No new HIV cure-related trials or studies were added to the clinicaltrials.gov registry over the past month. A total of eight updates have been made to TAG’s listing:
A phase II study sponsored by AbbVie that was added to the listing in September (see prior blog update) is now open for enrollment. The company initiated an exploratory HIV cure research program several years ago focused on budigalimab, an anti-PD-1 antibody, and ABBV-382, an anti-α4β7 integrin antibody similar to the commercially available vedolizumab (an approved treatment for ulcerative colitis and Crohn's disease). The phase II trial plans to enroll 140 participants and administer both antibodies, either alone or in combination. The study design includes an analytical treatment interruption (ATI) to assess the effect of the interventions on time to viral load rebound above 1,000 copies/ml.
The past month also saw the first public presentation of results from AbbVie’s phase I trials of budigalimab in people with HIV. The researcher Jean-Pierre Routy described the findings at the 19th European AIDS Conference (EACS 2023) in Warsaw and the abstract is publicly available, but access to the presentation is limited to conference registrants. The abstract indicates that budigalimab was well tolerated although three participants experienced non-serious (lower than grade 3) immune-related adverse events that reportedly resolved (two cases of thyroiditis and a skin reaction). In a study that involved an ATI, there was evidence of atypically low viral load rebounds in several participants and two cases of prolonged post-treatment viral load control to below 200 copies/ml for around 1.5 years. A detailed review of the results by Liz Highleyman was published by AIDSMap. While it’s far too early to make any definitive evaluations, there’s a hint that PD-1 inhibition may have enhanced the immune response against HIV in some study participants, as it has been shown to do against certain cancers.
A key question about the use of PD-1 inhibitors in people with HIV who don’t have cancer is safety. Several PD-1 inhibitors are licensed for the treatment of cancers, but have the potential for causing autoimmune side effects in which T cells attack healthy tissues instead of only cancerous cells. A prior ACTG study of a PD-1 inhibitor in people with HIV on antiretroviral therapy (ART) was stopped early because of two cases of potential immune-related adverse events: thyroiditis, which is a known side effect of PD-1 inhibitors, and liver toxicity which was not definitively linked to the antibody. Another ACTG study of a related anti-PD-L1 antibody in people with HIV on ART documented a delayed case of hypophysitis that required treatment but eventually resolved. The management of immune-related adverse events caused by PD-1 inhibitors has improved but it will be important to carefully assess safety in the larger number of people being enrolled in AbbVie’s phase II trial. TAG is planning a community webinar about the AbbVie program to be held on December 5th at 12pm ET, additional information and a registration link will be posted to the TAG website next week.
An ongoing study of a therapeutic HIV vaccine candidate at the University of Pittsburgh is now fully enrolled and no longer recruiting participants. The research is led by Dr. Sharon Riddler and is investigating different methods of using an individual’s dendritic cells to try to stimulate improved immune responses against HIV in people on antiretroviral therapy (ART).
A study sponsored by Gilead Sciences investigating potential drug interactions with their TLR-7 agonist candidate vesatolimod has been stopped early, with a notation in the clinicaltrials.gov registry record stating the decision was due to a change in development plans and wasn’t related to concerns about safety or efficacy. Another Gilead-sponsored combination study including vesatolimod remains ongoing in the FRESH cohort in South Africa.
Preliminary safety results from the first trial of CRISPR/Cas9 gene editing technology in people with HIV were presented by Dr. Rachel Presti at the European Society for Gene & Cell Therapy annual congress on October 25, 2023 in Brussels. The approach is being developed by the biotech company Excision Biotherapeutics, who issued a press release describing the presentation. The conference abstract doesn’t appear to be publicly available online but video on demand is listed as forthcoming on the congress website.
In the trial, a CRISPR/Cas9 gene editing tool designed to target and remove (or disable) HIV in persistently infected cells is delivered into the body by an adeno-associated virus serotype 9 (AAV9) vector. The presentation indicated that so far the approach has appeared safe in the first three study participants who received the initial lowest dose, allowing the trial to proceed to administering higher doses. No information about anti-HIV effects was disclosed, with the company noting that additional results should become available next year. At the moment the small trial is only open to people assigned male at birth because of an unspecified Food and Drug Administration (FDA) concern about potential reproductive toxicity.
The lack of data relating to efficacy unfortunately didn’t stop the notoriously unreliable UK news outlet the Daily Mail (often colloquially referred to as the Daily Fail) from publishing a story with a grossly inaccurate headline stating that a cure for HIV “could be months away.” Thankfully the trustworthy community news website AIDSMap published a careful and accurate take on the news, and TAG has covered the media reaction to this and past stories about the use of CRISPR in HIV on our HIV Cure Research Media Monitor webpage.
There was encouraging news today about the approval of a CRISPR-based therapy for sickle cell anemia and thalassemia in the UK, underscoring why there’s excitement about the technology. But it’s important to note that this approach performs gene editing in the laboratory on stem cells that are isolated from individuals and then reinfused. In contrast, the Excision Biotherapeutics candidate is delivered into the body by the AAV9 vector in an attempt to deplete HIV from the relatively small number of virus-infected cells that persist in the blood and various tissues of people on ART. Achieving success via delivery into the body (in vivo) is likely to be more challenging than performing gene editing of cells in a laboratory (ex vivo).
Additional links to results added to the listing this month include an open access paper describing a social science study conducted as part of the BEAT-2 clinical trial in Philadelphia. The trial tested the ability of a combination of two broadly neutralizing antibodies (bNAbs) and the cytokine alpha interferon to promote suppression of HIV viral load during an ATI. The social science element was led by Andrea Bilger and focused on participant experiences, particularly as related to stopping ART during the ATI. Feedback was generally positive but the researchers, who worked together with the BEAT Collaboratory Community Advisory Board, highlight some concerns about the mental health aspects of ATIs and provide a table listing considerations for future HIV cure-directed clinical research (see table 5 of the paper).
Lastly, the AIDS Malignancy Consortium 095 Study investigating the use of the approved PD-1 inhibitor nivolumab to treat advanced cancers in people with HIV has reported that safety was similar to results obtained in HIV-negative cohorts, with evidence of meaningful efficacy against Kaposi’s sarcoma (a partial response lasting an average of just over a year in six of 15 participants). The results were published in the journal Cancer on November 14th. The study is included in TAG's listing because while it's only enrolling people with cancers, the investigators are also assessing the effects of nivolumab (with or without ipilimumab) on the HIV reservoir.
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