TAG HIV Basic Science, Vaccines, and Cure Project Blog

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

recent posts

  • HIV Cure Research at IAS 2025

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

    Sunday July 13

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

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

    Monday July 14

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

    Tuesday July 15

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

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

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

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

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

    Wednesday July 16

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

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

    Thursday July 17

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

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

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

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

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

    New Additions

    Two studies were added:

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

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

    Updates to Enrollment Status

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

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

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

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

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

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

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

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

    New Links to Study Results

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

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

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

    For March, April, and May 2025, there were 38 updates to entries in TAG’s listing. The majority involved the addition of links to results presented at the annual Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.

    As is covered further below, this period has seen a horrific and unprecedented political attack on scientific research in the US under the regime that assumed power on January 20th. The US National Institutes of Health (NIH) is by far the most significant funder of biomedical research in the world, and that also holds true for HIV cure research. We’ll continue to monitor and respond to developments, and collaborate with allies to try to ensure that this work can continue.  

    New Additions

    One newly registered HIV cure-related clinical trial was added in March. The protocol is investigating chimeric antigen receptor (CAR) T cells, a gene therapy approach that involves equipping T cells with receptors designed to recognize a specific target (in this case, HIV). Several CAR T cell therapies have been approved for the treatment of cancers in recent years.  The study is taking place at Tsinghua University in Beijing, China, and has yet to start recruiting participants.

    There were two additions in April:

    Jun Chen, MD is leading an investigation of a combination of the PD-1 inhibitor sindilizumab with chidamide, a candidate latency-reversing agent from the HDAC inhibitor class. The study plans to enroll 33 participants at the Shanghai Public Health Clinical Center in China and includes an analytical treatment interruption (ATI). Some evidence of PD-1 inhibitors enhancing control of HIV viral load after an ATI have emerged from early-phase studies conducted by the pharmaceutical company AbbVie.

    An observational protocol is inviting participants from a large trial of dual broadly neutralizing antibodies (bNAbs) to undergo an ATI. The parent study has been ongoing since 2023, involving the administration of the long-acting bNAbs 3BNC117-LS and 10-1074-LS to around 200 participants with HIV on antiretroviral therapy (ART).

    The invitational trial will assess whether receipt of the bNAbs promotes viral load suppression after ART interruption. The research is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID),  and the registration of this study in late April suggests that some work is proceeding at the NIH despite the ongoing efforts of the current US regime to disrupt and stop taxpayer-supported scientific research (funded with money appropriated by Congress for this purpose and committed to investigators in a peer-reviewed, highly competitive process).

    No new HIV cure-related trials were identified in registries for the May update.

    Withdrawn

    A clinical trial planned by IAVI to investigate potential HIV vaccine components in people with HIV in Africa has been withdrawn from the clinicaltrials.gov registry, with withdrawal of funding given as the reason.  IAVI is a vaccine organization that has been affected by the recent malevolent, politically motivated destruction of the United States Agency for International Development (USAID).

    Updates to Enrollment Status

    Enrollment status has been updated for 13 studies in the listing:

    The TatLat observational study in France is now recruiting. The purpose is to collect blood samples from people on ART for use in laboratory assessments of a candidate latency-reversing agent designed to induce HIV production by activating the viral Tat protein.

    An investigation of the effects of increased doses of certain antiretrovirals on the HIV reservoir is also now open for enrollment in Madrid, Spain.

    The effects of recent attacks on the NIH have manifested in the form of pauses on screening and enrollment for HIV cure-related trials sponsored by the ACTG (Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections). The ACTG and other US government-supported HIV research networks operate on seven year cycles but money is allocated annually in a process that usually proceeds smoothly. This year, the monies that are due have been held up, leaving the networks in a funding crunch.

    Part of the reason is an ongoing attempt to stop all US funding to South Africa, including research funding (TAG and MSF issued an analysis of the effects on US-supported HIV and TB research on May 15, see brief and associated press statement). Reporting from the journal Nature now indicates that NIH support for any research outside the US is at risk of imminent termination. The longer the funding is held up, the greater the possibility that the research networks are forced to close (leaving participants stranded in violation of US law), and there are fears this may be a deliberate strategy to try to claw back the unspent money through a process known as rescission.

    The paused studies are: 

    • The recently opened ACACIA, which was intended to be the largest evaluation (n=135) of whether dual bNAbs given at the time of ART initiation can promote post-treatment control of viral load during an ATI. The study is taking place on the African continent, with the majority of enrollment slated to be at South African sites. The registry record is yet to be updated. 
    • A second trial in Africa named PAUSE which is administering dual bNAbs to people on long-term ART with suppressed viral loads, followed by an ATI (also with multiple South African sites). The registry record is yet to be updated. 
    • A dual bNAb/ATI protocol recruiting people with acute HIV infection in Brazil, Peru and the US.
    • An investigation of a combination of immunotherapies (therapeutic vaccines, bNAbs, and a toll-like receptor 7 agonist) followed by ATI in people who initiated ART soon after HIV acquisition, with sites in Brazil and the US.

    Four trials in the listing have now closed to further enrollment:

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

    New Links to Study Results

    March and April were particularly busy months for the addition of links to new results because of CROI, which took place in San Francisco from March 9-12. All CROI abstracts and webcasts were made publicly available on April 15, and relevant embedded links are included below. TAG also helped organize and co-sponsor the annual Pre-CROI Community HIV Cure Research Workshop held at the San Francisco AIDS Foundation on March 8th (recordings are available on the TAG website).

    Two particularly prominent presentations at CROI covered the first results from trials of bNAbs administered to participants who started ART soon after HIV acquisition. In both cases ATIs were undertaken to assess effects on control of viral load after ART withdrawal.

    Thumbi Ndung’u from the Africa Health Research Institute presented results from a study in the FRESH cohort of young women in South Africa sponsored by Gilead Sciences. The protocol was a single arm, open label design administering a combination of two long-acting bNAbs (VRC07-523LS and CAP256V2LS) and the toll-like receptor 7 agonist vesatolimod. The 20 participants had received ART for an average of seven years, after starting a median of just one day after the detection of acute HIV infection. Sensitivity of HIV samples to at least one of the two bNAbs was a requirement for study entry.

    Vesatolimod was dosed every other week for ten weeks, the bNAbs were given via infusion on day seven. An ATI was initiated after four weeks. The researchers observed three patterns of viral load rebound: seven early cases while bNAbs were still likely present; another seven during the period bNAb levels were waning, and six participants who restarted ART late or displayed post-treatment control of viral load and remained off ART through 48 weeks.

    Unusually, four participants (20%) continued to experience post-treatment control until week 55 and are still off ART post-trial, now for an average of 1.5 years. Krista Dong also discussed the study during the Pre-CROI Community HIV Cure Research Workshop, highlighting that in one case control of viral load has now persisted for more than two years.

    Ndung’u noted that only one of the bNAbs (CAP256V2LS) was specific to the prevalent local HIV clade C, leaving open the possibility that better results might be attainable if both components of dual bNAb regimens are targeted to geographically relevant variants. 

    Sarah Fidler debuted broadly consistent results from the RIO trial, which is larger and includes a comparator placebo arm. A total of 68 cisgender men who began ART during acute HIV infection were evenly randomized to receive infusions of the long-acting bNAbs 3BNC117-LS and 10-1074-LS or placebo, followed by an ATI.

    Receipt of the bNAbs was associated with a significantly greater likelihood of maintaining viral load suppression during ATI at multiple timepoints. After 20 weeks, 75% of bNAb recipients were controlling viral load compared to 8.8% of those in the placebo arm, consistent with prior studies demonstrating prolonged activity after a single infusion of long-acting bNAbs.

    Participants with suppressed viral load at week 20 were eligible for a second infusion of bNAbs or placebo, and this was associated with high rates of continued control of viral load: 57% at 48 weeks and 39% after 72 weeks. Demonstrating the importance of control arms, there were also two cases of post-treatment control to beyond 72 weeks in the placebo arm (5%).

    Fidler pointed out that there were three observed patterns of viral load rebound during ATI, “very similar to the FRESH cohort”: rapid (8/34 participants), delayed (14/29) and post-treatment control (7/29 for >72 weeks). There no safety concerns related to the bNAbs, but several participants experienced high viral load rebounds during ATI to greater than a million copies/ml – the ART restart criteria was a confirmed measurement >100K copies/ml, but in these cases levels continued to ascend while confirmation was pending (see detailed reporting by Simon Collins for HIV i-Base).

    Additional information was presented from RIO in the form of two posters. John Frater and colleagues described a participant with extended post-treatment control for two years (and counting), associated with enhanced HIV-specific T cell immune responses and a reduction in the size of the intact HIV reservoir. The second poster, led by Mohammed Altaf, reported that the bNAbs had a “vaccinal effect” by promoting HIV Gag-specific T cell responses that were associated with control of viral load.

    Taken together, the FRESH cohort and RIO studies offer encouraging evidence that the proportion of participants who experience post-treatment control can be increased beyond the rare cases reported previously. For both protocols, the rates of post-treatment control were around 20%. Dr. Ole Søgaard gave an excellent plenary talk on HIV cure research at CROI 2025 that delineated factors that likely contribute to control of viral load off ART.

    A number of other clinical trials and observational studies in TAG’s listing had preliminary results presented at CROI 2025:

    • The biotech company ImmunoCore is developing a soluble bispecific T cell engager called ImmTAV for HIV. The molecule is designed to facilitate recognition and destruction of HIV-infected cells by CD8 T cells regardless of their original specificity (e.g. a CMV-specific CD8 T cell could potentially be brought into action against HIV by ImmTAV). At CROI 2025, Beatriz Mothe presented evidence of safety, a reduction in the active HIV reservoir, and some modulation of viral load rebound in a small phase I trial.
    • The PENTA Foundation’s assessment of a therapeutic HIV vaccine combination in adolescents with perinatal HIV in South Africa (the HVRRICANE Study) reported that the regimen induced sustained HIV-specific T cell and B cell responses.
    • A trial sponsored by the US Military HIV Research Program (MHRP) investigating the IL-15 superagonist N-803 in people with acute HIV initiating ART in Thailand: One poster described evidence of enhanced CD8 T cell and natural killer cell proliferation, a second poster stated there were transient indications of accelerated viral load decline at the time of N-803 administration. The major adverse event was injection site swelling, which was severe in eight cases but resolved within seven days. Participants are now being given the option of receiving a second N-803 dose followed by ATI.
    • A study of two therapeutic vaccine candidates being developed by Gilead Sciences indicated improvements in HIV-specific T cell functionality in some recipients but not breadth (how many different parts of HIV are being targeted).
    • Researchers at UCSF assessed the capacity of T cell receptor (TCR) sequencing approaches to identify changes in CD8 T cell immune responses after receipt of the PENNVAX HIV vaccine in a completed therapeutic trial. The analysis demonstrated that it’s possible to document both induction of new CD8 T cell responses and the boosting of pre-existing CD8 T cells targeting HIV.
    • AbbVie presented a poster featuring results from a phase I trial of their anti-α4β7 integrin antibody ABBV-382, now given the name trosunilimab. The antibody is intended to facilitate presentation of HIV components to T cells and may also have some capacity to block viral entry into cells. The study recruited both people with HIV and HIV-negative participants, and the antibody was found to be safe and displayed favorable pharmacokinetics. Trosunilimab is now being evaluated by AbbVie in combination with their PD-1 inhibitor budigalimab in a large international phase II trial that includes an ATI.
    • Sara Gianella Weibel gave a talk describing potential benefits of the anti-CMV drug letermovir in people with HIV; in an ACTG trial, there was long-term reduction in inflammatory biomarkers and improvements in measures of aging-related physical function. Another study of letermovir in people with HIV on ART has been registered in the UK but isn’t yet listed as open for enrollment.
    • A poster by Timothy J. Henrich and colleagues reported results from a small trial of stem cells gene-modified to promote resistance to HIV. The study recruited people with HIV and lymphoma who required a stem cell transplant. The gene-modified cells persisted in recipients and there was evidence of expansion and protection from HIV infection in one individual who underwent ATI, however they met ART restart criteria within eight weeks.
    • MHRP investigators preparing for a combination HIV cure-related protocol in Thailand involving bNAbs and therapeutic vaccines have developed “a strategy combining sequence analysis, in silico bnAb sensitivity predictions and neutralization assays to prioritize enrollment of participants with the most sensitive viruses to the bnAbs that will be used in an ATI.” The idea is to try to maximize the benefits to the participants. Notably, HIV samples from only 21.5% of 116 people screened showed sensitivity to both bNAbs (PGDM1400LS and VRC07-523LS).
    • Rafick P. Sekaly’s research group conducted a randomized 30-person clinical trial of a gene therapy originally developed by Sangamo to assess for any reductions in the HIV reservoir. The approach involves infusions of CD4 T cells genetically modified to abrogate expression of the CCR5 co-receptor. A poster presentation disclosed that no significant decline in the intact HIV reservoir was detectable after either 48 or 96 weeks of follow up.
    • Researchers in France shared two abstracts about a trial of a full-spectrum cannabidiol in people with HIV on ART. Eighty participants were assigned to receive either 1mg/kg twice a day of a full-spectrum, pharmaceutical grade, CBD oil or a placebo medium-chain triglyceride oil for 12 weeks. There were no significant adverse events and a reported diminution of bilirubin levels and a lower median heart rate in male participants. A second poster abstract described potential anti-inflammatory effects that appeared greater in male participants.
    • Mauro Garcia used samples from the BEAT-2 clinical trial in Philadelphia to show that when considering the effects of bNAb infusions on time to viral load rebound during ATI, the natural antibody responses of the recipients (autologous neutralizing antibodies or aNAbs) need to be taken into account. The presence of aNAbs against HIV was significantly correlated with delayed time to the reappearance of viral load after ATI.
    • Samples from participants in two studies in TAG’s listing, DGVTAF and APRIL, were used by researchers to interrogate research questions not directly related to the primary purpose of the protocols. In the former case, Hunter M. Courtney and colleagues tracked the evolution of aNAbs and HIV in people who started ART very early. Samples from APRIL were utilized to show that the capsid inhibitor lenacapavir can promote the degradation of viral Gag proteins in HIV-infected cells.
    • Multiple abstracts were presented from the very large 2000 HIV Human Functional Genomics Partnership Program (2000HIV) observational study in the Netherlands. Findings included:
      • A lack of linkage between residual viremia on ART and immune activation/inflammation (but other possible associations of interest);
      • Highest levels of PD-1 expression observed in participants with “higher CMV reactivity, higher HIV reservoir size, males, and immunological non-responders”;
      • Samples from females with HIV display enhanced IFN pathway gene expression but lower pro-inflammatory IL-1β production upon TLR7 activation compared to males with HIV;
      • An association between mitochondrial gene variants and natural immune control of HIV, and lower HIV reservoirs;
      • Differential regulation of immune responses to CMV in natural HIV controllers compared to non-controllers;
      • Three distinct clusters of HIV reservoir profiles identified by multiomics in people on ART: 1) High total HIV DNA, low intact HIV DNA (n=348), 2) low total HIV DNA, low intact HIV DNA (n=421), and 3) high total HIV DNA, high intact HIV DNA (n=467).

    In addition to these studies presented at CROI 2025, links to were added to newly published information from five trials in the listing:

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

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

    New Additions

    Four new protocols were added.

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

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

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

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

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

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

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

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

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

    Updates to Enrollment Status

    Two studies in the listing updated their enrollment status:

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

    New Links to Study Results

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

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

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

    For January 2025 there were only two updates to TAG’s listing, likely reflecting the holiday period since the December update. 

    New Links to Study Results

    Both updates were links to newly available results from studies in the listing.

    At the HIV Persistence Workshop last December in Fort Lauderdale, James McMahon and colleagues presented preliminary information from an ongoing trial of low doses of the PD-1 inhibitor nivolumab in people with HIV on antiretroviral therapy (ART). A total of 17 participants had been enrolled, with 12 receiving a single dose of either 0.1 or 0.3 mg/kg of nivolumab (six participants per dose group).

    No immune-related adverse events (a known risk associated with the doses used to treat cancer) have occurred, with the main side effect appearing to relate to a sampling procedure to extract lymph node tissue from the groin area: mild groin bruising or pain in 11 participants. Six participants also reported mild fatigue.

    Nivolumab successfully bound to PD-1 receptors on CD4 and CD8 T cells, with higher occupancy seen at the higher dose. The abstract doesn’t contain any data from the ongoing highest dose cohort receiving 1 mg/kg (which also plans to include six participants). A second part of the trial will evaluate whether receipt of nivolumab influences HIV viral load rebound during an analytical treatment interruption (ATI).

    Mareva Delporte from the HIV Cure Research Center at Ghent University has led work to develop a new type of test to measure the size of the HIV reservoir. The test is novel because it captures both total HIV DNA and the amount of HIV DNA that appears intact and potentially capable of generating new virus copies. Initial testing involved participants from one of the observational studies included in TAG’s listing, HIV-Mercuri (NCT04305665).  Results were published in the journal Clinical Chemistry and indicate that the test, named the Rainbow proviral HIV-1 DNA dPCR assay, may have advantages compared to others already in use (such as the intact proviral DNA assay or IPDA).

    Coda

    Sadly there are also broader issues relating to HIV cure research that deserve mention this month. The incoming new US Presidential administration has launched an unprecedented attack on science, stopping external communications, travel, and hiring at the US National Institutes of Health (NIH) and derailing their work in multiple other ways that are still coming to light – including stopping essential grant reviews, which will drastically affect the conduct of studies. The administration’s nominee for the position of Secretary of the Department of Health and Human Services (HHS), which oversees NIH, supports AIDS denialism and has recently uttered the following egregious lie that indicates complete ignorance of more than three decades of scientific research:

    RFK Jr: "There are much better candidates than HIV for what causes AIDS."

    This is in addition to his reprehensible, lucrative history of denying the efficacy of vaccines.

    TAG is collaborating with many others to fight back against these politically motivated anti-science attacks and oppose the nomination of RFK Jr. See also TAG’s statements on the appalling executive orders attempting to deny the humanity of transgender, non-binary, and intersex people and withdrawing the US from the World Health Organization.

  • 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 November 2024 Update

    For November 2024, there were 11 updates to TAG’s listing. We’ve also added the country locations for each of the current trials (previously, site locations were only included in the table in our annual Research Toward a Cure and Immune-Based Therapies Pipeline Report).

    New Additions

    Four new clinical trials were identified in registries:

    Researchers in Madrid, Spain are planning to investigate the effects on the tissue HIV reservoir of higher than usual doses of the antiretroviral drugs dolutegravir, maraviroc, and lamivudine. While most studies have concluded that current antiretroviral therapy (ART) regimens completely suppress HIV replication, the registry entry for this new trial states that there’s some evidence of reduced drug concentrations in lymphoid tissue that may be linked to higher levels of HIV RNA. The goal of the protocol is to assess whether ART that can be safely administered at slightly higher doses affects measures of HIV persistence. Previous studies that explored the same question by adding antiretrovirals to standard regimens (treatment intensification) haven’t reported any notable effects on the HIV reservoir. The trial aims to enroll 24 participants but is not yet recruiting.

    Several years ago a company named Zion Medical made a variety of implausible claims about the potential efficacy of an HIV drug candidate they named Gammora, a compound supposedly based on protein fragments derived from HIV integrase. A small clinical trial was said to have taken place in Uganda, but — if it did occur — wasn’t approved by appropriate regulatory authorities, as the company eventually admitted in response to an investigation by Bekhisisa. Even more concerningly, substances called Gammora started to be sold as a purported HIV cure, both online and locally. The company issued a release stating they’d entered into an agreement with a Swiss “seller of unlicensed medicines” but the extent of their role in sales is unclear. At least some of the substances sold have turned out to be other potentially dangerous drugs. Representatives from Zion Medical published an abstract rehashing claims about the Uganda trial in 2021, not mentioning that they’d already admitted it was improperly conducted.

    Some of the same protagonists now appear to have returned with a different company, Code Pharma, and seemingly a different name for the same compound: Codivir. They’re collaborating with researchers in Brazil to conduct a study in which Codivir is administered alone and then in combination with standard ART. This group recently reported another set of implausible-sounding results at the HIV Glasgow conference (abstract P212), claiming that Gammora (as they were still calling it in the abstract) led to a one-log decline in HIV DNA levels.

    TAG will continue to monitor for the presentation of results from the new trial, with the caveat that we’re extremely skeptical regarding the integrity of any data reported by this company. Sales of the compound still appear to be a major focus, as stated on the company website: “Code Pharma has already received emergency approvals from several countries and is preparing for mass production of Gammora in different production sites worldwide based on the received orders.” (TAG has written to the company to ask which countries have granted emergency approvals, because no such reports can be found online).

    ViiV Healthcare is recruiting for a new first-in-human clinical trial of a bispecific broadly neutralizing antibody (bNAb) currently codenamed VH4527079. Bispecific means that the antibody has been engineered to block two different parts of HIV that are involved in the process of infecting vulnerable cells (a regular bNAb only has one target). The study will administer VH4527079 to people with HIV on ART and a cohort of participants without HIV.

    A collaborative study led by researchers in Denmark and Australia will assess the effects of an immunomodulatory anti-cancer drug, pomalidomide (a safer analog of thalidomide), in people with HIV on ART. The protocol includes an analytical treatment interruption (ATI) to evaluate whether receipt of pomalidomide alters HIV viral load rebound. Pomalidomide has previously shown evidence of efficacy and immune modulation in people with HIV and Kaposi’s sarcoma.

    Updates to Enrollment Status

    A clinical trial sponsored by CAPRISA in South Africa investigating dual bNAbs in people with HIV is now open for enrollment. The protocol includes CAP256V2LS, a bNAb isolated by South African scientists from an individual with subtype C HIV,  and VRC07-523LS, which was identified in samples from an individual with subtype B HIV. The bNAbs will be administered either at the time of ART initiation or a week prior, with an ATI scheduled after around a year of ART to measure any effects on HIV viral load rebound.

    Two studies in the listing assessing combinations of interventions are now closed to further enrollment:

    • A clinical trial involving two therapeutic vaccines and three bNAbs led by Boris Juelg at the Beth Israel Deaconess Medical Center, taking place at six sites in the United States. Estimated completion date is April 2026.
    • A study combining two bNAbs with N-803, a superagonist of the cytokine IL-15 intended to enhance immune responses. Sites are located in New York City and Philadelphia. The principal investigator is Marina Caskey from Rockefeller University, and the estimated completion date is December 2025.

    New Links to Study Results

    At the recent HIV Glasgow conference Gilead Sciences presented the first results obtained with GS-1966 and GS-1144, experimental therapeutic HIV vaccine candidates licensed from Gritstone Bio. GS-1966 is based on a chimpanzee adenovirus while GS-1144 is a self-amplifying mRNA-lipid nanoparticle, and both include conserved elements of HIV-1 Gag, Pol and Nef in either single (monovalent) or dual (bivalent) forms.

    The vaccines were found to be generally safe in people on ART but there was one case of Bell’s palsy leading to discontinuation, which resolved within 14 days. The largest change from baseline to peak T cell responses against HIV was observed among recipients of vaccines containing a bivalent form of the encoded HIV proteins, but the effect of immunization was difficult to distinguish because participants already possessed high levels of pre-existing HIV-specific T cells. Additional detailed analyses of T cell functionality are ongoing. As is often the case with Gilead Sciences, this phase I trial isn’t registered in clinicaltrials.gov or any other online registry, which runs contrary to the company’s oft-repeated claims about prioritizing community engagement with their research (it’s difficult to engage with a trial that’s essentially hidden from public view).

    Researchers involved in the RIVER trial in the UK, which investigated early ART initiation plus therapeutic vaccination, published new findings in the Journal of Experimental Medicine. Detailed assessments of the HIV reservoir uncovered evidence that innate immune mechanisms — but not vaccine-induced T cells — appeared to contribute to clearing the virus-infected cells most likely to be visible to the immune system, leaving behind cells containing HIV integrated into regions of the genetic code which are less hospitable to viral reactivation.

    Sarah Lefebvre and colleagues have published a social science study looking at reasons for declining the opportunity to participate in an HIV cure-related clinical trial that ultimately wasn’t able to proceed (AMEP-EHVA-T02). The protocol included an ATI, but the ART interruption wasn’t the main reason for lack of interest, rather it was concerns over the logistics and psychological burdens associated with attending frequent study visits.

    The final addition this month is a simple replacement of a link to a preprint of a paper with the link to the final published peer-reviewed version in the journal Nature Communications. The research describes a rapid biphasic decline in levels of intact and defective HIV DNA in a study of people who started ART very quickly after HIV acquisition (the results were first presented at the IAS 2023 conference).

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

    There were 14 updates to TAG’s listing for October 2024.

    New Additions

    Two new clinical trials were identified in registries, neither yet open for enrollment:

    Researchers in the UK are initiating a study of the anti-CMV drug letermovir primarily to assess effects on T cell activation in people with HIV on antiretroviral therapy (ART). Markers of HIV persistence will also be measured as secondary endpoints. The trial appears similar to a previous pilot protocol conducted by Peter Hunt and colleagues, which reported evidence of modulation of inflammatory pathways but didn’t document changes of sufficient magnitude to meet pre-specified criteria for expanding the number of participants (see prior blog post from March 2024).

    IAVI has registered a new trial that plans to investigate an HIV vaccine candidate based on an adenovirus variant derived from gorillas. The study will recruit people with HIV on ART and a cohort of HIV-negative participants. The modified gorilla adenovirus serves as a vector for delivering selected HIV components known to induce CD8 T cell responses. The main outcome measures will be safety and levels of vaccine-induced HIV-specific T cells. For the cohort of people with HIV, individuals with past CD4 nadirs (lowest ever values) less than 200 are excluded, presumably based on concerns that immune responses to the vaccine might be diminished.

    Updates to Enrollment Status

    A multi-site protocol investigating infusions of HIV-specific T cells for people undergoing autologous stem cell transplantation to treat HIV-associated lymphoma is now closed to further recruitment. The research is sponsored by Dr. Catherine Bollard at the National Heart, Lung, and Blood Institute (NHLBI) and has an estimated final completion date of June 2026.

    A study of the immune checkpoint inhibitors nivolumab and ipilimumab in people with HIV and relapsed or refractory cancers has been stopped, with the reason given as “inadequate accrual rate.” The trial was sponsored by the AIDS Malignancy Consortium and recruited enough participants to publish several conference abstracts and papers reporting on safety and effects on the HIV reservoir (see table entry for registry # NCT02408861 for complete links).

    New Links to Study Results

    Results from two trials in the listing were presented at the recent HIVR4P conference in Lima, Peru:

    Jorge Gallardo-Cartagena described findings from a study involving participants who acquired HIV during the Antibody-Mediated Prevention (AMP) trial at sites in Peru. A total of 18 participants who started ART early and maintained viral load suppression for at least a year were enrolled. The demographics reflected the diversity of participants in the parent AMP trial and included 14 men who have sex with men, three transgender women, and one gender non-conforming individual.

    All participants underwent an analytical treatment interruption (ATI) to assess whether receipt of the broadly neutralizing antibody VRC01 prior to HIV acquisition delayed or reduced viral load rebound after an ATI. Gallardo-Cartagena reported that the average time to viral load rebound above 200 copies/ml was 4.1 weeks, and the average time to reaching ART restart criteria was 7.9 weeks. There were no significant differences between participants who received VRC01 in the AMP trial and those who were in the placebo arm.

    There was one adverse event related to the ATI, an acute retroviral syndrome associated with a rapid rise in viral load from 1,450 to 679,000 copies/ml which prompted immediate reinitiation of ART. There were four cases of participants resuming ART at their request and one due to clinician request, although biomarker criteria for restarting hadn’t been met. This represents a higher proportion of participants returning to ART by request than has typically been the case historically in ATI studies and this may be an issue to pay attention to as this type of protocol expands into new geographic locations where there may be less familiarity with HIV cure-related research.

    Aljawharah Alrubayyi from the Ragon Institute of Mass General, MIT and Harvard presented a new analysis of results from a therapeutic HIV DNA vaccine study conducted at the University of California San Francisco (UCSF). Alrubayyi reported that the PENNVAX construct induced new CD8 T cell responses targeting conserved HIV proteins in a small subset of participants (11%). This type of CD8 T cell response has previously been associated with immune control of HIV, suggesting that additional research could help shed light on both the anti-HIV efficacy of the vaccine-induced CD8 T cells and strategies for increasing the rate of the response among vaccine recipients.

    Links to published results were added for nine studies in the TAG listing:

    Anastasia Korolkova and colleagues evaluated how participants in an HIV cure-related ATI study at UCSF recalled and appraised the risks, benefits, and purpose of the protocol. The investigators found a high level of recall and highlighted the important role of the study staff in communicating key information about participation. There was no evidence that participants had mistaken expectations about being cured as a result of joining the study (referred to as therapeutic misconception). The results were published in the journal AIDS and Behavior.

    In the journal Cell Reports Medicine, Tim Henrich and colleagues shared results from an ACTG trial of sirolimus in people with HIV on ART. Sirolimus belongs to a class of drugs called mTOR inhibitors which are known to suppress T cell proliferation, and is most commonly used to prevent organ transplant rejection. There were two serious adverse events among 30 participants who received at least one dose: stomatitis and elevated fasting glucose. Additionally, one participant experienced a decrease in CD4 T cell counts to below 300 cells.

    A total of 16 participants completed the full planned 20 weeks of sirolimus dosing, experiencing an average decline of 118 CD4 T cells but also an average reduction in HIV DNA levels of 31%. Immune-modulating effects included reduced CD4 T cell proliferation and decreased expression of the immune checkpoint PD-1 on CD8 T cells. The researchers note that the side effect profile is problematic, but suggest that lower doses in combination with other approaches might still have a role to play in HIV cure research.

    A belated link addition for four trials in the listing is a paper published in Clinical Infectious Diseases back in 2020. The research analyzed the central nervous system (CNS) safety of ATIs among participants in four different studies conducted in Thailand. By most measures there were no apparent adverse effects in terms of inflammation in the CNS or cognitive performance, but magnetic resonance spectroscopy (MRS) did reveal evidence of mild cell membrane damage in the basal ganglia. Due to lack of extended of follow up, the researchers weren’t able to investigate whether this resolved with additional time on ART after the ATI. The abstract concludes: “Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.”

    A French study of twice-daily cannabidiol full-spectrum oil in people with HIV on ART has published results from a quality of life analysis showing limited effects. The protocol included measurements of the HIV reservoir and immunological parameters as secondary endpoints, but the initial paper doesn’t include information addressing those outcomes.

    The final addition to mention is a link to Rachel Presti’s AIDS 2024 conference presentation of results from the first clinical trial of EBT-101, a CRISPR approach targeting the HIV reservoir. The outcomes were reported in our August 2024 update, and a recording is now available on the conference website.

  • 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.