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.
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