For February 2025, there were eight updates to TAG’s listing.
New Additions
Four new protocols were added.
In Toronto, a trial is underway that aims to assess whether the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz may be able to promote the death of HIV-infected cells.
The rationale derives from evidence that certain NNRTI molecules can cause the HIV protease enzyme to be produced prematurely during the viral life cycle, which triggers an antiviral signaling cascade leading to the death of the infected cell. As described in detail in a prior blog post, Merck is pursuing the development of new NNRTIs optimized for this activity, which they call Targeted Activators of Cell Kill (TACK) compounds.
Merck researchers have stated that currently FDA-approved NNRTIs are unlikely to be able to mediate TACK activity, but not all scientists have reached the same conclusion – at least one published study has suggested that efavirenz (EFV) and rilpivirine (RPV) might be exceptions:
“In NNRTI-treated patients, NNRTI plasma concentrations are in the range of efficient NNRTI-induced PR [HIV protease] cytotoxicity reported here. For example, EFV remains above 3.2 μM (1 μg/mL) and RPV remains above 0.4 μM (400 ng/mL). However, lower penetration of NNRTIs occur in peripheral compartments such as lymphoid tissues, which are primary sites of the HIV-1 reservoir.”
The trial in Toronto, led by Dr. Mario Ostrowski, is recruiting people on antiretroviral therapy (ART) with a history of low-level detectable HIV viral load (between 20-400 copies/ml). Participants will add a daily dose of 600mg of efavirenz to their regular ART regimen for two months, with various measures of HIV persistence compared before and after the intervention. The hope is that efavirenz might have sufficient TACK activity to deplete the HIV-infected reservoir cells suspected of generating low-level viral load that can’t be suppressed by ART (sometimes referred to as “unsuppressible viremia,” see TAG/HIV i-Base webinar from 2023 for additional background).
Another new study involving an FDA-approved antiretroviral has been registered but isn’t yet recruiting participants. The researchers plan to add the capsid inhibitor lenacapavir to standard ART and evaluate whether the approach can promote greater reductions in the size of the HIV reservoir. A recently published paper has reported that lenacapavir may enhance natural antiviral mechanisms in HIV-infected cells by disrupting the capsid protein, which typically shields viral DNA from recognition by innate immune sensors.
The trial is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and scheduled to take place at the National Institutes of Health (NIH) Clinical Center. It’s currently unclear if the egregious, politically motivated disruptions to the conduct of science at NIH might affect these plans.
A research group led by Dr. Ricardo Diaz at the Federal University of São Paulo in Brazil has registered two HIV cure-related protocols over the past month. The first is a 70-person trial investigating a combination regimen that previously showed some promise in enhancing post-treatment control in a smaller study that first reported results at CROI in 2019, but to our knowledge hasn’t shared the full findings in a journal article yet. The components being added to standard ART include the CCR5 inhibitor maraviroc, the integrase inhibitor dolutegravir, a dendritic cell-based therapeutic vaccine, auranofin, and nicotinamide (a form of vitamin B3). The protocol includes an analytical treatment interruption (ATI).
The second trial may be a late registration of a study that already had results presented at the HIV Glasgow conference last November. The intervention is a product called Gammora added to ART. The checkered and dubious history of Gammora — sometimes named Codivir — was covered in a prior blog post. The results reported in Glasgow indicated very rapid declines in HIV DNA levels (see abstract P212), but the past actions of the manufacturer leave some uncertainty regarding the extent to which the data can be trusted (at least from TAG’s perspective).
Updates to Enrollment Status
Two studies in the listing updated their enrollment status:
- Now open for recruitment is ACACIA, a trial sponsored by the ACTG evaluating dual bNAbs and ART that includes an ATI. The aim is to enroll 135 people, making it the largest HIV-cure related study on the African continent so far (current sites include Botswana and South Africa). The US President’s heinous recent decision to dismantle USAID and stop PEPFAR funding could conceivably affect this type of research, because some potential participants may depend on the program for access to ART.
- The largest international HIV-cure related clinical is being undertaken by the pharmaceutical company AbbVie to assess whether receipt of budigalimab (a PD-1 inhibitor) with or without ABBV-382 (an anti-α₄β₇ integrin antibody) can promote control of viral load during an ATI. The protocol is now closed to new enrollment and in follow up.
New Links to Study Results
Links to were added to newly published information from two trials in the listing:
- Karine Dubé and colleagues published findings from the social science component of a small study investigating a combination of interventions at the University of California, San Francisco (UCSF). The researchers found that overall satisfaction with participation was high, with the altruistic desire to contribute to the scientific development of an HIV cure being a major motivation. Several issues of potential concern were identified, including misestimation of the likelihood of therapeutic benefit, mixed feelings about restarting ART after ATI with some difficulties maintaining adherence, and social harms related to worries about HIV transmission risk and intimacy with partners.
- A paper published in the Journal of Virology draws on data from a trial involving people who started ART very rapidly after HIV acquisition. The investigators describe evidence of preferential depletion of the intact HIV reservoir, and encouragingly note that: “Our findings suggest the existence of immune responses that act selectively to reduce HIV transcriptional completion and/or preferentially kill cells making completed or intact HIV RNA.”
Leave a Reply