TAG HIV Basic Science, Vaccines, and Cure Project Blog

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

recent posts

  • TAG’s HIV Cure-Related Clinical Research Listing: Background on the 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.

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

    There are twelve updates to the listing this month: four new interventional trials and one observational study have been added (all yet to start recruiting), a planned observational study was withdrawn, a trial of immunomodulators has begun recruiting in China, one trial has shifted to the completed studies table, and links to presentations/publications describing results were added for four studies in the listing.

    The ACTG is sponsoring a new placebo-controlled study of a single infusion of each of two long-acting broadly neutralizing antibodies (bNAbs) followed by an analytical treatment interruption (ATI) in people on antiretroviral therapy (ART) at sites in Botswana, Malawi, and South Africa. The bNAbs are 3BNC117-LS-J and 10-1074-LS-J. The plan is to enroll a total of 48 participants, who’ll be randomized to receive the bNAb infusions or placebo versions and start an ATI two days later. The eligibility criteria require that participants have been on a suppressive ART regimen for at least 96 weeks (with some allowance for a short interruption during that period). The researchers will evaluate the capacity of the bNAbs to delay viral load rebound above a threshold of 200 copies/ml (suggesting that an increase of viral load above this level will trigger the restarting of ART). The ACTG is currently in the process of revising their former name AIDS Clinical Trials Group to just the acronym, which has been altered to stand for: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (to reflect the broadening of their mission).

    At the Research Institute of the McGill University Health Centre in Canada, Jean-Pierre Routy is initiating a trial that will investigate the safety and effects of fecal microbiota transplantation (FMT) on gut integrity, inflammatory biomarkers, and HIV reservoir measures in people on ART. As outlined in a recent meta-analysis of 10 prior studies, FMT has shown some potential efficacy in restoring healthy gut bacteria and reducing the rate of gastrointestinal infections in PWHIV, with a safety profile similar to that observed in HIV-negative people. Routy’s study will enroll 20 participants with half randomized to receive FMT capsules and half receiving a placebo equivalent. The researchers are limiting the study to people with a CD4:CD8 ratio <1 in order to focus on a population most at risk for persistent inflammation.

    The pharmaceutical company AbbVie recently entered the realm of HIV cure research without great fanfare and is now about to launch a combination trial assessing a combination of two antibody-based therapeutics that they’ve previously studied individually in PWHIV (results from those studies have not been publicly presented yet to our knowledge). Budigalimab is an anti-PD-1 antibody that belongs to the class of interventions called immune checkpoint inhibitors (several are licensed for the treatment of cancers), while ABBV-382 is an anti-α4β7 integrin antibody similar to vedolizumab (an antibody approved for ulcerative colitis and Crohn's disease). According to the study record, AbbVie plans to recruit 140 participants at approximately “90 sites worldwide.” The protocol involves an ATI and will evaluate the effect of the antibodies (alone or in combination) compared to placebo on time to viral load rebound greater than 1,000 copies/ml. Based on the company’s website pipeline page, it appears that the ultimate goal may be to combine the two antibodies into a single construct (codenamed ABBV-1882) that can target both PD-1 and the α4β7 integrin. The interventional trial that was completed this month is AbbVie’s phase Ib assessment of ABBV-382 alone — although results don’t appear to be available yet, it seems reasonable to assume that the data supported progressing to the larger combination study.

    The last of the new interventional trials is sponsored by the HIV Vaccine Trials Network and aims to test an HIV vaccine construct in PWHIV on ART who will undergo an ATI. The vaccine is part of an effort to develop a “germline targeting” strategy that can eventually lead to the generation of bNAbs. The main goal of the study is to assess how HIV viral load rebound during ATI affects the B cell and antibody responses induced by the vaccine. The rationale is that further stimulation of vaccine-induced B cells by HIV may conceivably drive a process called maturation that can lead to the production of more effective antibody responses, and the researchers plan to study this very carefully. There are also a number of secondary outcome measures focused on the experience and perspectives of the study participants, because while this work may be able to contribute to cure research, the primary focus is on informing the development of an effective preventive HIV vaccine.

    The lone new observational study is sponsored by the University Hospital, Ghent and intends to undertake a detailed characterization of the HIV reservoir in individuals who are naturally controlling viral load to low levels in the absence of ART. The observational study that was withdrawn this month was from the same sponsor; the clinicaltrials.gov record notes that it wasn’t able to open because a commercial partner decided not to proceed with the project.

    A study of two potential immunomodulators, lenalidomide and adenosylmethionine (added to the listing in November 2022) is now open for enrollment at the First Affiliated Hospital of Zhejiang University School of Medicine in China.

    The new links to publications and presentations include:

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

    There are ten updates this month: a newly entered therapeutic HIV vaccine trial in China, a new observational study in Belgium, one observational study shifted to the completed studies table, and links added to presented/published results for seven of the studies in the listing.

    The therapeutic HIV vaccine trial is testing a novel DNA construct called ICVAX, which encodes a mosaic form of the HIV Gag protein fused to a soluble human PD-1 protein. Mosaic means that the Gag protein consists of elements from multiple different HIV variants, with the aim of inducing T cell responses capable of responding to diverse viruses (in this case the focus is on variants circulating primarily — but not only — in China). The reason for the inclusion of the PD-1 protein is to target the HIV Gag protein to dendritic cells, which are responsible for initiating immune responses. Dendritic cells express molecules called ligands which interact with PD-1, and delivering antigens such as the HIV Gag protein via this pathway is associated with superior induction of CD8 T cell responses.

    The approach is being developed by a biotech company, Immuno Cure, and promising results have been reported in both macaque and mouse models. The launch of the phase I trial in Shenzhen was announced in February 2023, but initially we were unable to identify a trial registry entry. We’ve since found a link describing the study and a recent news article indicates results are anticipated soon (however the bulk of the piece is behind a paywall).

    In a presentation at the recent IAS HIV Cure & Immunotherapy Forum in Brisbane (see video), Zhiwei Chen from the University of Hong Kong described the vaccine approach and disclosed that the first doses were administered to study participants in March 2023. The study design involves a stepwise assessment of escalating doses, and Chen explained that the lowest dose cohort has been completed with no safety issues identified. The researchers have now initiated a medium dose cohort. An analytical treatment interruption (ATI) will be considered in the future if all goes according to plan.

    The new observational study is taking place in Belgium, sponsored by the University Hospital, Ghent. The plan is to recruit two cohorts of people living with HIV on ART: one group will include people who started ART during acute HIV infection a minimum of three years ago but no more than 10 years ago (designated the short-term ART cohort), while the second group will comprise people receiving ART for more than 20 years (long-term ART cohort).

    Participants will be selected based on continuous use of ART and maintenance of viral load suppression to undetectable levels. The latter criteria are quite strict, with only one prior viral load blip (that didn’t exceed 200 copies/ml) allowed. Cells will be collected via leukapheresis in order to study the HIV reservoir in each cohort in great detail and test the effect of potential interventions on HIV-infected cells in the laboratory (in vitro). The goal is to generate information that can contribute to the development of curative interventions. The principal investigator is Dr. Linos Vandekerckhove.

    The observational study that’s now completed is named DOLUVOIR and involved a detailed assessment of antiretroviral drug levels and the HIV reservoir in men on first line treatment including the integrase inhibitor dolutegravir combined with abacavir/lamivudine or tenofovir/emtricitabine. The aim was to quantify drug levels in multiple body tissues and in semen, in addition to looking for evidence of residual HIV replication in these compartments. The research took place at multiple sites in France and was led by principal investigator Antoine Chéret. To our knowledge, results have not been published or presented as yet.

    Five studies in the listing have had links added to results presented during IAS 2023 in July:

    Among the most widely publicized news from the conference was Asier Sáez-Cirión’s description of a case of extended HIV remission after stem cell transplantation for cancer in a person who didn’t receive cells from a donor with the HIV-resisting CCR5Δ32 mutation (covered previously on the blog and the subject of detailed reporting by Liz Highleyman for AIDSMap). The individual is being followed as part of the IciStem project (an "International Collaboration to guide and investigate the potential for HIV cure by Stem Cell Transplantation"), which is included in our table of observational studies.

    At the pre-conference HIV Cure & Immunotherapy Forum (see video), Monica Reece from Emory University presented an analysis of the effects of ruxolitinib, a Janus kinase inhibitor, on the HIV reservoir in people on antiretroviral therapy (ART) with suppressed viral loads. The information was also shared as a poster at IAS 2023.

    The results derive from a randomized, open label trial sponsored by the AIDS Clinical Trial Group (ACTG) that assigned 40 participants to receive ruxolitinib in addition to ART while 20 participants continued on ART alone (information on safety, inflammatory markers and pharmacokinetics has been published previously in Clinical Infectious Diseases and the Journal of Clinical Pharmacology). Ruxolitinib was dosed at 10mg twice a day for the first five weeks and then stopped, with all participants in both arms followed for 12 weeks. The drug was generally well tolerated; three participants prematurely discontinued but in only one case was this due to an adverse event considered related to ruxolitinib (severe elevation of the liver enzyme AST).

    Reece’s presentation showed that there was no significant decline in the size of the HIV reservoir (as measured by the intact proviral DNA assay or IPDA) when ruxolitinib recipients were analyzed as a group and compared to the controls. But when the researchers divided the ruxolitinib recipients into three tiers based on the baseline size of their HIV reservoir, those in the top third with the highest baseline levels experienced a statistically significant decline during weeks 5-12 after dosing was stopped. No difference was evident after five weeks.

    Reece also described several biomarkers that were associated with this apparent reservoir decline, and used the kinetics of the decay to create a mathematical model suggesting that — in the subset of participants who experienced this decline or people who respond similarly — 99.99% of the HIV reservoir might be cleared after 2.86 years. The data appears somewhat encouraging, but there are some potential caveats to bear in mind:

    • The decision to conduct an analysis of HIV reservoir decline by dividing ruxolitinib recipients into different groups based on baseline reservoir size was post hoc, meaning it was not planned in the original trial protocol. Post hoc analyses of subsets of study participants are unfortunately notorious for producing unreliable results.
    • The fact that the apparent decline in the size of the HIV reservoir only occurred after ruxolitinib dosing was stopped, combined with the unreliable nature of post hoc subset analyses, raises questions about the wisdom of using the data to make a mathematical model suggesting 99.99% clearance of the HIV reservoir after a little less than three years. The model certainly garnered some publicity, but may be premature given that no decline was seen while ruxolitinib was being administered.

    More positively, the biomarkers reported to be associated with a decline in HIV reservoir size were consistent with ruxolitinib’s proposed mechanism of action (inhibiting the survival of virus-infected cells) and, as Reece noted, there’s speculation that ongoing use of the drug may have contributed to the extended case of HIV remission reported at the conference by Asier Sáez-Cirión. The publication of Reece’s results and further investigation into Janus kinase inhibitors in people with HIV will hopefully help clarify the promise of the approach.

    Researchers led by Dr. Jun Chen from the Shanghai Public Health Clinical Center at Fudan University are conducting an ongoing clinical trial combining an anti-PD-L1 antibody (ASC22) with chidamide, an HDAC inhibitor licensed for use in China. A prior small study has suggested that chidamide may have HIV latency-reversing activity, and antibodies against PD-L1 aim to restore function to T cell responses that have become exhausted and dysfunctional. An antibody against PD-L1 has previously been tested in people with HIV by the ACTG, generating some evidence of enhanced HIV-specific T cell responses but also reporting a delayed autoimmune adverse event that was potentially linked to the intervention (hypoadrenalism and hypogonadism, which was eventually resolved).

    In their IAS 2023 poster abstract, Chen and colleagues describe preliminary results in 15 participants on antiretroviral therapy (ART) who’d maintained viral load suppression for at least a year prior to study entry. Administration of ASC22 and chidamide was associated with transient increases in HIV RNA consistent with latency-reversing activity and an elevation in the proportion of a subset of CD4 and CD8 T cells (effector memory cells) that are known to be important for killing pathogen-infected cells. Some participants also demonstrated evidence of enhanced T cell function.

    There were eight adverse events, all of which were grade 1 and resolved on their own. Study follow up was 24 weeks, and additional follow up may be needed to confirm safety because the autoimmune adverse event in the ACTG study occurred 36 weeks after administration of the anti-PD-L1 antibody. The abstract concludes that: “This strategy holds promise for activating and clearing latent HIV reservoirs and deserves further investigation.”

    The manufacturer of ASC22, Ascletis Pharmaceuticals, also has a separate ongoing 30-person phase II trial evaluating the safety, tolerability and efficacy of two different doses in people with HIV on ART, which is due to complete at the end of the year.

    David Margolis from the University of North Carolina and the Martin Delaney CARE Collaboratory debuted results from a small trial that combined the HDAC inhibitor vorinostat with an adoptive immunotherapy approach (HIV-1 antigen expanded specific T cell therapy or HXTC). The immunotherapy requires extraction of T cells from study participants, expansion of HIV-specific T cells in the laboratory, and reinfusion back into the participant. The combination led to some evidence of a decline in the size of the HIV reservoir measured by the quantitative virus outgrowth assay (QVOA), but Margolis noted that the effect was not large enough to rule out a role of assay variability (based on previous work that defined a six-fold change in QVOA measures as the minimum necessary to indicate a true difference). The poster abstract suggests that more potent interventions are likely needed to achieve more significant effects.

    The last of the studies in the listing with results presented at IAS 2023 is an investigation into the effects of oral cannabinoid capsules (with or without THC) on inflammation and HIV reservoir size in people on ART. Led by Cecilia Costiniuk at the McGill University Health Centre in Canada, the study reported evidence of potentially beneficial reductions in some markers of inflammation and T cell exhaustion, but no significant changes in HIV reservoir measurements. The researchers propose that the data support the initiation of larger trials. The results were also published in the journal Cells shortly before the conference got underway.

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

    An analysis of samples from participants in the completed BCN02 trial, which investigated a combination of a therapeutic HIV vaccine and the HDAC inhibitor romidepsin, found that lower levels of the cell receptor CD33 were associated with partial control of viral load after an ATI (while higher CD33 levels were associated with an absence of control). The researchers note that additional research is needed to confirm the findings and expand to broader populations, because the majority of participants in the trial were men. The results are published in the open access journal eBioMedicine.

    A completed observational study investigating the HIV reservoir in people on ART in Uganda has provided samples for an analysis of the timing of reservoir formation, with results published in the journal Virus Evolution. The rationale derived from previously presented evidence that, in many cases, the bulk of the persistent HIV reservoir in people on ART shows evidence of having been formed close to the time ART was started. The suggestion from these findings was that HIV-infected cells may be more prone to die when viral load is high and T cells are more activated and show higher rates of death, whereas suppression of viral replication by ART allows a more favorable environment for some HIV-infected cells to de-activate and create the reservoir from which the virus can reemerge if ART is stopped.

    However, the results from men and women on ART in Uganda weren’t consistent with prior findings and indicate that their HIV reservoir formed across an extended period of time before treatment initiation. Only two of 11 participants displayed evidence of HIV reservoirs formed close to the time ART was started. The researchers state that larger studies are needed to better understand variation in the timing of HIV reservoir formation, but the research will likely depend on the availability stored pre-ART samples now that immediate ART initiation is the standard of care. The question is not just academic because there are implications for when candidate anti-reservoir interventions should be given, with some investigators already testing administration at the time that ART is begun (such as the eCLEAR study, which offered support for the idea).

  • HIV Cure Research News from the Opening IAS 2023 Press Conference

    The first press conference of the upcoming IAS 2023 meeting was held yesterday evening (US time) and featured several cure-related presentations.

    Most notably, Asier Sáez-Cirión and Alexandra Calmy described a possible case of an HIV cure (or at least extended remission) in an individual in Geneva who received a stem cell transplant to treat cancer. There are five previously reported cases of HIV cures (or likely cures) in people who received stem cell transplants for cancer diagnoses, but all have involved stem cell donors homozygous for the CCR5Δ32 mutation, which makes immune cells resistant to infection by most HIV strains. In this new case report, the donated stem cells were “wild type,” meaning they lacked this mutation.

    A full description of the case won’t occur until the conference track A late breaker session on Monday July 24, 4-5pm local time in Brisbane, Australia (in the US, 2-3am ET, 11-12pm PT). The study abstract has been shared with journalists and is no longer under embargo, but it’s still unavailable and listed as embargoed for the public on the IAS 2023 website.

    The individual is in his early 50s and received the stem cell transplant to treat a biphenotypic sarcoma. Afterward, HIV became undetectable by multiple tests and antiretroviral therapy (ART) was stopped in 2021. After 20 months of subsequent follow up, no viral load rebound has occurred, no HIV-specific T cell responses can be detected, and antibodies against HIV are waning. Sáez-Cirión noted that traces of HIV DNA have been detected at some timepoints, but it didn't appear to comprise intact, replication-competent virus.

    There are similarities to two people with HIV known as the Boston patients who also received wild type stem cell transplants to treat cancers and subsequently stopped ART without a viral load rebound. But in those prior cases, HIV viral load did return after three months and eight months, respectively.

    The reasons for the far more extended absence of HIV viral load rebound in the Geneva case are uncertain at this juncture. Speculative possibilities include:

    • The effects of graft-versus-host disease (GVHD), which involves the newly transplanted immune cells attacking and clearing the original host immune cells (potentially including CD4 T cells harboring HIV). GVHD was also reported in the Boston patients.
    • The use of the drug ruxolitinib to facilitate the transplant, which wasn’t reported in the Boston patients. Ruxolitinib belongs to a class of compounds called Janus kinase (JAK) inhibitors that have been shown to inhibit HIV infection and the seeding of the reservoir in laboratory studies. Ruxolitinib and other JAK inhibitors are being investigated in people with HIV on ART, and on Saturday in Brisbane at the HIV Cure and Immunotherapy pre-meeting Monica Reece is giving a presentation on the effects of ruxolitinib on the HIV reservoir in an AIDS Clinical Trials Group (ACTG) study.
    • The occasional use of pre-exposure prophylaxis (PrEP) after stopping his therapeutic ART regimen. This wasn’t discussed during the press conference but is mentioned by Tim Henrich in an excellent, detailed article for POZ Magazine by Liz Highleyman. Henrich suggests that PrEP use might have suppressed any lingering embers of HIV infection and prevented transfer of the virus to the transplanted immune cells.

    The hope is that the individual may be cured of HIV infection, but — as has been emphasized in some of the media coverage of the case — this cannot be considered proven. Mathematical modeling work by Alison Hill and colleagues indicates that if HIV has infected a tiny number of the new immune system cells generated by the transplant, viral load rebound could potentially occur after a delay of several years.

    The risk is considered higher in this case because the stem cell donor lacked the CCR5Δ32 mutation and hence the newly generated immune system remains vulnerable to HIV infection. Ongoing monitoring will be important and the potential for rebound needs to be borne in mind because, as Gary Steinkohl explained after disclosing his identity as one of the Boston patients, the reemergence of virus after a long delay can be very traumatic (in his words: “emotionally devastating”).

    Another cure-related presentation at the press conference was given by Gabriela Cromhout from the University of KwaZulu-Natal. Cromhout reported the identification five male infants with HIV who experienced apparent control of viral load in the absence of ongoing ART. The cases were identified during a project assessing ART blood levels among infants who acquired HIV via vertical transmission. The testing revealed an absence of sustained ART levels suggestive of non-adherence, but without HIV viral load rebound. Time off ART was estimated to range from 3-10 months.

    One of the infants has never been restarted on ART and has maintained an undetectable viral load after around 19 months of ongoing follow up. The four others have had ART restarted, with three enrolled in a study that plans to eventually undertake an analytical treatment interruption (ATI) to assess if control of viral load will recur.

    Cromhout explained that the results may provide evidence of a sex difference in the capacity to control HIV replication among infants, because the cohort comprises 60% females but all the cases were males. In beginning to look for contributing factors, the researchers have noted that when male infants acquire HIV, the virus typically displays sensitivity to the inhibitory effects of the cytokine alpha interferon but a high replication capacity. In females, this is reversed with viruses showing reduced sensitivity to alpha interferon and lower replication capacity.

    In the five cases reported by Cromhout, this pattern wasn’t observed – the viruses detectable in the male infants at acquisition were sensitive to alpha interferon and had a low replication capacity.

    The detailed presentation of the study will occur on Monday July 24 during a session that starts at 10:30am local time (in the US, on Sunday July 23 at 8:30pm ET, 5:30pm PT). As is the case with Sáez-Cirión’s report, the abstract remains embargoed to the public on the IAS Programme website even though the media embargo has been lifted and the abstract shared with journalists. TAG and many other advocates are calling for a revision of this policy of publicizing results ahead of their actual presentation at the conference.

  • HIV Cure Research at IAS 2023

    The 12th International AIDS Society Conference on HIV Science, IAS 2023, officially gets underway in Brisbane, Australia on Sunday July 23, with several pre-meetings occurring the day before. Appended below are links to events and sessions related to HIV cure research. Abstracts should become publicly available starting on Monday July 24, but access to session recordings will be delayed until sometime after the conference has ended.

    Saturday July 22

    HIV Cure & Immunotherapy Forum (not broadcast live, but according to IAS a recording will be made available afterward)

    Sunday July 23

    Target setting and leadership for Cure – Insights that show the way to HIV and Sick Cell Disease Cures for Africa
    SAT003 – Satellite
    Plaza Auditorium/Channel 4
    July 23, 7:30-9am local time (US Eastern time: July 22, 5:30-7pm)

    Monday July 24

    Vaccines and cure: Spotlight on antibodies
    PL01 – Plenary session
    Great Hall/Channel 1
    July 24, 9-10am local time (US Eastern time: July 23, 7-8pm)

    OALBX01 Co-Chairs' Choice (includes a presentation by Gabriela Cromhout on potential post-treatment control of HIV in several male infants)
    OALBX01 – Oral abstract session
    Cross-track
    Great Hall/Channel 1
    July 24, 10:30-11:30am local time (US Eastern time: July 23, 8:30-9:30pm)

    HIV cure research: Why are single cells harbouring HIV latent?
    SY07 – Symposium
    Track A: Basic science
    M4/Channel 6
    July 24, 2:45-3:45pm local time (US Eastern time: July 24, 12:45-1:45am)

    Track A late-breaker
    OALBA05 – Oral abstract session
    Track A: Basic science
    Plaza Terrace Room/Channel 2
    July 24, 4-5pm local time (US Eastern time: July 24, 2-3am)

    Viral replication and reservoirs beyond the periphery: A deeper look at tissues
    OAA01 – Oral abstract session
    Track A: Basic science
    Boulevard Auditorium/Channel 7
    July 24, 4-5pm local time (US Eastern time: July 24, 2-3am)

    Tuesday July 25

    Advances in gene delivery and engineering of T and B cells: Implications for prevention, therapy and cure
    SY12 – Symposium
    Track A: Basic science
    Boulevard Auditorium/Channel 7
    July 25, 10:30-11:30am local time (US Eastern time: July 24, 8:30-9:30pm)

    Immune-based interventions towards an HIV cure
    OAA02 – Oral abstract session
    Track A: Basic science
    Boulevard Auditorium/Channel 7
    July 25, 2:45 – 3:45pm local time (US Eastern time: July 25, 12:45-1:45am)

    Novel insights into viral persistence
    OAA03 – Oral abstract session
    Track A: Basic science
    M3/Channel 5
    July 25, 4-5pm local time (US Eastern time: July 25, 2-3am)

    bnAbs: From prevention to cure
    SAT054 – Satellite
    Boulevard Auditorium/Channel 7
    July 25, 6:30-8pm local time (US Eastern time: July 25, 4:30-6am)

    Wednesday July 26

    Understanding the HIV reservoir: New technologies and specific populations
    PL07 – Plenary session
    Great Hall/Channel 1
    July 26, 9-10am local time (US Eastern time: July 25, 7-8pm)

    Immune responses critical for viral control and approaches to harness them in vivo
    SY20 – Symposium
    Track A: Basic science
    Boulevard Auditorium/Channel 7
    July 26, 10:30-11:30am local time (US Eastern time: July 25, 8:30-9:30pm)

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

    The past month has seen few changes to TAG’s listing: since the previous update on June 15, two ongoing trials have closed to enrollment, one planned protocol has been withdrawn, and links have been added to three recently published papers presenting study results. For the second month in succession, no new HIV cure-related clinical studies have been registered in clinicaltrials.gov.

    One of the studies that has closed to enrollment involves participants who acquired HIV during the Antibody Mediated Prevention (AMP) trial HVTN 704/​HPTN 085, which enrolled men and transgender persons who have sex with men in the Americas and Switzerland. The follow up protocol (designated HVTN 804/HPTN 095), is evaluating whether the presence of the broadly neutralizing antibody (bNAb) VRC01 at the time of HIV acquisition altered the immune response to the virus to the extent that there’s a greater chance of control of viral load after an analytical treatment interruption (ATI). All the participants were started on ART soon after HIV diagnosis.

    There were two separate AMP trials in different populations, and likewise there are two ATI studies enrolling AMP participants who acquired HIV and started ART – the other ATI protocol (HVTN 805/HPTN 093) remains open for participants in HVTN 703/HPTN 081, which enrolled cisgender women in several countries on the African continent.

    Dr. Shelly Karuna from the HIV Vaccine Trials Network (HVTN) gave an excellent presentation about the two ATI studies for AMP participants at the 2023 Pre-CROI Community HIV Cure Research Workshop. After the workshop, Gail Broder from HVTN kindly made available the informed consent videos that were created for potential participants in this research:

    The second study in the listing to have closed for enrollment during the last month is an AIDS Clinical Trials Group (ACTG) investigation of SAR441236, a trispecific (three-pronged) antibody designed to block three different targets on the HIV envelope. The antibody is made by Sanofi and combines the specificity of three previously described single bNAbs: VRC01, PGDM1400, and 10E8v4.

    The protocol that’s been withdrawn was an ACTG trial that planned to assess the capacity of a dual bNAb combination, 3BNC117-LS and 10-1074-LS, to promote control of viral load after an ATI. The decision to not move ahead with the study was based on overlap with several other ongoing similar trials addressing the same question, including the RIO trial in the United Kingdom and RHIVIERA-02, which is due to get underway in France.

    Added links to publications include a paper in Science Translational Medicine describing outcomes in a trial of a dual bNAb combination among HIV-positive infants in Botswana. The results have previously been presented at CROI, demonstrating that the combination was safely able to maintain HIV viral load suppression in a little under half the infants (44%) during an ART interruption.

    In the Journal of Infectious Diseases, Javier Martinez-Picado and colleagues report additional results from a trial of obefazimod (formerly known as ABX464). Data from the study has been described previously in journal articles and at CROI 2020. Obefazimod has a novel mechanism of action that inhibits the generation of HIV RNA. The researchers report evidence of transient decreases in HIV DNA and levels of some inflammatory biomarkers. There were no serious adverse events but headache and GI side effects were common and three of the 24 HIV-positive study participants withdrew due to tolerability issues. The fate of obefazimod as a therapeutic candidate for HIV appears uncertain at the current time, because the manufacturer Abivax is now focused primarily on the use of the drug for inflammatory diseases and longer lists HIV in its research pipeline.

    A publication by Karine Dubé and colleagues in the Journal of Virus Eradication reports results from a social science study investigating the perceived risks and benefits of enrolling in the Last Gift, a cure-related research project for people with HIV reaching the end of their lives. Participants join in order to contribute their bodies for postmortem autopsy studies of the HIV reservoir. The article outlines the significant community involvement in the development and oversight of the protocol, which has enrolled over 30 participants to date. Both participants and their next of kin/loved ones were interviewed, with overall findings indicating that perceived risks were minimal and the altruistic benefits of participation were valued by both groups.

    Since last month’s update, the clinicaltrials.gov online registry that is the primary source for TAG’s cure-related studies listing has been changed over to a modernized version. All the links have been updated accordingly.

    TAG’s 2023 Research Toward a Cure and Immune-Based Therapies Pipeline Report is completed and will be posted online by this Friday, immediately ahead of IAS 2023, the 12th IAS Conference on HIV Science in Brisbane.

  • TACK Molecules: Sabotaging HIV to Trigger the Death of Virus-Infected Cells

    A newly published review by Lennice Castro and Matthew Daugherty from the University of California San Diego provides a detailed look at a mechanism of cell death that researchers are attempting to exploit in HIV cure research. The mechanism involves certain proteins that can innately sense the presence of components from pathogens (like viruses) inside a cell, triggering a cascade of signals that ends with the demise of the infected cell by pyroptosis.

    One such protein, CARD8, can sense the activity of the HIV protease enzyme. The normal task for HIV protease is to act as a scissor, cleaving apart viral proteins to assemble new virions (virus particles). As explained in the review, CARD8 contains mimics of the sites that HIV protease typically cuts, and if the CARD8 protein is cleaved by mistake it precipitates cell death.

    Under normal circumstances, however, HIV protease avoids this cellular booby trap by remaining inactive until the end of the viral replication cycle when newly-made viruses are in the process of exiting the cell (see the HIV life cycle diagram from HIV i-Base).

    In recent years, scientists — including researchers at the drug company Merck — have discovered that some antiretrovirals in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class have the capacity to prematurely activate HIV protease inside virus-infected cells, which leads to recognition by CARD8 and the initiation of the signaling cascade that ends with cell death by pyroptosis.

    Merck is now actively pursuing the development of novel NNRTIs that trigger this mechanism, based on the theory that it could lead to the progressive clearance of the reservoir of HIV-infected cells that persists in people on standard antiretroviral therapy (ART). The company describes these new candidates as Targeted Activator of Cell Kill (TACK) molecules, and earlier this year they published laboratory work identifying lead candidates in the journal Science Translational Medicine.

    The researchers tested a TACK molecule — codenamed Pyr01 — for activity against HIV-containing CD4 T cells sampled from people on ART and found that virus production (as measured by the HIV p24 protein) was decreased by 94-97%, with no effects on the viability of uninfected cells.

    In a separate paper published last year, Merck researchers also identified compounds called DPP9 inhibitors that activate CARD8 and synergize with NNRTIs that have TACK activity.

    The hope is that these candidates can be moved into clinical trials, but Merck has not yet publicly disclosed a timeline for when this may occur.

    Whether any licensed NNRTIs can achieve levels sufficient to mediate killing of HIV-infected cells is uncertain. In their paper describing TACK molecules, the Merck researchers write:

    “For currently approved NNRTIs, the selective HIV-1–infected cell death activity is much less potent than their RT [reverse transcriptase] inhibition activity, and this secondary effect is unlikely to be observed at a clinically achievable dose.”

    But one of the papers cited in support of this statement leaves open the possibility that efavirenz (EFV) and rilpivirine (RPV) could exert the activity at standard doses:

    “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.”

    There have been some anecdotal suggestions that non-suppressible low-level HIV viral load is a less common phenomenon in people receiving efavirenz, but this hasn’t been proven (and the drug has known downsides in terms of tolerability). As Dr. Francesco Simonetti kindly noted in a tweet, work is ongoing in collaboration with the laboratory of Liang Shan (who pioneered this area of research) to investigate whether any licensed NNRTIs may also be capable of causing the death of HIV-infected cells.

    The identification of methods to promote clearance of the HIV reservoir is obviously a priority for the HIV cure research field. Results so far with immune-based approaches have been mixed and generally underwhelming. The possibility of inducing the selective killing of HIV-infected cells with a known class of antiretroviral compounds is novel and encouraging, making this an area of investigation to watch. The mechanism would only be operational in cells when HIV is at least somewhat active and attempting to generate new virions, but recent evidence suggests that the HIV reservoir in people on ART is more active than was originally assumed. Ultimately, clinical trials will be needed to assess whether TACK molecules (or similar compounds) can significantly deplete the HIV reservoir in people on ART.

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

    Since the previous update on May 16, there have only been two changes identified for TAG’s HIV cure-related clinical research listing, making it one of the quietest periods since the initiation of the resource in 2014.

    A small clinical trial sponsored by the AIDS Malignancy Consortium investigating gene-modified stem cells for people with HIV and cancers who require stem cell transplants has closed for enrollment but remains in follow up (see the Gene Therapies for HIV+ People with Cancers section of the listing). The broad goal of work in this area is to find ways to create HIV-resistant immune systems for people who need stem cell transplants but do not have access to appropriate donors with the CCR5Δ32 mutation.

    As noted last month, a social science study assessing the perspectives of people screening for an HIV cure related trial — EHVA T02 — has now been terminated and shifted to the completed studies table. The research could not proceed further because the parental trial had to be closed due to slow enrollment and the experimental interventions reaching expiration dates that precluded administration. The researchers were able to present a limited analysis of the reasons why people who screened for the study chose not to enroll at the AIDS Impact conference in Stockholm earlier this week.

    For a more comprehensive overview of progress in HIV cure research over the past year — including coverage of developments at the Conference on Retroviruses and Opportunistic Infections (CROI) that we haven’t been able to get to on the blog — look out for the 2023 Research Toward a Cure and Immune-Based Therapies Pipeline Report, which will be published next month immediately ahead of IAS 2023, the 12th IAS Conference on HIV Science in Brisbane.

    TAG’s recently updated HIV Cure Research Information Sheet contains a briefer summary of the status of HIV cure research, including information on all the cases of HIV cures that have been publicly reported to date.

    As a point of information for anyone else who uses clinicaltrials.gov regularly, work is ongoing at the National Library of Medicine to switch to an improved version of the registry. The new version is available in beta form, and as the planned change gets closer new studies are appearing slightly quicker (by ~1 day) in the beta database, making it the best source if you want to be extremely rigorous about ensuring search results are current.

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

    The past month has seen relatively few updates for TAG’s HIV cure-related clinical research listing. One new observational study was entered into the clinicaltrials.gov registry, two trials have been completed or ended, an ongoing investigation of the anti-CMV drug letermovir has reopened for enrollment after a pre-planned pause, and a social science assessment of factors associated with declining to enroll in a cure-related trial is presenting results at the AIDS Impact conference next month.

    The new observational study is sponsored by Bayside Health in Australia and aims to assess the size of the HIV reservoir and HIV-specific immune responses in three cohorts:

    • People who initiated antiretroviral therapy (ART) with high CD4 T cell counts (>800 cells/μL).
    • People who achieved a CD4 count increase to >1000 cells/µL within 48 months of starting ART.
    • Age-matched HIV positive controls from the Alfred HIV clinic who have CD4 T cells counts between 500 and 800 cells/µL, or who do not reconstitute their CD4+ T cells to >1000 cells/µL within 48 months.

    The study is recruiting at The Alfred in Melbourne Australia, the primary contact is researcher and writer Jillian Lau, MBBS, who also shares HIV cure research information and news via an excellent twitter account.

    Two trials have ended and shifted to the completed table:

    • An investigation of canakinumab (an antibody that inhibits the cytokine IL-1β) has been completed by Priscilla Hsue, MD, at the University of California, San Francisco. The primary purpose was to assess effects on markers of inflammation and cardiovascular disease risk, but the protocol also cites evaluation of HIV reservoir size as an additional outcome measure. Results from an initial safety cohort of ten participants were published in the Journal of the American College of Cardiology in 2018. Results from an additional 33 participants are reported in the clinicaltrials.gov registry entry, but the format is difficult to interpret and hopefully additional publications or presentations will be forthcoming.
    • A small study of kansui, a substance used in traditional Chinese medicine that may have HIV latency-reversing activity, has been ended at the University of Utah. The rationale for the research derived from evidence that a particular component of kansui, ingenols, can reverse HIV latency in laboratory studies. The study enrolled five participants but the original plan to add several more was stymied by the COVID-19 pandemic and the ending of funding support. Lack of funding is also slowing plans to analyze collected samples, but the researchers hope to eventually present any findings.

    Back in January we noted that the AIDS Clinical Trials Group (ACTG) had temporarily paused recruitment for a trial of the anti-CMV drug letermovir in people with HIV. The pause was planned in the protocol to allow for a preliminary evaluation of the effects of the drug on inflammatory markers among the first 40 participants before deciding whether to continue enrollment. The trial registry record was updated on April 26 to indicate that it's recruiting again, with a target of 180 participants in total. The study is taking place in the United States with sites in Alabama, California, Colorado, Illinois, Massachusetts, Missouri, New York, Ohio, Pennsylvania, Tennessee, Texas, and Washington State. The main outcome measures are markers of inflammation, but analyses of effects on HIV persistence are also planned.  

    EHVA T02 was a muti-site HIV cure-related trial in Europe that intended to investigate the effects of therapeutic vaccination and the antibody vedolizumab (trade name Entyvio). Unfortunately, the study was unable to proceed due to slow enrollment and the expiry dates of the experimental interventions that were due to be administered. However, a related social science investigation into the perspectives of potential enrollees conducted by Sarah Lefebvre and colleagues was able to collect information from a small number of people who declined to participate. The results are being presented at the upcoming AIDS Impact conference in Stockholm next month (see abstract). The registry record for the social science study was updated late yesterday to note that it has now been terminated, so it will shift to the completed studies table when the next monthly update to TAG’s listing is posted in June.

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

    The April 2023 update to TAG’s HIV cure-related clinical research listing adds five new studies, two involving interventions and three observational.

    Researchers at the University of Sao Paulo General Hospital in Brazil are opening a study of a therapeutic HIV vaccine based on dendritic cells (DCs). DCs are immune system cells tasked with initiating the immune response against pathogens like HIV, and the researchers aim to exploit this aspect of their function to bolster anti-HIV immunity and potentially enhance control of viral load after an antiretroviral therapy (ART) interruption. DCs are sampled from participants, cultured in a laboratory to promote their immune-stimulating function, exposed to HIV protein fragments sampled from the intended recipients, and then infused in large numbers.

    The goal is to induce highly functional CD4 and CD8 T cell responses targeting HIV. The approach was tested as part of a combination regimen in a prior trial, with the researchers reporting encouraging preliminary results. The new trial will divide 30 participants into three arms: one will receive placebo (dummy infusion), one will receive dendritic cells (called alpha-type-1 polarizing dendritic cells or aDC1 for short), and the third will receive aDC1 and then undergo an analytical treatment interruption (ATI). Primary outcome measures will be safety and viral load and CD4 counts after ATI.

    A trial of dasatinib, a tyrosine kinase inhibitor drug approved for the treatment of certain forms of chronic myelogenous leukemia and acute lymphoblastic leukemia, is being initiated at Hospital Universitari Germans Trias i Pujol in Barcelona, Spain. The rationale is based on previously published evidence that dasatinib therapy for cancer in people with HIV is associated with a smaller HIV reservoir and a reduced ability to reactivate viable HIV from latently infected cells. Proposed mechanisms include enhancement of 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.

    The main aim of the trial is to investigate safety and effects on SAMHD1 in people with HIV on ART, with secondary outcome measures assessing any impacts on the HIV reservoir. Another clinical study of dasatinib in people with HIV was registered in September 2022 and is also taking place in Spain. The design is slightly different, involving recruitment of people with recent HIV infection who’ve not yet started ART. Participants will receive dasatinib or placebo for a total of 16 weeks, with the first four-week period occurring prior to initiating an ART regimen.

    Newly added observational studies are:

    • The EARTH study (part of the larger EPIICAL project), which has enrolled children treated with ART within 90 days of birth. The goal is to assess virus and immune system parameters to identify potential participants for cure-related interventional trials. The study is sponsored by the PENTA Foundation and is taking place in South Africa, Mali, and Mozambique. The listed start date is May 2018 and participants are no longer being recruited, suggesting that the registry record has been created somewhat belatedly.
    • MERCI (measuring the HIV-1 reservoir during cure interventions studies) is an observational study planned at Ghent University Hospital that will conduct detailed evaluations of the HIV reservoir using blood and tissue sampling (lymph node and colon biopsies) from 30 participants, before and after receipt of cure-related interventions in other (unspecified) trials.
    • Similarly, a study at Icahn School of Medicine at Mount Sinai Hospital in New York City is investigating the HIV reservoir and immune system parameters in the gastrointestinal-associated lymphoid tissue (GALT) of eight participants in cure-related interventional trials (again, the specific interventional trials from which the participants are being recruited are not named).

    Completed Studies

    Multiple entries in the listing were shifted into the “completed studies” table this month. These include a first-in-human trial of a gene therapy approach developed by American Gene Technologies that aims to protect HIV-specific CD4 T cells (the cells responsible for coordinating the immune response against HIV) from infection and disruption by the virus. Preliminary results were published in Frontiers in Medicine in November 2022. Study participants were offered the opportunity to move into a follow up protocol involving an ATI, which remains ongoing.

    IMPAACT P1107 was a study that sought to identify donor cells with the CCR5Δ32 mutation for people with HIV requiring stem cell transplants for life-threatening cancer diagnoses. The research project led to the widely publicized fourth case of a likely cure of HIV infection by this method, in a woman of mixed race in New York City. The case was described in detail in a paper published in the journal Cell last month. The paper notes that there was one other participant in P1107, a middle-aged man with HIV who died after a relapse of Hodgkin’s lymphoma within a year of receiving the stem cell transplant.

    One observational study — ANRS CO24 OncoVIHAC — was moved to the completed table in error because the registry record hasn’t been updated since January 2018. After reaching out by email to investigators, Dr. Olivier Lambotte kindly replied to let us know that the research is still ongoing. The error will be corrected when the listing is updated again next month.

    Two additional studies were moved to the completed table due to out-of-date registry records:

    Neither was ever listed as open for enrollment and study contacts haven’t responded to email inquiries, so it’s not known if the trials went ahead as planned. We’ll continue to attempt to find out more information and update the table entries if successful.

    Results

    Results have been published from a completed study of valproic acid and pyrimethamine as candidate latency-reversing agents. Pyrimethamine is an old, FDA-approved antiparasitic drug used for the treatment of toxoplasmosis that has been shown to inhibit a cellular mechanism involved in maintaining HIV latency (the BAF complex). In an article published in the open access journal Science Advances, the investigators report evidence of “a rapid, modest, and significant increase in [cell-associated unspliced] HIV-1 RNA in response to pyrimethamine exposure.” The finding suggests that the drug could have a role in reactivating latent HIV, although the authors note that there was no evidence of a reduction in the size of the HIV reservoir. Valproic acid did not show any significant effects.