune responses). A poster presentation of results from a 45-person phase I trial featured at AIDS 2024, reporting that the approach was safe and deserving of further evaluation. Future plans include conducting ATIs to measure any effects on viral load rebound. For additional background see blog post from August 2023.

Researchers from the AIDS Malignancy Consortium presented information on immune responses to PD-1 inhibitor therapy in people with HIV and cancers. The analysis focused on the CD8 T cell repertoire, a measure of the ability of a person’s CD8 T cells to recognize a broad variety of targets. The investigation discovered that participants with a more diverse CD8 T cell repertoire at baseline generated new CD8 T cell responses rapidly in response to a single dose of the PD-1 inhibitor, whereas those with more limited CD8 T cell diversity required multiple doses to achieve similar effects.

An analysis of 21 participants in the Zurich Primary HIV Infection Study compared the evolution of the viral reservoir in people with detectable low level viral load (50-500 copies/ml) compared to those with viral loads consistently below 50 copies/ml. All had started ART soon after HIV acquisition with high levels of adherence. The researchers didn’t find any evidence that low level viral load was associated with ongoing HIV replication or the development of drug resistance. The results suggest that the phenomenon of “unsuppressible” HIV viral load generated by the reservoir (but not indicative of ongoing viral replication) that’s been described in chronic HIV infection can also occur in people who started ART very early.

Italian researcher Barbara Ensoli continues to evaluate the long-term effects of a novel therapeutic vaccine candidate designed to induce immune responses against the HIV Tat protein. At AIDS 2024, Ensoli reported on extended observational follow up of two trial cohorts in Italy and South Africa, respectively, showing evidence that the vaccine was safe and induced sustained immune responses against the Tat protein. Positive changes in immune cell subsets and reductions in the HIV reservoir were also noted, with a manuscript said to be in preparation. The vaccine has been the subject of past controversy and it’s unclear at this time whether further development is likely to occur.

A link to an article in the Journal of Personalized Medicine was added for a completed trial of oral cannabinoids in people with HIV on ART. Preliminary results have already been published and the new paper focuses on the overall feasibility of the research and lessons learned.

Finally there was one AIDS 2024 poster presentation on GS-8588, a new bispecific T-cell engager being developed by Gilead that recently entered clinical testing. However a link wasn’t added to our listing because the poster describes initial encouraging laboratory findings rather than results from the ongoing phase I trial. Encouragingly, the preclinical laboratory testing demonstrated efficient killing of HIV-infected cells sampled from people on ART.

TAG’s HIV Cure-Related Clinical Research Listing: Background on the July 2024 Update

There are seven updates in the July 2024 revision to TAG’s listing.

New Additions

Only one new cure-related clinical trial was identified in registries over the past month, which is a revised version of a protocol that was previously withdrawn. The study is sponsored by the US Military HIV Research Program (MHRP), and will assess a combination of broadly neutralizing antibodies and therapeutic vaccines in people with HIV in Bangkok, Thailand. The long-acting broadly neutralizing antibodies are VRC07-523LS and PGDM1400LS, while the therapeutic vaccine regimen involves two viral vectors — chimpanzee adenovirus (ChAd) and modified vaccinia Ankara strain (MVA) —and an HIV envelope protein with adjuvant. The version of the protocol that was initially registered and then withdrawn also included the IL-15 superagonist N-803, now nixed.

The trial plans to enroll people with HIV between 18 and 60 years old who were diagnosed during acute infection (soon after HIV acquisition) and have either been on antiretroviral therapy (ART) for at least 48 weeks or are willing to initiate ART as part of the protocol. After receipt of the interventions, participants will undergo an analytical treatment interruption (ATI) to evaluate any effects on the timing and magnitude of HIV viral load rebound. 

Updates to Enrollment Status

Two recently added trials have now opened for enrollment:

• A novel gene therapy study at the City of Hope Medical Center in California. The protocol involves sampling T cells targeting the common virus CMV from participants living with HIV, and then genetically modifying them so that they can also recognize HIV (see blog post from February)
• A trial sponsored by Hookipa Biotech investigating replication-competent arenaviruses as therapeutic vaccine vectors (see last month’s blog post).

Completed Studies

A trial that closed to enrollment several months ago is now listed as completed: MacroGenics study of two dual-affinity re-targeting (DART) proteins (MGD020 and MGD014), which are designed to recognize and promote clearance of HIV-infected cells. Results from an evaluation of MGD014 were presented at the AIDS 2022 conference, demonstrating safety and favorable pharmacokinetics. To our knowledge, results from the study of MGD020 and MGD014 haven’t been publicly presented as yet.

New Links to Study Results

Preliminary results from an ongoing trial of an adoptive immunotherapy approach were presented in May at the 27th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). The protocol involves sampling T cells from participants (autologous T cells) via leukapheresis and then selecting and expanding cells that recognize parts of the HIV Gag, Pol and Nef proteins that are genetically conserved and represent more stable and potentially vulnerable targets for the immune response. The expanded T cells, which the researchers call HIV-Specific T Cells Targeting Non-Escaped Epitopes (HST-NEETs), are then reinfused back into the participants as a candidate immunotherapy. Details on the manufacturing process were published in October 2019.

The ASGCT abstract (#1908) is available online from the journal Molecular Therapy and describes results in six study participants after receipt of two infusions. No serious side effects were observed and the HST-NEETs showed evidence of expansion and persistence after administration in most recipients. Three of six participants experienced declines in the size of the intact HIV reservoir although the average magnitude of the reduction and statistical significance isn’t reported in the abstract. The authors write: “This promising therapeutic approach presents opportunities for combination therapies for HIV cure strategies.”

A link was also added to a previous abstract about the trial we’d missed, which was presented at the 64th American Society for Hematology Annual Meeting in 2022. This abstract reports individual data and notes decreases in the intact HIV reservoir in two participants whose samples had been analyzed at that stage.

Researchers led by Maria Reyes Jimenez-Leon from the research group of Ezequiel Ruiz-Mateos at the Institute of Biomedicine of Seville (IBiS) have published results from a clinical trial of vedolizumab, an antibody that blocks the α4β7 integrin receptor on cells. The rationale for the approach derives from studies in the SIV/macaque model showing reductions in the reservoir, although notably an initial report of SIV viral load control after ART interruption wasn’t reproducible in additional macaque experiments or in the first human trial in people with HIV.

The trial in Spain also included an ATI and was unable to document a substantial effect in delaying or reducing HIV viral load rebound. However, the researchers found that the blocking of the α4β7 integrin receptor by vedolizumab in the gut was incomplete and there was a correlation between the extent of the blocking and levels of HIV DNA in the ileum and caecum. Because vedolizumab administration has been shown to be safe in several studies in people with HIV, the researchers suggest that higher doses could be considered and conclude: “this clinical trial suggests that α4β7 is an important determinant of HIV-1 reservoir levels seeding in peripheral blood and specially in tissues in humans and therefore, supports further testing of vedolizumab in combination with other compounds, as a promising tool for HIV-1 cure strategies.”

The last added link is to an analysis of biomarkers associated with HIV viral rebound in a previously published trial of the toll-like receptor agonist vesatolimod. The study recruited people who displayed natural control of HIV viral load to low but detectable levels prior to starting ART (“viremic controllers”) and administered vesatolimod prior to initiating an ATI. Receipt of the intervention was associated with a slight delay in time to viral load rising over 200 copies/ml (about a week on average), and the new paper identifies a number of biomarkers associated with the speed of the rebound. Higher levels of several proinflammatory glycans, lipids, and metabolites were linked to more rapid reappearance of HIV viral load, but the authors note that the findings should be considered exploratory and require validaton.

Another trial in the listing had additional results presented at the ASGCT meeting in May, but the abstract doesn’t appear to be available for us to link to. The study has already received considerable publicity because it represents the first-in-human evaluation of a CRISPR gene editing approach to targeting the HIV reservoir. The candidate, EBT-101, is manufactured by Excision Biotherapeutics and emerged from extensive preclinical research conducted by Kamel Khalili and colleagues at Temple University in Philadelphia. EBT-101 uses an adeno-associated virus serotype 9 (AAV9) vector to deliver a CRISPR gene editing tool designed to target relatively conserved parts of HIV genetic’s code. The goal is to either remove the HIV genome from infected reservoir cells or render it non-functional.

Preliminary safety information was first presented at the Annual Congress of the European Society of Gene and Cell Therapy in Belgium in October 2023 (see abstract OR31 in the published abstracts). At the ASGCT meeting in May, principal investigator Rachel Presti debuted efficacy information, revealing that three recipients underwent an ATI but only one experienced a delay in HIV viral load rebound of 16 weeks, which appeared to be associated with a slight but statistically significant decline in the size of their intact HIV reservoir after EBT-101 administration. Excision Biotherapeutics issued a press release and details were reported by Liz Highleyman for AIDSmap.  Rachel Presti is also presenting about the trial next Thursday, July 25, at the International AIDS Conference (AIDS 2024) In Munich.

Other candidates in TAG’s listing featured at AIDS 2024 include the ICVAX therapeutic vaccine (poster exhibition, Tuesday July 23) and GS-8588, a bispecific T-cell engager (poster exhibition, Wednesday July 24). For a full set of links to HIV cure-related research sessions and events at AIDS 2024, see previous blog post.

HIV Cure Research at AIDS 2024

The 25th International AIDS Conference is taking place in Munich, Germany from July 22-26, with several pre-conference events scheduled on Sunday, July 21st. Remote access will also be possible for registered attendees, with recordings made publicly available at some point after the meeting ends. Links to events and sessions related to HIV cure research are appended below (please leave a comment if we've missed anything).

In addition to the sessions on the conference agenda, several Martin Delaney Collaboratory Community Advisory Boards are hosting a Networking Zone in the Global Village titled CureCanvas: A collective vision for HIV cure. Activities will include surveys, meet-ups, interviews by HIV advocate Raif Derrazi, and a digital mural that will be built with visitors over the week. Image contributions for the digital mural can also be submitted online. Thanks to co-organizer Michael Louella for sharing this information. 

Sunday July 21

Towards a truly global HIV cure will continue a longstanding International AIDS Society policy of holding a pre-conference event on the topic of cure research. Information on the agenda is available via the AIDS 2024 programme:

Towards a truly global HIV cure
Pre-conference session
Hall B0b/Channel 5
July 21, 8:00am-4:30pm local time (US Eastern time: 2:00-10:30am)

Session 1: Opening and setting the scene
Session 2: Opportunities and challenges in reservoir and persistence measurement
Session 3: Creating an enabling environment for research and advocacy
Session 4: Communicating cure
Session 5: The changing landscape for cure – Gene therapy and long-acting antivirals 

Monday July 22

Satellite: Revitalizing advocacy for HIV and sickle cell disease cure access in the era of $2million cell and gene-based therapy treatments
SAT004
Room 13a/Channel 6
Organizer: HIV Cure Africa Acceleration Partnership (HCAAP) & Global Gene Therapy Initiative (GGTI)
July 22, 7:30-9:00am local time (US ET: 1:30-3am)

Satellite: Impact of broadly neutralizing antibodies on HIV CNS reservoirs: Potential benefits, challenges and risks
SAT007
Room 14a/Channel 9
Organizer: Division of AIDS Research, National Institute of Mental Health
July 22, 7:30-9:00am local time (US ET: 1:30-3am)

Satellite: "I once had HIV" - The story of a cure
SAT024
Room 5/Channel 8
Organizer: Deutsche AIDS Gesellschaft e.V.
July 22, 11:30am-12:30pm local time (US ET: 5:30-6:30am)
Note: presentation by Marc Franke, formerly known as the Düsseldorf patient. 

Tuesday July 23

Oral abstract session: It's about timing: When to start, when to stop
OAA02
Room 13a/Channel 6
July 23, 10:30-11:30am local time (US ET: 4:30-5:30am)
Note: potentially misleading title, the entire session is focused on HIV cure-related research.

Oral abstract session: HIV in children: What are the challenges?
OAA06
Room 5/Channel 8
July 23, 3:00-4:00pm local time (US ET: 9:00-10:00am)
Note: features a presentation by Faiaz Shaik Abdool on the HIV reservoir.

Symposium: How sex influences HIV pathogenesis
SY10
Hall B0b/Channel 5
July 23, 4:30-5:30pm local time (US ET: 10:30-11:30am) 

Satellite: HIV cure research in Africa
SAT066
Room 14c/Channel 10
July 23, 6:00-7:30pm local time (US ET: 12-1:30pm)
Organizer: Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) 

Wednesday July 24

Oral abstract session: The quest for HIV vaccines
OAA13
Room 13b/Channel 7
July 24, 10:30-11:30am local time (US ET: 4:30-5:30am)
Note: features at least two presentations of potential relevance to HIV cure-related research. 

Special session: AIDS 2024 Co-Chairs' Choice
SS04
Hall C1/Channel 1
July 24, 10:30am-12:00pm local time (US ET: 4:30-6:00am)
Note: features a presentation by Christian Gaebler about a possible new case of HIV cure in a recipient of a stem cell transplant from a donor heterozygous for the CCR5Δ32 mutation (administered to treat a cancer diagnosis).

Special session: HIV science for the future
SS02
Hall C1/Channel 1
July 24, 1:30-2:30pm local time (US ET: 7:30-8:30am)
Note: moderated by Juan Michael Porter II from TheBody.com, HIV cure research may be part of the discussion.

Symposium: Determinants of HIV infection and rebound
SY22
Room 5/Channel 8
July 24, 4:30-5:30pm local time (US ET: 10:30-11:30am)

Thursday July 25

Symposium: The different flavours of gene therapy for HIV cure
SY26
Room 5/Channel 8
July 25, 10:30-11:30am local time (US ET: 4:30-5:30am)
Note: includes a presentation by Rachel Presti on results from the first-in-human trial of a CRISPR-based strategy targeting the HIV reservoir.

Oral abstract session: Cracking the code of the tissue reservoir
OAA28
Room 5/Channel 8
July 25, 3:00-4:00pm local time (US ET: 9:00-10:00am) 

Satellite: Immune control of viral reservoirs
SAT110
Room 5/Channel 8
Organizer: ANRS RHIVIERA and DZIF HIV
July 25, 6:00-7:30pm local time (US ET: 12:00-1:30pm) 

Friday July 26

Plenary session: Preparing for the future
PL04
Hall C1/Channel 1
July 26, 8:30-10:00am local time (US ET 2:30-4am)
Note: opens with an HIV cure-related research presentation by Melanie Ott.

Oral abstract session: Immune dysfunction and residual viremia
OAA35
Room 13a/Channel 6
July 26, 10:30-11:30am local time (US ET: 4:30-5:30am) 

Symposium: Metabolism and inflammation during suppressive therapy
SY35
Room 14b/Channel 3
July 26, 12:00-1:00pm

Plenary session: Rapporteur report back session
PL05
Hall C1/Channel 1
July 26, 2:45-4:00pm local time (US ET: 8:45-10am)

TAG’s HIV Cure-Related Clinical Research Listing: Background on the March 2024 Update

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.

TAG’s HIV Cure-Related Clinical Research Listing: Background on the December 2023 Update

No new HIV cure-related trials or studies were added to the clinicaltrials.gov registry over the past month. A total of seven updates were made to TAG’s listing:

A clinical trial in Barcelona, Spain investigating the effects of the drug dasatinib on HIV persistence and inflammation is now open for enrollment. Dasatinib is a tyrosine kinase inhibitor approved for the treatment of certain forms of chronic myelogenous leukemia and acute lymphoblastic leukemia. Studies in people with HIV receiving the drug to treat cancer have reported an association with a smaller HIV reservoir size and reduced capacity to reactivate viable HIV from latently infected cells. Proposed mechanisms include enhancing the activity of an innate antiviral enzyme, SAMHD1 (by preventing phosphorylation of the enzyme), immunomodulatory effects on natural killer cells and T cells, and possibly also a reduction in the proliferation of HIV-infected CD4 T cells. Two poster presentations at the XIV Congreso Nacional GeSIDA last month reported additional evidence that the use of tyrosine kinase inhibitors in people with HIV and cancers is associated with reductions in the size of the viral reservoir and potential enhancement of the cell-killing potential of natural killer cells and CD8 T cells (see abstracts PT-07 and PT-08).

An ongoing clinical trial sponsored by Gilead Sciences in the FRESH cohort of young women in South Africa is now closed to enrollment. The study is investigating whether a combination of two broadly neutralizing antibodies (bNAbs) and vesatolimod, a toll-like receptor 7 agonist, can enhance viral load control during an analytical treatment interruption (ATI) in participants who started antiretroviral therapy (ART) very early after HIV acquisition.

A phase IIa study of the long-acting broadly neutralizing antibody GSK3810109A (formerly named N6-LS) is now completed. The focus of the research was more on potential use as a treatment rather than cure. The most recent presentation of results was at the European AIDS Clinical Society (EACS) conference, where researchers reported a good safety profile and favorable pharmacokinetics. A phase IIb trial is planned.

Two observational studies sponsored by Radboud University in the Netherlands have also been completed. The 2000HIV and 2000HIVTrained studies used new multi-omics approaches to investigate biological pathways and biomarkers potentially linked to a variety of variables including non-AIDS comorbidities, elite control, and the latent viral reservoir in a large cohort of people with HIV. Two abstracts reporting results were presented at CROI earlier this year (see abstracts 313 and 314).

Links to newly published results were added for two trials in the listing:

The IMPAACT P1115 study assessing the potential for HIV remission in infants treated very soon after birth described results in a paper in the Lancet HIV (access free with registration), following a presentation by principal investigator Deborah Persaud at CROI 2022. A subset of ten out of 54 infants studied became HIV antibody negative and had non-detectable HIV-1 DNA after two years, which represent the criteria for considering an ATI. The researchers note that overall HIV suppression rates were not optimal and improved pediatric ART regimens are still needed. The second iteration of IMPAACT P1115 is now testing regimens including an integrase inhibitor (raltegravir) and a broadly neutralizing antibody (VRC-01).

Scientists affiliated with the ACTG published a paper in the journal AIDS presenting results from a phase I/IIa study of an HIV-1 Gag conserved element DNA vaccine in people on ART. The aim is to induce or boost T cell responses targeting parts of the HIV Gag protein that appear constrained in their ability mutate, and are thus typically conserved among HIV variants. The vaccine, combined with vaccine containing the full Gag protein, induced new T cell responses to conserved elements in a little less than half of the 18 recipients (44.4%). Whether these T cell responses can effectively kill HIV-infected cells is not yet known. A paper published in Science yesterday reported that the ability of HIV vaccine-induced T cells to kill HIV-infected cells may be impaired by poor avidity - a measure of the ability of T cells to efficiently recognize and engage with low amounts of viral fragments displayed (like alarm signals) by cells infected with HIV.

Lastly we made an adjustment to the current clinical trials table this month, creating a separate category specifically for broadly neutralizing antibodies rather than using a general category of just “antibodies.” Other antibodies are now categorized based on mechanism of action e.g.  anti-α₄β₇ integrin antibodies, CD4 attachment inhibitors.

TAG’s HIV Cure-Related Clinical Research Listing: Background on the November 2023 Update

No new HIV cure-related trials or studies were added to the clinicaltrials.gov registry over the past month. A total of eight updates have been made to TAG’s listing:

A phase II study sponsored by AbbVie that was added to the listing in September (see prior blog update) is now open for enrollment. The company initiated an exploratory HIV cure research program several years ago focused on budigalimab, an anti-PD-1 antibody, and ABBV-382, an anti-α4β7 integrin antibody similar to the commercially available vedolizumab (an approved  treatment for ulcerative colitis and Crohn's disease). The phase II trial plans to enroll 140 participants and administer both antibodies, either alone or in combination. The study design includes an analytical treatment interruption (ATI) to assess the effect of the interventions on time to viral load rebound above 1,000 copies/ml.

The past month also saw the first public presentation of results from AbbVie’s phase I trials of budigalimab in people with HIV. The researcher Jean-Pierre Routy described the findings at the 19th European AIDS Conference (EACS 2023) in Warsaw and the abstract is publicly available, but access to the presentation is limited to conference registrants. The abstract indicates that budigalimab was well tolerated although three participants experienced non-serious (lower than grade 3) immune-related adverse events that reportedly resolved (two cases of thyroiditis and a skin reaction). In a study that involved an ATI, there was evidence of atypically low viral load rebounds in several participants and two cases of prolonged post-treatment viral load control to below 200 copies/ml for around 1.5 years. A detailed review of the results by Liz Highleyman was published by AIDSMap. While it’s far too early to make any definitive evaluations, there’s a hint that PD-1 inhibition may have enhanced the immune response against HIV in some study participants, as it has been shown to do against certain cancers.

A key question about the use of PD-1 inhibitors in people with HIV who don’t have cancer is safety. Several PD-1 inhibitors are licensed for the treatment of cancers, but have the potential for causing autoimmune side effects in which T cells attack healthy tissues instead of only cancerous cells. A prior ACTG study of a PD-1 inhibitor in people with HIV on antiretroviral therapy (ART) was stopped early because of two cases of potential immune-related adverse events: thyroiditis, which is a known side effect of PD-1 inhibitors, and liver toxicity which was not definitively linked to the antibody. Another ACTG study of a related anti-PD-L1 antibody in people with HIV on ART documented a delayed case of hypophysitis that required treatment but eventually resolved. The management of immune-related adverse events caused by PD-1 inhibitors has improved but it will be important to carefully assess safety in the larger number of people being enrolled in AbbVie’s phase II trial. TAG is planning a community webinar about the AbbVie program to be held on December 5th at 12pm ET, additional information and a registration link will be posted to the TAG website next week.

An ongoing study of a therapeutic HIV vaccine candidate at the University of Pittsburgh is now fully enrolled and no longer recruiting participants. The research is led by Dr. Sharon Riddler and is investigating different methods of using an individual’s dendritic cells to try to stimulate improved immune responses against HIV in people on antiretroviral therapy (ART).

A study sponsored by Gilead Sciences investigating potential drug interactions with their TLR-7 agonist candidate vesatolimod has been stopped early, with a notation in the clinicaltrials.gov registry record stating the decision was due to a change in development plans and wasn’t related to concerns about safety or efficacy. Another Gilead-sponsored combination study including vesatolimod remains ongoing in the FRESH cohort in South Africa.

Preliminary safety results from the first trial of CRISPR/Cas9 gene editing technology in people with HIV were presented by Dr. Rachel Presti at the European Society for Gene & Cell Therapy annual congress on October 25, 2023 in Brussels. The approach is being developed by the biotech company Excision Biotherapeutics, who issued a press release describing the presentation. The conference abstract doesn’t appear to be publicly available online but video on demand is listed as forthcoming on the congress website.

In the trial, a CRISPR/Cas9 gene editing tool designed to target and remove (or disable) HIV in persistently infected cells is delivered into the body by an adeno-associated virus serotype 9 (AAV9) vector. The presentation indicated that so far the approach has appeared safe in the first three study participants who received the initial lowest dose, allowing the trial to proceed to administering higher doses. No information about anti-HIV effects was disclosed, with the company noting that additional results should become available next year. At the moment the small trial is only open to people assigned male at birth because of an unspecified Food and Drug Administration (FDA) concern about potential reproductive toxicity.

The lack of data relating to efficacy unfortunately didn’t stop the notoriously unreliable UK news outlet the Daily Mail (often colloquially referred to as the Daily Fail) from publishing a story with a grossly inaccurate headline stating that a cure for HIV “could be months away.” Thankfully the trustworthy community news website AIDSMap published a careful and accurate take on the news, and TAG has covered the media reaction to this and past stories about the use of CRISPR in HIV on our HIV Cure Research Media Monitor webpage.

There was encouraging news today about the approval of a CRISPR-based therapy for sickle cell anemia and thalassemia in the UK, underscoring why there’s excitement about the technology. But it’s important to note that this approach performs gene editing in the laboratory on stem cells that are isolated from individuals and then reinfused. In contrast, the Excision Biotherapeutics candidate is delivered into the body by the AAV9 vector in an attempt to deplete HIV from the relatively small number of virus-infected cells that persist in the blood and various tissues of people on ART. Achieving success via delivery into the body (in vivo) is likely to be more challenging than performing gene editing of cells in a laboratory (ex vivo).

Additional links to results added to the listing this month include an open access paper describing a social science study conducted as part of the BEAT-2 clinical trial in Philadelphia. The trial tested the ability of a combination of two broadly neutralizing antibodies (bNAbs) and the cytokine alpha interferon to promote suppression of HIV viral load during an ATI. The social science element was led by Andrea Bilger and focused on participant experiences, particularly as related to stopping ART during the ATI. Feedback was generally positive but the researchers, who worked together with the BEAT Collaboratory Community Advisory Board, highlight some concerns about the mental health aspects of ATIs and provide a table listing considerations for future HIV cure-directed clinical research (see table 5 of the paper).

Lastly, the AIDS Malignancy Consortium 095 Study investigating the use of the approved PD-1 inhibitor nivolumab to treat advanced cancers in people with HIV has reported that safety was similar to results obtained in HIV-negative cohorts, with evidence of meaningful efficacy against Kaposi’s sarcoma (a partial response lasting an average of just over a year in six of 15 participants). The results were published in the journal Cancer on November 14th. The study is included in TAG's listing because while it's only enrolling people with cancers, the investigators are also assessing the effects of nivolumab (with or without ipilimumab) on the HIV reservoir.

TAG’s HIV Cure-Related Clinical Research Listing: Background on the October 2023 Update

No new HIV cure-related trials or studies have been added to the clinicaltrials.gov registry over the past month. Two trials in the listing have changed status:

A study sponsored by the ANRS in France investigating the link between specific immune system genetics (MHC B35/53Bw4TTC2) and post-treatment control of HIV is now open for enrollment. Participants are being recruited from the large ongoing ANRS CO6 PRIMO cohort of people in France who were identified within three months of HIV acquisition. The rationale for the study derives from evidence that people with this particular genetic profile may be more likely to control viral load after an antiretroviral therapy (ART) interruption (see the session recording of Asier Sáez-Cirión’s presentation at IAS 2021, which starts at around 29 minutes). The mechanism is thought to involve the enhancement of natural killer cell immune responses against HIV.

A clinical trial of the drug baricitinib in people with HIV on ART has been temporarily suspended. The study is sponsored by Emory University and the registry record notes that the suspension is because the U.S. Food and Drug Administration (FDA) is requesting a new investigational new drug (IND) application to be filed. The drug is FDA-approved for the treatment of several conditions including severe rheumatoid arthritis but has not previously been specifically studied in people with HIV. Laboratory experiments in humanized mice have found that baricitinib can cross the blood-brain barrier and reduce the persistence of HIV in the central nervous system. The clinical trial aims to investigate if similar effects can be obtained in people with HIV, using blood samples, neurocognitive testing, magnetic resonance imaging (MRIs), and lumbar punctures.

The remaining updates this month are the additions of links to presented or published results from ten studies in the listing.

In seven cases, the results were presented as poster abstracts at the NIAID Strategies for an HIV Cure meeting which took place last week October 12-13. A recording of the event will soon be available on the NIH Videocast website and the poster abstracts are contained in the program book. Unfortunately we can’t link directly to the individual abstracts, so they need to be looked up by number. It’s unclear if the meeting book will remain online permanently, but if it’s taken down we’ll host a copy on the TAG website and redirect the links. A very brief summary of the presented results is below.

• Among participants in a small analytical treatment interruption (ATI) study in San Francisco, robust lymph node proliferation of CD8 T cells targeting the virus appeared to be linked to better control of HIV viral load off ART.
• An imaging study at the National Cancer Institute reported very preliminary information from the first participant to undergo ATI, indicating that lymph node metabolic activity associated with immune activation didn’t significantly increase prior to the detection of low level viral load in blood.
• Analyses of the HIV reservoir in neonates in the ongoing IMPAACT P1115 study found a high proportion of intact viruses mixed with defective and hypermutated viruses, indicating that HIV replication had occurred and established persistent infection in utero, prior to birth.
• The experiences of participants in a combination therapy trial with an extended ATI were assessed by John Sauceda and colleagues. During the ATI “depression and anxiety ratings increased to reach the mild severity category, and then reduced after re-starting ART.”
• Two poster abstracts presented information from the Last Gift study, which offers people with HIV reaching the end of life an opportunity to donate postmortem tissues to cure research. Karine Dubé and colleagues measured quality of life among participants and found it to be stable with some indication of a benefit to study participation. A second abstract described evidence of persistent HIV reservoirs in long-lived brain myeloid cells in tissues donated by four study participants.
• Researchers who conducted a completed ATI study Belgium used new techniques to investigate whether the detectable presence of intact HIV in the reservoir was associated with viral load rebound. Intact HIV couldn’t be detected in five participants but they still experienced a return of viral load after stopping ART, suggesting that this measure alone is insufficient to predict the outcome of an ATI.
• Lastly, in a study sponsored by Gilead Sciences investigating the toll-like receptor agonist vesatolimod in individuals with low viral load prior to starting ART (“viremic controllers”), a subset of CD8 T cells targeting the HIV Gag protein with broad functionality and cell-killing (cytotoxic) properties were associated with HIV reservoir reductions and a delayed time to viral load rebound after ATI.

Three other studies have had links added to published results:

• A small trial of high dose vitamin D₃ supplementation in Australia, previously presented at CROI 2022, has now been described in a paper in the Journal of Virus Eradication which reports evidence of immune modulation and an apparent decline in HIV DNA levels after supplementation was stopped.
• The Research in Viral Eradication of HIV Reservoirs (RIVER) trial in the UK tested therapeutic vaccination in people starting antiretroviral therapy (ART) early after HIV acquisition and published primary results in 2020. In a new paper in the journal Scientific Reports, study investigators report that the therapeutic vaccines (ChAdV63.HIVconsv and MVA.HIVconsv) increased the frequency and functionality of CD4 and CD8 T cells targeting HIV. These immunological effects weren’t associated with reductions in the HIV reservoir and the study didn’t include an analytical treatment interruption (ATI), so it’s not clear if the vaccine-induced T cell responses could mediate enhanced control of viral load in the absence of ART. The same vaccines have previously been studied by researchers in Spain with some evidence of reductions in viral load after an ATI, but there were no cases of sustained post-treatment control to undetectable levels.
• The Journal of Medical Virology has published results from an Italian study assessing three different ART regimens to treat acute HIV infection. HIV DNA levels were significantly reduced over 48 weeks and there was no difference between the regimens.