TAG HIV Basic Science, Vaccines, and Cure Project Blog

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

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

New Additions

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

Updates to Enrollment Status

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

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

New Links to Study Results

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

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

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

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

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

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

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

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

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

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

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

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

New Additions

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

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

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

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

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

Updates to Enrollment Status

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

Completed Studies 

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

New Links to Study Results

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

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

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

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

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

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

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

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

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

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

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

New Additions

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

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

Updates to Enrollment Status

Two recently added trials have now opened for enrollment:

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

Completed Studies

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

New Links to Study Results

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

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

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

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

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

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

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

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

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

HIV Cure Research at AIDS 2024

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

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

Sunday July 21

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

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

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

Monday July 22

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

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

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

Tuesday July 23

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

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

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

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

Wednesday July 24

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

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

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

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

Thursday July 25

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

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

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

Friday July 26

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

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

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

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

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

There are 14 updates in the June 2024 revision to TAG’s listing.

New Additions

Three newly registered studies have been added: two interventional and one observational.  

The German company Hookipa Biotech is sponsoring a clinical trial assessing two therapeutic HIV vaccine candidates based on an arenavirus vector platform in people with HIV on antiretroviral therapy (ART). The majority of vaccine vectors are altered to prevent replication, but Hookipa’s arenaviruses can replicate, while also being modified and attenuated for safety. The two arenavirus vectors under investigation are derived from Pichindé virus (PICHV) and lymphocytic choriomeningitis virus (LCMV).

The Hookipa vaccines have induced immune responses associated with a significant lowering of simian immunodeficiency virus (SIV) viral load in macaque experiments, which were published in the journal npj Vaccines in November 2023. Shortly after publication, Hookipa announced that the US Food and Drug Administration (FDA) had given the green light to launch a clinical trial. The registry record currently only lists one site, Beth Israel Deaconness Medical Center in Boston, and enrollment has not yet begun. The research is part of a collaborative agreement with Gilead Sciences aiming to develop curative interventions for HIV and hepatitis B.

The other interventional trial is the second of a newly emerging type of study that’s recruiting people with HIV, but primarily focusing on generating information relevant to efforts to develop preventive HIV vaccine candidates that induce broadly neutralizing antibodies (bNAbs). The idea is to assess how natural pre-existing immune responses against HIV influence the B cell and antibody responses generated by the vaccines. We were initially uncertain whether to include these trials in TAG’s listing, but since there’s potential to produce data relevant to HIV cure research the compromise is to add an italicized note to the entries indicating that preventive vaccines are the main focus.

The study is sponsored by IAVI and will administer various HIV Env proteins containing a mix of components from different viral clades (referred to as mosaic immunogens). The researchers plan to test whether immunization can lead to the induction of neutralizing antibody responses in people on ART. The trial doesn’t feature an analytical treatment interruption (ATI). Sites are located in Uganda and Zambia, but recruitment isn’t underway as yet. The first example this type of trial, sponsored by the HIV Vaccine Trials Network (HVTN), was added to our listing in September 2023 and is currently ongoing at multiple sites in the US (this protocol does include an optional ATI).

The new observational study plans to recruit people on ART and draw blood samples that will be used to measure the activity of a candidate HIV latency-reversing agent. The research is taking place at the University Hospital in Montpellier, France. The candidate is codenamed D10 and designed to specifically target the HIV Tat protein to promote latency reversal, with the approach having been patented by listed study contact Bruno Beaumelle and colleague Laurent Chaloin. As with all three newly added studies, the registry entry indicates that recruitment is pending.

Updates to Enrollment Status

A clinical trial sponsored by the ACTG is now open for enrollment at multiple sites in Botswana, Malawi, and South Africa. The A5416 study, also named PAUSE, is investigating a combination of two long-acting bNAbs (3BNC117-LS-J and 10-1074-LS-J ) that have shown some ability to enhance control of HIV viral load after ATI in prior research. The HVTN and the HIV Prevention Trials Network (HPTN) are co-sponsors because, while the primary focus in this case is HIV cure research, there’s potential to generate information on bNAbs that will be relevant to the HIV prevention field. The start of recruitment was announced via press release on June 13, but the release isn’t available yet on the ACTG website and A5416 isn’t included among their listing of open trials – hopefully this updating lag will be addressed soon.

The ANRS in France is now recruiting participants for an investigation into factors that can contribute to the lack of generation of HIV-specific antibody responses in children started on ART very early. The study was originally registered and added to the TAG listing in March of this year.

Completed Studies

Five studies were shifted to the completed table this month. In three cases this was due to updates to the registry record:

• Case Western Reserve University’s trial evaluating a gene therapy originally developed by Sangamo (NCT03666871), which first opened in 2019. The therapy involves genetically modifying CD4 T cells to prevent expression of the CCR5 coreceptor. Results are pending, and further development of the approach is being pursued by the company RORA Biologics.
• A PENTA Foundation-sponsored investigation of early antiretroviral treatment in children with HIV named the EARTH study (NCT05784584). A paper describing clinical outcomes was published in the journal eClincalMedicine in May 2024 (see also accompanying press release).
• An investigation of a combined approach to stem cell transplantation for the treatment cancers in people with HIV. The study involved umbilical cord blood cells and an off-the-shelf product named dilanubicel containing expanded cord blood stem cells, and was taking place at the Fred Hutchinson Cancer Research Center. The registry entry notes that the study has been “terminated” due to the expiration of funding and lack of accrual. However, one person is listed has having enrolled suggesting some information could be reported from the research, hence it’s been retained in the completed studies table.

Two additional protocols have been listed as completed because the original estimated end dates have long since passed and no updates to the registry records have been made. Additionally, our attempts to contact the investigators have failed:

• IDOLTIB (NCT04034862), an assessment of any effects on the HIV reservoir of simplifying ART to a two-drug regimen (dolutegravir and lamivudine). The original estimated completion date was June 2023 and the registry record hasn’t been updated since May 2022; it’s now flagged as “unknown status.”
• A combination study of the anti-PD-L1 antibody ASC22 and the HDAC inhibitor chidamide (NCT05129189). The registry entry lists the study as still recruiting, but the estimated completion date was July 2023 and the record hasn’t been updated since September 2022. Furthermore, the estimated enrollment target was 15 and encouraging-looking results from 15 participants were reported at the IAS 2023 conference last year, strongly suggesting the trial has been completed. We continue to email investigators in an attempt to clarify the status and find out if there are now plans for larger studies.

New Links to Study Results

Links to results were added for six studies in the listing.

Researchers from the IciStem consortium have published a comprehensive analysis from an observational study of 30 individuals with HIV undergoing stem cell transplants (SCT) for the treatment of cancers. The work focuses on the evolution of markers of HIV persistence after receipt of SCT, reporting that clearance of virus-infected host CD4 T cells by transplanted donor cells is the major mechanism of reservoir reduction. The authors also suggest that a decline in levels of T cell responses targeting HIV may be a better marker of virus depletion than measuring HIV-specific antibody responses (which decay more slowly).

IMPAACT2015 enrolled 18 adolescents and young adults with perinatal HIV and evidence of neurocognitive impairment in order to measure levels of HIV RNA and DNA in the cerebrospinal fluid (CSF). Results are now available in the journal AIDS. Detection of HIV DNA was more common than cell-free HIV RNA (13/18 vs 2/18). Male sex at birth and lower CD4 count at enrollment were both associated with a higher likelihood of HIV DNA detection in CSF. The authors conclude in their abstract: “This evidence of persistent HIV-DNA in CSF suggests that the CNS should be considered in treatment and cure studies.”

Additional results from a completed therapeutic HIV vaccine trial conducted in Thailand have been presented in Cell Reports, following publication of the primary results in Nature Medicine in 2020. The vaccine constructs were developed by Janssen, based on adenovirus serotype 26 (Ad26) and modified vaccinia Ankara strain (MVA) vectors. Immunization didn’t substantially delay HIV rebound or lead to control of viral load after ATI, but the new paper reports that vaccination had a boosting effect on antibody-dependent cellular phagocytosis (ADCP) responses against the circulating HIV CRF01_AE subtype. The magnitude of this type of antibody response correlated with time to viral load rebound: higher levels were linked to a longer a delay.

The authors note, however, that the tested vaccines primarily induced immune responses to other HIV subtypes and hence greater benefit might be obtained with improved targeting of viruses predominant in the study population: “Our results suggest that vaccines eliciting cross-reactive responses with circulating viruses in a target population could be beneficial and that ADCP responses may play a role in viral control post treatment interruption.”

The first results from a study of a similar therapeutic vaccine regimen, with or without an additional HIV Env protein boost, are now published in the journal npj Vaccines. The study population was different in this case, involving 25 participants with longer term HIV infection recruited in Boston, Massachusetts. The regimens were safe and successfully induced HIV-specific immune responses, which appeared to be enhanced by the HIV Env protein boost. The protocol didn’t include an ATI, precluding any assessment of viral load suppression off ART. The researchers conclude that the immunogenicity results are sufficiently encouraging to support further studies.

INACTION P25 was a multi-site investigation of early ART in people with HIV in Italy led by Adriano Lazzarin, MD. Results were published last year in the Journal of Medical Virology, and now additional analyses are available in the International Journal of Antimicrobial Agents. The focus of the new paper is assessing antiretroviral drug concentrations in blood and tissues and evaluating factors linked to the speed of HIV DNA and RNA declines after treatment initiation. The findings indicate that earlier treatment (defined as Feibig stages I or II) promoted a more rapid drop in HIV DNA levels. During later follow up (48 weeks and beyond), an association between intracellular levels of tenofovir diphosphate (the active form of the drug) was also observed, although in discussing this finding the authors offer the caveat that it may not be directly related to antiretroviral activity.

Lastly, preliminary results from an ongoing gene therapy trial sponsored by American Gene Technologies (AGT) that were previously available as a preprint have now been published in a peer reviewed journal, Frontiers in Medicine. The preprint was covered on the blog in January of this year; the results show some evidence of viral load declines off ART but are difficult to parse, partly because multiple ATIs were undertaken. Diminutions in HIV viral load as a result of repeated ART interruptions – sometimes referred to as an “autoimmunization” effect – have been reported historically in the absence of any additional intervention. An AGT spinoff company named Addimmune is now trying to raise funds to support a larger trial of the approach.

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

There are ten updates in the May 2024 revision to TAG’s listing. No new HIV cure-related clinical trials or observational studies were identified in registries this month, and one protocol was withdrawn: a combination study codenamed RV582 sponsored by the US Military HIV Research Program (MHRP). No explanation for the withdrawal is provided in the registry entry except “protocol was changed during development.”

Updates to Enrollment Status 

A clinical trial investigating the approved anti-cancer drug venetoclax in people with HIV on antiretroviral therapy (ART) is now open for enrollment. The background to the research was covered on the blog in January of 2023 when the trial was first entered into clinicaltrials.gov; the aim is to evaluate whether venetoclax can promote the death of HIV-infected cells. At the moment the only listed study location is the University of Aarhus in Denmark, but as noted by Dr. Jillian Lau in a presentation at the recent Pre-CROI Community HIV Cure Research Workshop the plan is to add a site in Melbourne Australia.

Several studies in the listing have closed to new enrollment:

• The MHRP HVRRICANE trial in South Africa, which is investigating the effects of therapeutic HIV vaccines on the HIV reservoir in children and adolescents nine years and above. Preliminary safety results were presented at CROI earlier this year.
• A MacroGenics study of two dual-affinity re-targeting (DART) proteins (MGD020 and MGD014) designed to recognize and promote clearance of HIV-infected cells.
• The phase I first-in-human trial of EBT-101, a CRISPR/Cas9 gene editing tool intended to target and disable or remove HIV DNA from infected cells. This research has attracted considerable publicity, with very limited safety information on the first two participants presented last year. The original estimated enrollment target was nine participants, but the study has closed to new enrollment with six participants according to the registry entry. The principal investigator Rachel Presti is giving a presentation about the trial at the upcoming AIDS 2024 conference during a session on the use of gene therapy in HIV cure research on July 25th.

Additionally, an observational study at Mount Sinai in New York City has switched to enrolling by invitation; the research appears to be recruiting specifically from ongoing local interventional trials that are administering experimental broadly neutralizing antibodies (bNAbs). The goal is to assess effects specifically on gut-associated lymphoid tissue (GALT).

New Links to Study Results

Links to newly published results were added for five studies in the listing.

Researchers in China investigated the combination of chimeric antigen receptor (CAR) T cells (a gene therapy approach) and the candidate HIV latency-reversing agent chidamide (an HDAC inhibitor approved for the treatment of certain cancers in China). Their paper, published in the journal Cell Discovery, reports that administration of CAR T cells targeting HIV appeared to reduce the amount of HIV RNA generated by the repeated administration of chidamide. These results may be encouraging but it’s important to appreciate that this method of analyzing the activity of CAR T cells against HIV is novel and may have limitations – the amount of HIV RNA generated by receipt of HDAC inhibitors can be variable even in the absence of other interventions. In a separate analysis, measurements of the HIV reservoir using cell-associated HIV RNA showed evidence of a decline between baseline and the end of the study in a subset of ten participants (a little more than half the study cohort).

An analysis of neutralizing antibody responses targeting HIV after early ART has been published by Gregory Whitehill and colleagues in the Journal of Clinical Investigation. Participants were drawn from a study investigating rapid ART initiation after HIV acquisition at the University of California San Francisco (UCSF) led by Sulggi Lee. The researchers found that people who started ART very early (less than 60 days after HIV acquisition) didn't develop antibody responses capable of neutralizing HIV from their samples (called autologous neutralizing antibody responses). In contrast, most participants who initiated ART a little later – between 60 and 128 days after HIV acquisition – did develop autologous neutralizing antibody responses. In discussing their findings, the authors note that there appears to be a threshold of exposure to HIV viral load required to generate neutralizing antibodies and raise the possibility of using therapeutic vaccines to promote and accelerate the process.

A new publication in the journal AIDS from the ACTG’s large study of early ART initiation confirms that levels of the HIV reservoir (measured by a very sensitive test for HIV DNA) are reduced but not eliminated even in those starting earliest (at the Fiebig I stage). The authors note: “These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods.”

Finally a paper in the European Journal of Immunology reports on analyses of gut bacteria in people with HIV receiving the toll-like receptor 7 agonist vesatolimod in two clinical trials (NCT03060447 and NCT02858401). The investigators state that vesatolimod appeared to beneficially modulate the presence of different gut bacteria in samples from people who were naturally controlling HIV. Additionally, the presence of certain bacteria was associated with HIV viral load rebound in study participants who underwent an analytical ART interruption. Further research will be needed to validate and better understand these results.

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

The April 2024 update to TAG’s listing features eight changes.

New Additions

Three new studies were added this month. All are protocols being initiated by the U.S. government-funded ACTG Network (formerly known as the AIDS Clinical Trials Group, recently revised to Advancing Clinical Therapeutics Globally).

The Antiretrovirals Combined With Antibodies for HIV-1 Cure In Africa (ACACIA) trial will evaluate a combination of two long-acting broadly neutralizing antibodies (bNAbs), 3BNC117-LS and 10-1074-LS, with infusions given at the time antiretroviral therapy (ART) is initiated. After 24 weeks, eligible participants will have the option to undergo an analytical treatment interruption (ATI) to assess capacity to control HIV viral load in the absence of ART. The study aims to build on evidence that giving bNAbs when ART is first started can accelerate depletion of the HIV reservoir.

According to the listing, the study is pending and not yet open for enrollment. No location information is provided but the ACTG website indicates there are sites in Botswana, Malawi, and South Africa. The trial will enroll 135 participants, making it one of the largest cure-related protocols with an ATI (and the largest on the African continent), second only to an ongoing international study sponsored by the pharmaceutical company AbbVie which plans to recruit 140 people.

The ACTG has also launched a study of a “triple immune regimen” that consists of therapeutic vaccines, bNAbs, and vesatolimod (an immune-modulating toll-like receptor 7 agonist) in people who initiated ART within 28 days of being diagnosed with acute (recently acquired) HIV. The trial similarly involves an ATI to evaluate whether the interventions can enhance immune system control of HIV viral load. Enrollment is open and the intent is to recruit 45 participants at sites in the U.S. and Brazil.

The final addition is an ACTG observational protocol for any participants in these or other network (or related) trials who experience sustained (at least 24 weeks) low viral load levels after receiving a cure-related intervention and undergoing an ATI. The exact definition of low viral load will be based on the criteria used by the studies they were participating in, but the level cannot have risen to over 1,000 copies/ml for four or more consecutive weeks and CD4 T cell counts must be greater than 350.  

All three of these studies had been entered into the clinicaltrials.gov registry over the past few months, but a glitch with the search function of the recently overhauled website meant that we failed to identify them in searches of the database for “HIV” because the condition they’re listed under is “HIV-1-infection” and they fail to appear in results. The search function on the old “classic” version of clinicaltrials.gov doesn’t make the same error, which is something to be aware of for anyone who uses the registry to track HIV-related clinical research.

Updates to Enrollment Status

The RHIVIERA-02 study in France is now open for enrollment. The investigators are recruiting people with recently acquired HIV and testing whether giving the long-acting bNAbs 3BNC117-LS and 10-1074-LS at the time of ART initiation can lead to control of viral load during a subsequent ATI (after at least 52 weeks on treatment).

A clinical trial of baricitinib that was temporarily suspended is now open for enrollment at two sites in Atlanta. Baricitinib belongs to a class of drugs called Janus kinase inhibitors and is FDA-approved to treat severe rheumatoid arthritis and several other conditions. The HIV study is sponsored by William Tyor at Emory University, based on findings from laboratory experiments in humanized mice indicating that baricitinib has the potential to cross the blood-brain barrier and reduce viral persistence in the central nervous system. The trial will investigate if similar effects can be obtained in people with HIV, using blood samples, neurocognitive testing, magnetic resonance imaging (MRIs), and lumbar punctures.

Completed Studies

Occasionally research studies only get added to registries after completion, presumably due to an oversight. This is the case for AVIR, an observational study measuring the HIV reservoir in a large cohort of adolescents in Cameroon living with locally prevalent HIV clades. Results were published in the Journal of Virus Eradication on March 30, reporting that earlier ART initiation (within the first year of life) and longer duration of treatment (>9 years) were associated with smaller reservoirs as measured by HIV DNA. The researchers also identified modest correlations between levels of HIV DNA and HIV RNA, with higher viral loads linked to larger reservoirs.

New Links to Study Results

A link was added to another abstract from last month’s Conference on Retroviruses and Opportunistic Infections (CROI): Leah Carrere from the Ragon Institute presented a poster on a participant from the eCLEAR trial who has now maintained post-treatment control of HIV viral load for over five years after interrupting ART (the trial is completed and the primary results were published in Nature Medicine in 2022). Carrere also gave a brief talk during a poster discussion session at the meeting, which is now available for viewing via webcast (all the CROI materials were made publicly available on April 8th).

The study found evidence that cells containing intact, viable copies of HIV potentially capable of causing viral load rebound had been depleted by the individual’s immune responses, leaving behind a viral reservoir constricted in its ability to emerge and replicate. The constriction is a consequence of the HIV genetic code being integrated into areas of the cell’s DNA genome that are largely inactive, preventing the virus from hijacking the cell’s genetic machinery to make new copies of itself. A similar phenomenon has been reported in the two cases of HIV elite controllers who appear to have cleared all viable HIV from their bodies over time (Loreen Willenberg and the Esperanza Patient), and in some studies of people on long-term ART as well as in a small trial of panobinostat and alpha interferon (see also last month’s blog post and Tim Murphy's interview with Marie Armani-Tourret, Ph.D. for TheBody.com).

Results from a study of very early ART initiation being conducted at the University of California San Francisco that were presented at the IAS 2023 conference are now available as a preprint from medRxiv. Preprint means that the report has not yet been reviewed by scientific peers (a full publication in a peer-reviewed journal typically follows). The study documents a faster decline in levels of both intact and defective HIV after very early ART compared to studies of people who started treatment later.

Davey Smith and colleagues from the University of California San Diego have published their findings from a clinical trial that assessed the capacity of influenza and pneumococcal vaccines to essentially act as latency-reversing agents by stimulating the HIV reservoir to produce viral RNA. The analysis revealed that neither vaccine had significant effects on HIV RNA levels.

Lastly, 157 participants in the observational HEATHER (HIV Reservoir targeting with Early Antiretroviral Therapy) cohort study in the United Kingdom contributed samples to an analysis of the prevalence of resistance to the bNAb 10-1074, which is under investigation in multiple cure-related trials (the work was published in the journal Frontiers in Immunology).

The researchers found that HIV samples from around a third of the participants displayed genetic mutations associated with resistance to 10-1074, with evidence that the prevalence is increasing over time. Echoing previous reports, the study also documented that HIV from non-B clades (specifically CRF01-AE) displayed higher levels of resistance to 10-1074. The authors note that predicting resistance to bNAbs based on genetic analyses can be complex, and emphasize that improved tools are needed to screen potential recipients for baseline resistance to bNAbs.

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

The March 2024 revision to TAG’s listing includes 26 updates. The annual Conference on Retroviruses and Opportunistic Infections (CROI) took place in Denver from March 3-6, and the addition of links to results from HIV cure-related studies presented at the meeting typically makes this the busiest month for changes — hence the delay to this blog post.

New Additions

Three new studies were added this month.

Gilead Sciences is one of the few large pharmaceutical companies pursuing an HIV cure research program. As part of this effort, a phase I trial has been initiated of GS-8588, an immune-based therapeutic candidate described as a bispecific T cell engager.

The approach derives at least in part from research conducted with public funding at the National Cancer Institute by Dimiter Dimitrov and Weizao Chen. The scientists developed and patented a protein with two components (bispecific): mD1.22, an element from the human CD4 protein, and m36.4, from a human antibody, each specific for a different vulnerable target on HIV’s outer gp120 envelope protein. The Gilead construct includes a CD3 molecule to engage T cells to kill cells expressing the HIV gp120 protein; all the ingredients included in GS-8588 will be described in a presentation by Nathan D. Thomsen from Gilead at a conference in May of this year.

GS-8588 is an example of how research supported by public funding from the National Institutes of Health (NIH) can be licensed to a private company for potential profit. When the NIH requested public comment on their plan to license the fusion protein to Gilead, Jamie Love’s organization Knowledge Ecology International filed comments highlighting concerns about cost and the lack of any requirements for access and availability if the approach should prove successful:

“The NIH should include terms in the license that protect affordable, equitable access to patients in the US and around the world. Gilead has a track record of pricing its treatments - including HIV products - aggressively, and in the past, the high prices have been a barrier to the deployment of PrEP to prevent HIV infections.”

The response from NIH doesn’t disclose whether any such terms were included.

Gilead hasn’t entered the GS-8588 trial into the clinicaltrials.gov registry (at least so far), taking advantage of the lack of a requirement to register phase I trials. This has been a consistent problem with Gilead’s HIV cure research program, and it runs counter to their public commitments to community engagement in HIV research — it’s not possible for people to engage with a clinical trial if they’re not aware of it. Limited information is available online from individual study sites, such as the entry in the UPenn Medicine website. Gilead also states that GS-8588 is in a phase I trial on their website pipeline page, without providing any additional detail.

Casper Rokx and colleagues at the Erasmus Medical Center in the Netherlands are working to translate findings from laboratory analyses of candidate HIV latency-reversing agents into clinical interventions. Their newest trial (not yet recruiting) plans to investigate the activity of an approved antiepileptic drug, topiramate, in people with HIV on antiretroviral therapy (ART).

The rationale derives from laboratory studies showing that a particular cellular gene — glutamate ionotropic receptor kainate type subunit 5 (GRIK5 for short) — is involved in the maintenance of HIV latency. Topiramate is an inhibitor of GRIK5 and was found to reverse HIV latency in cell line models and in CD4 T cells isolated from people on ART, without inducing immune activation or causing significant toxicity.

The clinical trial will administer a single topiramate dose of 400mg to assess HIV latency-reversing activity, toxicity, and any differences in response related to sex assigned at birth.

The third addition is sponsored by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and involves participants in a cohort of children with HIV treated early with ART in the ANRS Pediacam III cohort in Cameroon. The goal of the study is to better understand the factors that contribute to maintenance of HIV-negative results on antibody tests in a subset of cohort members.

Updates to Enrollment Status

A clinical trial in Spain investigating the tyrosine kinase inhibitor dasatinib in people with HIV is now open for enrollment. The protocol aims to recruit people with recent HIV acquisition (past 3-12 months) and will administer dasatinib (70mg a day) alone for four weeks before ART is initiated. Dasatinib will then be continued as an adjunct to ART for another 12 weeks. Study endpoints include the safety and tolerability of dasatinib both alone and in combination with ART, effects on HIV viral load prior to ART, and measurements of the HIV reservoir.

The impetus for the study (and another recently opened trial in Spain recruiting people on ART for >3 years) comes from evidence that the use of dasatinib to treat cancers in people with HIV is linked to smaller reservoir size and a diminished capacity to reactivate viable HIV from latently infected cells.

A phase I trial in China of ICVAX, a therapeutic vaccine candidate, is now closed to new enrollment. ICVAX takes a novel approach by targeting the PD-1 pathway to try to improve immune responses against the HIV Gag proteins included in the vaccine construct. Preliminary information from the trial was presented at an IAS 2023 pre-conference by Zhiwei Chen (see blog post from August 2023).

Completed Studies

An interesting-looking trial that planned to investigate an off-the-shelf natural kill cell product called FT538 in people with HIV on ART has unfortunately been withdrawn (and deleted from TAG’s listing). The study record provides no information except stating: “Withdrawn, Abandoned.” Fate Therapeutics, the company that produced FT538, no longer lists it in their pipeline suggesting development has been discontinued.

New Links to Study Results

The majority of newly added links to study results derive from CROI 2024. Links are included to the conference abstracts, with PDFs of posters already available but webcast links for oral presentations due to be added to the respective abstract pages and made publicly accessible on April 8, 2024.

The multinational IMPAACT P1115 study is evaluating whether the extended period of remission from detectable HIV viral load that was documented in the Mississippi baby case may be reproducible in other infants with HIV treated very early after birth. At CROI 2024, Dr. Deborah Persaud presented the first study results after analytical treatment interruptions (ATIs), noting that six infants met pre-specified criteria for stopping ART, including absence of detectable HIV DNA. The average age at time of interruption was 5.5 years. Viral load returned quickly in two of the children. In another participant, there was a delay of 80 weeks before viral load rebounded necessitating the reintroduction of ART. The reappearance of viral load was associated with symptoms of acute HIV infection in two of these cases. Three study participants currently remain off ART without viral load rebound after 48, 52 and 64 weeks of ongoing follow up, respectively.

Persaud noted that the study demonstrates that extended remission from detectable viral load is possible in very early-treated infants, but better biomarkers are needed to identify the ideal candidates. A second version of the IMPAACT P1115 protocol is investigating whether the inclusion of an integrase inhibitor and a broadly neutralizing antibody (bNAb) in treatment regimens can improve outcomes. See Liz Highleyman’s report for Aidsmap for detailed coverage. A second IMPAACT P1115 abstract presented as a poster reported results from a detailed analysis of the HIV reservoir among infants in the study, showing that around half of the HIV DNA detected at birth represented intact virus genomes, with levels subsequently declining after ART initiation.

Marie Armani-Tourret from the Ragon Institute described results from a completed clinical trial of the HDAC inhibitor panobinostat combined with interferon-alpha2a in people on ART. The results were also published in the journal Cell shortly before CROI 2024. The researchers found evidence that the interventions altered the makeup of the HIV reservoir, with a trend toward a reduction in the proportion of intact HIV (viable virus that can cause viral load rebound) and an apparent depletion of cells containing virus integrated in places in the cell’s genetic code known to be susceptible to the latency-reversing activity of panobinostat. The authors conclude “these results provide proof-of-principle that the viral reservoir is vulnerable to ‘shock and kill’ interventions.”

Two oral presentations reported on different approaches to combining three bNAbs (see also Gus Cairns’s coverage for Aidsmap). Boris Juelg conducted a study of PGT121, PGDM1400, and VRC07-523LS given as monthly infusions, with ART interrupted after the first infusion. At CROI, Juelg reported that a majority of participants (10 of 12) maintained viral load suppression during bNAb dosing, and several (5 of 12) displayed extended post-treatment control after antibody levels waned. Participants weren’t pre-screened for evidence of baseline resistance to the bNAbs, and the two individuals with early viral load rebound were found to have HIV mutations associated with reduced susceptibility to PGT121 and PGDM1400. A poster from the same study identified inflammatory markers that appeared to increase prior to viral load rebound, suggesting they could have a role as predictors of loss of control of HIV replication.

Athe Tsibris debuted results from an ACTG study of SAR441236, a construct originally developed by Sanofi Pasteur that combines three bNAbs (VRC01, PGDM1400 and 10E8v4) into a single antibody construct. The antibody behaved similarly to other long-acting bNAbs in terms of the levels achieved in the body after administration, but the viral load effect in people not on ART was very weak for reasons that are unclear (0.38 log reduction at the highest dose, compared to declines averaging around 1.5 logs observed previously with single bNAbs). The candidate has been acquired from Sanofi Pasteur by a company called ModeX Therapeutics who issued a modest press release noting only that the safety and pharmacokinetics support further development of multispecific antibody approaches.

Several abstracts presented additional information from the BEAT-2 trial conducted by the BEAT-HIV Martin Delaney Collaboratory. Katherine Bar described evidence that both the bNAbs administered during the trial and the participants' own neutralizing antibody responses against HIV (called autologous neutralizing antibody responses) exerted activity against the virus that led to the selection of mutations associated with resistance. The bNAb infusions were also linked to improvements in the potency of participant autologous neutralizing antibody responses. In two participants who experienced the longest delay in viral load rebound after an ART interruption, autologous neutralizing antibody responses against HIV were already detectable when they first entered the study. The findings imply that autologous neutralizing antibody responses can contribute to post-treatment control of viral load.

A separate poster abstract from BEAT-2 reported an unexpected decrease in antibody-mediated cellular cytotoxicity (ADCC) associated with the interventions. Two additional posters provided information on the development of an experimental home viral load testing device evaluated as part of the protocol, and presented results suggesting that the approach may have utility for home monitoring of viral load rebound during ATIs. The device works by allowing the collection of capillary blood samples at home; the blood dries and is then sent for HIV viral load analysis via mail.

Tim Henrich from the University of California San Francisco (UCSF) gave an update from an ongoing imaging study assessing immune activation in people with HIV using positron emission tomography (PET) scanning. Henrich found that T cell activation was generally elevated in the participants with HIV compared to HIV-negative controls, including in people on ART. An exception was inguinal (groin) lymph nodes, where T cell activation was lower in people with HIV compared to the controls, possibly suggesting a decline in the capacity to activate T cells in these locations linked to the persistent presence of the virus. As an aside, Henrich noted that background levels of T cell activation detectable by this method have increased among all study participants in the post-COVID era, as evinced in a different study investigating long COVID (results are available as a preprint). A poster from Frank Maldarelli’s research group at the National Cancer Institute offered an update on the use of the same technique in a currently open study involving an ATI.

The pharmaceutical company AbbVie provided updates on their HIV cure research program in the form of an oral presentation on biomarkers associated with responses to their PD-1 inhibitor budigalimab and a poster describing the potential ability of a partner antibody targeting the α4β7 integrin (ABBV-382) to both directly inhibit HIV and enhance the presentation of viral antigens to T cells. Results from their phase I budigalimab program were previously covered on the blog. A large multinational phase II trial is now underway which plans to enroll 140 participants and explore the combination of budigalimab and ABBV-382.

Many other CROI 2024 posters featured results from studies in TAG’s listing.

The PENTA Foundation is sponsoring an ongoing trial in adolescents who acquired HIV perinatally, testing two therapeutic HIV vaccine candidates and the Cervarix human papilloma virus (HPV) vaccine (the latter given as an adjuvant because it contains a toll-like receptor 4 agonist). No efficacy data is available yet, but a poster presented information showing that the interventions have demonstrated safety.

Three posters reported analyses of participant samples from the large 2000HIV cohort study in the Netherlands. An investigation into genetic associations with natural control of HIV viral load found evidence to suggest that certain gene variants contribute to an increased capacity to restrict viral replication by modulating the function of natural killer (NK) cells. A separate study conducted the largest assessment of the intact HIV reservoir in different populations of people living with HIV (total = 863), finding that participants with various degrees of natural control of viral load have lower levels of intact HIV DNA compared to those with a more typical pattern of disease progression (designated “normal progressors”). People with suboptimal CD4 T cell recovery despite ART displayed significantly higher levels of intact HIV DNA compared to the normal progressors. Additionally, participants with HIV variants that use the CXCR4 co-receptor to enter cells had higher levels of intact HIV DNA than counterparts with viruses targeting the CCR5 co-receptor. In a novel companion study that also involves HIV-negative family members of participants with HIV, a particular profile of increased responsiveness among innate immune cells called monocytes (referred to as trained immunity) was associated with elite controller status.

Two abstracts covered analyses from a small trial of multiple interventions (therapeutic HIV vaccines, bNAbs and a TLR9 agonist) being led by Michael Peluso at UCSF. Results were presented as a poster at CROI last year indicating viral load rebound after ATI was reduced compared to the typical pattern, with 5 out of the 10 participants controlling viral load to <1,000 copies/ml (there’s no placebo control group in the study). One participant maintained undetectable viral load for 18 months of follow up, which is potentially encouraging albeit a challenging situation for the individual, Luis Canales, as he described in a recent article for Positively Aware. The posters presented at CROI 2024 reported an association between control of viral load and the ability of CD8 T cells to proliferate (copy themselves) in response to the rise in HIV levels after ATI, as well as assessing the impact of bNAb levels and concluding that they likely didn’t directly contribute to the apparent reductions in set point viral load but were linked to the timing of rebound (with higher bNAb levels linked to a longer delay).

Another study at UCSF led by Sulggi Lee is investigating the effects of rapid ART initiation after HIV acquisition on the viral reservoir. Initial results presented at IAS 2023 showed that participants who started ART earliest experienced the most rapid declines of both intact and defective HIV DNA. One poster at CROI 2024 outlined an association between higher levels of the cytokines IL-10 and type I interferons and more rapid declines in intact HIV. A second poster featured an analysis by Steven Yukl and colleagues which found that ART reduced both the proportion of cells in which the HIV life cycle was being completed, and levels of intact HIV RNA (which is transcribed from intact HIV DNA during the viral life cycle).

The SCOPE cohort at UCSF is recruiting participants for an ATI study that restarts ART as soon as viral load is confirmed to have increased to detectable levels (or after around three weeks if viral load remains undetectable). Two poster abstracts at CROI reported initial results from current participants. An analysis by Mauro Garcia and colleagues found an association between time to viral load rebound and the levels of HIV variants in the reservoir that were susceptible to autologous neutralizing antibodies: participants with higher levels of HIV in their reservoir that could be inhibited by their autologous neutralizing antibody responses experienced a longer time to rebound. The results echo those of Katie Bar and add to the evidence that neutralizing antibody responses can play an important role in post-treatment control of HIV. The second poster presentation from Natalia de la Force notes that an increase in levels inflammatory monocytes preceded the rise of viral load to detectable levels.

An ACTG trial of the anti-CMV drug letermovir was stopped early because changes in the levels of certain inflammatory markers didn’t meet criteria prespecified in the protocol as necessary for recruiting additional participants. In a late-breaker poster at CROI, Sara Gianella Weibel described an analysis involving 40 participants after eight weeks. Unexpectedly, there was an increase in one marker of inflammation, soluble tumor necrosis factor receptor 2 (sTNFR2), likely connected to a reduction in levels of an immune-suppressive protein generated by CMV. However, other markers associated with inflammation and cardiovascular disease risk declined, suggesting the approach may deserve further evaluation.

The last of the CROI abstracts so far identified as related to trials in the TAG listing came from the RIVER trial in the UK, which tested therapeutic vaccination in people starting ART early after HIV acquisition. In a subset of 10 participants whose samples were studied in detail, early ART initiation was linked to a shift in the composition of the HIV reservoir suggestive of immune-mediated clearance of cells containing HIV capable of making viral proteins either intermittently or persistently (thereby making the infected cell visible to the immune system). The evidence derived from an increase in the proportion of cells with HIV integrated into locations in the cellular genetic code known to restrict the capacity of the virus to emerge and make new proteins, keeping it hidden. However, these effects on the HIV reservoir were associated with markers of innate immunity and not with receipt of the therapeutic vaccine.

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

In the journal Open Forum Infectious Diseases, Cynthia Gay and colleagues reported complete findings from an ACTG trial of the PD-1 inhibitor cemiplimab which was stopped early due to two serious adverse events (already described at the 2020 Pre-CROI Community HIV Cure Research Workshop and in a paper in JAIDS). The new publication notes there was evidence of an increase in HIV-specific T cell responses in one of four recipients studied. Multiple other studies of PD-1 inhibitors in people with HIV (with or without cancer) remain ongoing.

An observational study in people on ART in Rakai, Uganda found evidence of a temporary increase in the size of the replication-competent HIV reservoir after switching to an integrase inhibitor-based ART regimen (primarily from previous NNRTI-based ART). The researchers note there might be possible confounding variables and that it will be important to assess whether a similar phenomenon occurs in other cohorts. The results were published in the open access journal EBioMedicine.

An ongoing observational study in France titled APRIL (Analysis of the Persistence, Reservoir and HIV Latency) presented an analysis of HIV target cells in people with late stage disease in the journal Pathogens & Immunity. The authors report that productively infected cells in people with AIDS were highly differentiated and exhausted — indicating they’d been exposed to multiple rounds of stimulation leading to dysfunction.

Lastly, the researchers conducting the Zurich Primary HIV Infection Study published a description of their cohort in the journal Microorganisms.

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

A total of nine changes were made to TAG’s listing for the February 2024 update.

New Additions

Two new clinical trials have been added, both not yet open for enrollment.

Researchers at the City of Hope Medical Center in Los Angeles are planning to initiate a trial of a novel approach to chimeric antigen receptor (CAR) T cell therapy in people with HIV. CAR T cells are a form of gene therapy based on modifying the receptors on the surface of T cells that facilitate recognition of a given target (e.g. part of HIV or other pathogens, or a cancerous cell). T cells are extracted from individuals, genetically modified in the laboratory to endow them with a particular type of receptor or receptors, then expanded and reinfused. Several CAR T cell therapies that target cancers are licensed for use.

The City of Hope study will focus on sampling T cells from study participants that specifically target cytomegalovirus (CMV), a very common virus that most people carry for life. These CMV-specific T cells will then be genetically modified to equip them with an additional receptor that recognizes part of the outer HIV envelope. The rationale is that the low levels of CMV present in a person’s body will help stimulate and maintain the modified CMV-specific CAR T cells, allowing them to persistently target HIV-infected cells via the secondary receptor.

One caveat is a recently emerging concern that, in some rare cases, CAR T cells approved for cancer therapy can become cancerous themselves as a result of the gene modification. An update from the Food and Drug Administration (FDA) was published yesterday in the New England Journal of Medicine. Far fewer people have received experimental CAR T cells targeting HIV (none are approved), and while the same concern may apply there are studies that have conducted extended follow up without any cases of T cell cancers observed to date.

TAG has contacted the FDA to ask about relevance to HIV and whether new studies like those proposed by City of Hope could be delayed as the problem is investigated - any response will be covered in next month's update. There are newer approaches to performing CAR T cell gene modification that don’t involve lentiviral vectors, which offer hope that a new generation of products can be developed that carry no risk of cancerous transformation.

The second new study is being led by Casper Rokx at the Erasmus Medical Center in the Netherlands, with support from Aidsfonds. The phase I/II trial will take place at multiple sites and aims to build on evidence from a prior study that the antiparasitic drug pyrimethamine has HIV latency-reversing activity.

A total of 49 participants will be recruited and given single doses of pyrimethamine, the HDAC inhibitor panobinostat and the immunomodulator lenalidomide either alone or in the following dual combinations: panobinostat + lenalidomide, panobinostat + pyrimethamine, or lenalidomide + pyrimethamine.

Investigators will assess levels of HIV RNA production by latently infected cells after dosing, and any change in the size of the HIV reservoir between the baseline visit and the end of study follow up (120 days later).

While not quite a new addition, an ongoing phase I trial of the therapeutic HIV vaccine candidate ICVAX is now entered into the clinicaltrial.gov registry, allowing us to update a previous link. For additional information on the vaccine and study, see the blog post on the August update to TAG’s listing.

Updates to Enrollment Status

One observational study closed for enrollment this month, also led by Casper Rokx in the Netherlands. CHRONO has created a cohort of people on antiretroviral therapy (ART) who are contributing samples for laboratory studies of the HIV reservoir and candidate therapeutic approaches.

Completed Studies

Two clinical trials in the listing have officially ended and been moved to the completed studies table.

An ACTG study conducted by Eileen Scully and colleagues specifically enrolled postmenopausal cisgender women with HIV to investigate the effects of the candidate HIV latency-reversing agent vorinostat administered with or without tamoxifen, a drug which modulates estrogen receptors on cells (including CD4+ T cells). Results were published in 2022, finding no enhancing effect of tamoxifen on HIV latency reversal but, importantly, establishing “both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV.”

A long-term follow up protocol for people with HIV who participated in studies of a gene therapy developed by Sangamo Biosciences has been stopped. The clinicaltrials.gov registry record explains that no safety signals have emerged over 7.5 - 13.5 years since administration. The Sangamo candidate involved extracting CD4 T cells from participants and genetically modifying them to abrogate expression of the CCR5 co-receptor that most HIV strains use as a route into target cells. The modified CD4 T cells were then expanded in the laboratory and reinfused. Sangamo has discontinued development, but a small biotech company named RORA Biologics is now pursuing a potentially improved version that targets a subset of CD4 T cells called T stem cell memory cells.

New Links to Study Results

Three of the studies in the listing have had links added to newly published results.

Karine Dubé and colleagues conducted in-depth interviews with participants in a small cure-related clinical trial at the University of California San Francisco (UCSF) that involves a complex combination of different components (therapeutic HIV vaccines, broadly neutralizing antibodies and a TLR9 agonist). The study also includes an extended analytical treatment interruption (ATI). The paper is available open access in the journal HIV Research & Clinical Practice.

The informative interviews with seven of the 10 participants capture a range of individual responses, but anxiety related to interrupting ART during the ATI was reported by six out of seven. Trust in the research team was high, with all participants already involved in the UCSF SCOPE cohort. Several issues related to communication to sexual partners about viral load rebound during the ATI were identified.

The participant who controlled viral load for the longest time off ART, around 18 months, expressed the feeling of being in a limbo state during that period and was uncomfortable with the degree of uncertainty about how the control was being mediated. Examples of extended post-ART control in cure-related research offer some encouragement to the field, but it’s also important to appreciate that the experiences of the individuals concerned may be more complex, particularly as post-treatment control has become viewed as a potentially more achievable outcome than complete clearance of HIV.

Jonathan Li led an investigation into predictors of viral load rebound among people interrupting ART in the ACTG A5345 study, which was published in JCI Insight on February 8th. The key findings were that predictors of the time to viral load rebound were different among participants who started ART early compared to during chronic HIV infection. Residual levels of viral load (measured by an ultrasensitive test) were the strongest predictor in the former group, whereas in the latter group it was levels of intact HIV DNA. The paper is open access.

Results from a trial combining the latency-reversing agent vorinostat with an adoptive immunotherapy in people on ART have been published in the Journal of Infectious Diseases by Cynthia Gay and colleagues. The immunotherapy is called HIV-1 Antigen-Expanded Specific T-Cell Therapy (HXTC): T cells targeting HIV are sampled from participants, expanded in the laboratory, and then reinfused.

The interventions proved safe and three participants who received the highest dose of transferred T cells showed some evidence of a decline in the size of their HIV reservoir as measured by the quantitative virus outgrowth assay (QVOA). However, the researchers emphasize that these declines were not greater than 6-fold, which is the magnitude of difference they’ve previously identified as necessary to rule out variability in the test as the cause. The results offer some tentative support for the idea of combining latency reversal with T cell therapies, but the authors note that “even if these trends were validated in a larger, controlled study, we would still conclude that achieving an HIV cure requires more effective latency reversal coupled with efficacious immune interventions.”

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

A total of eight changes were made to TAG’s listing for the first monthly update of 2024.

New Additions

One new study has been added from the Pan African Clinical Trials Registry: Scientists affiliated with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) are launching a phase I cure-related trial investigating a combination of two long-acting broadly neutralizing antibodies (bNAbs) in people with HIV.

One of the two bNAbs, CAP256V2LS, was discovered by CAPRISA researchers in samples from a person living with locally prevalent clade C variants of HIV. The other, VRC07-523LS, is an enhanced version of the bNAb VRC01, which was isolated in 2008 from an untreated slow progressor living with clade B HIV infection by scientists at the National Institutes of Health in the United States. Both bNAbs are already being investigated as potential preventive options in HIV-negative women South Africa and have been found to be safe.

The new study, designated CAPRISA 095 or NeutArt, isn’t yet open for enrollment but plans to recruit 30 participants and assess whether the bNAb combination can enhance the immune system’s ability to control HIV viral load after an analytical treatment interruption (ATI). A number of similar studies are ongoing around the world with other dual bNAb combinations (see bNAb section of table 1 in the listing).

Updates to Enrollment Status

A clinical trial sponsored by the HIV Vaccine Trials Network (HVTN) that was added to the listing in September 2023 is now open for enrollment. The protocol is unusual because the primary focus is on generating information that may help with the design of preventive HIV vaccines that aim to induce bNAb responses. However, the results may also have the potential to inform the design of curative strategies, particularly therapeutic vaccines, and hence we’ve included it in our listing with an explanatory notation. Participants will receive a vaccine and then be asked to undergo an optional ATI to assess how rebounding viral load influences and modifies vaccine-induced immune responses.

Completed Studies

Three studies in the listing were completed over the past month:

A therapeutic vaccine study in Spain, BCN03, which assessed the effects of a combination of three vaccine constructs on control of viral load after an ATI. Two of the vaccines aim to induce T cell responses against HIV, while the third is designed to induce antibodies against the virus’s outer envelope. To our knowledge, results haven't been publicly presented yet. The work is building on two prior therapeutic vaccine studies conducted by the same team, BCN01 and BCN02.

An ACTG study of the anti-CMV drug letermovir (Prevymis) is now listed as completed after enrolling 44 participants. The study protocol included an option to recruit more participants based on an interim analysis, so it seems possible that certain targets involving measures of anti-inflammatory activity weren’t met. However, even if that’s the case, the results may still be relevant and of interest. More information is likely to be presented soon.

Another ACTG clinical trial investigating the trispecific bNAb SAR441236 (developed by Sanofi) has been stopped early. Trispecific means that the bNAb is engineered to target three different parts of the HIV envelope, essentially combining three distinct bNAbs into a single antibody molecule. Based on the updates to the clinicaltrials.gov entry, it appears that it was difficult for the researchers to recruit participants for Arm B of the study protocol, which planned to enroll people with HIV who hadn’t yet started antiretroviral therapy (ART) despite detectable viral loads. The problems encountered may highlight both ethical and practical concerns related to asking people to delay ART initiation in the era of immediate treatment and undetectable=untransmittable (U=U). As a consequence of the delays, the available SAR441236 study product passed its expiration date and hence the trial was ended.

Preliminary results are posted on clinicaltrials.gov, but the formatting used by the website makes them difficult to interpret. It appears that a total of 52 participants were enrolled, with 42 completing the study as planned. No serious adverse events considered related to SAR441236 were documented, but one participant was diagnosed with melanoma during the trial. Seven participants who weren’t on ART with baseline viral loads greater or equal to 5,000 copies/ml received doses of either 1 mg/kg or 30 mg/kg of SAR441236, but the resultant viral load declines measured a week later were minor (0.10 or 0.38 logs, respectively) and not sustained. Results will almost certainly be presented or published in the near future, possibly at the upcoming Conference on Retroviruses and Opportunistic Infections (CROI) in early March.

New Links to Study Results

Links to results were added for three entries in the listing:

The biotechnology company American Gene Technologies (AGT) is working on a candidate cure strategy that genetically modifies CD4 T cells capable of targeting HIV (HIV-specific CD4 T cells) to make them resistant to infection. The rationale for the approach is that HIV-specific CD4 T cells should be responsible for coordinating an effective immune response against the virus, but instead become preferential targets for infection and dysregulation.

AGT’s therapeutic candidate is named AGT103-T and involves sampling HIV-specific CD4 T cells from study participants, introducing genetic modifications to block HIV infection, expanding their number in the laboratory, and then reinfusing them. After an initial published report that indicated the infusions appeared safe with evidence of persistence of the modified cells, participants were given the option of undergoing an ATI to assess the immune system’s ability to control viral load in the absence of ART.

Preliminary results from this ATI portion of the research were published on the preprint server medRxiv in October of last year, but were only recently brought to our attention courtesy of Jeff Galvin from AGT. A preprint means that the paper has not yet been subjected to peer review.

The results offer some evidence of diminished viral load rebound, particularly after a second ATI, although the limited number of participants and open label study design make it difficult to evaluate the contribution of the gene-modified HIV-specific CD4 T cells. The authors also emphasize the expansion of CD8 T cells that occurred after ATI, which is atypical and may suggest that the modified HIV-specific CD4 T cells were able to better support proliferation of HIV-specific CD8 T cells in response to viral load rebound.

One potentially troubling issue mentioned in the paper is that some participants undertook ATIs on their own, which might suggest unrealistic expectations about the efficacy of AGT103-T. American Gene Technologies has made some misguidedly bullish statements about the prospects for their candidate in the past, and this may offer a regrettable cautionary tale about how such claims can affect adherence to a study protocol and the wellbeing of study participants.

American Gene Technologies has now spun off a company called Addimmune to pursue continued development of AGT103-T. According to a recent news report, the next step is a larger trial that will evaluate stopping ART at different timepoints after infusion of the gene-modified CD4 T cells.

A newly published paper by Tim Schacker and colleagues from the University of Minnesota has reported results from two clinical trials that investigated infusion of natural killer (NK) cells as an adoptive immunotherapy strategy. The researchers took inspiration from cancer research and used natural killer cells sampled from donors (typically family members) that were only partially genetically matched to the recipients, referred to as haploidentical NK cells.

The initial protocol combined the NK cell infusions with the cytokine IL-2 in an attempt to promote persistence and expansion of the cells, but was subsequently modified to administer N-803, which enhances production of the cytokine IL-15 (and avoids a potential issue involving IL- 2 stimulating regulatory or immunosuppressive responses). Two participants received NK cells plus IL-2, and four received NK cells plus N-803.

The interventions were generally safe with no serious adverse clinical events. Two serious (grade 3) toxicities were documented by laboratory measures: a low estimated glomerular filtration rate (eGFR) in one participant receiving IL-2 and a transient low absolute lymphocyte count in a recipient of N-803 that returned to normal around nine days after administration.

The researchers found evidence of persistence of infused NK cells in blood for around 6-8 days, and in tissues for as long as 28 days. In terms of efficacy against HIV, the proportion of cells producing HIV RNA declined in lymph node and gastrointestinal tissues, but because of the small number of participants the researchers weren’t able to formally confirm this with statistical analyses.

In discussing their findings, the authors write:

“These data suggest that providing functional NK cells could be a potential part of a successful strategy to cure HIV. Although it is not practical to consider infusions of haploidentical NK cells on a scale that would benefit the millions of PLHIV worldwide, this approach does provide the proof of principle for the potential role of these cells in controlling HIV. Several companies are currently studying the effect of NK cells with specific anti-tumor properties in both hematologic and solid organ malignancies. These cells are commercially manufactured and provided in simple dose packs that are kept frozen until infusion with no special equipment or processing needed, which allows this approach to be scalable.”

Investigators at the University of Minnesota are planning to soon launch a clinical trial of an off-the-shelf NK cell product called FT538 in people with HIV.