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

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

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

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

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

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

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

Three other studies have had links added to published results:

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