First HIV cure trial affirms tolerability of investigational combo in women with HIV

A phase IIa study affirms the tolerable safety of a combination regimen comprising three investigational compounds – two broadly neutralizing antibodies (bNAbs), VRC07-523LS and CAP256V2LS, and the TLR7 agonist vesatolimod – in women with HIV-1.

“The regimen was well tolerated. There were no serious adverse events (AEs). [Although] most participants (n=18/20) experienced infusion-related reactions, these were mostly mild,” said principal investigator Professor Thumbi Ndung’u from the Africa Health Research Institute, Mtubatuba, South Africa, at CROI 2025.

Two participants had grade ≥3 drug-related treatment-emergent AEs (TEAEs). One patient had grade 1 cytokine release syndrome deemed related to vesatolimod, which led to drug discontinuation.

Early ART

Twenty women from the FRESH* cohort who were virologically suppressed for ≥12 months received oral vesatolimod 6 mg Q2W beginning on day 0 (10 doses) and IV infusions of the single-dose bNAbs at a dose of 20 mg/kg each on day 7. Prior to enrolment, participants had been on antiretroviral therapy (ART) for a median 6.9 years. [CROI 2025, abstract 105]

Most women started ART a day after HIV detection, which, according to Ndung’u is “very early, meaning they had very minimal exposure to the virus”. Hence, all had a baseline peak viral load of <5,000 copies/mL, with nine having only ≥50 to <2,000 copies/mL.

Three ATI outcome patterns

Analytical treatment interruption (ATI) was started on day 35. Participants remained off ART until week 48 or until they met ART restart criteria**.

“ATI is done to see whether the virus rebounds and how long it takes for the virus to rebound,” Ndung’u explained. The mean bNAb concentrations remained above the presumed therapeutic doses before ATI, but the antibody levels fell below therapeutic levels when ATI was in progress.

“We saw three distinct ATI outcome patterns,” he said. The first pattern was seen in participants who restarted ART early or before 16 weeks when antibody levels were presumed to be above the therapeutic dose or when the antibody was in circulation (n=7). The second was seen among those who delayed restarting ART and only did so when the antibodies were waning (n=7).

The third pattern was observed among the six who restarted ART late, as they were on ATI for 44 weeks (four for 55 weeks). “Post-trial, the four controllers are still off ART now and have been so for a median 1.5 years,” said Ndung’u.

Two viral rebound patterns

The median time to viral rebound (≥50 copies/mL) post-ATI was 11 weeks. “We observed two patterns of viral rebound,” Ndung’u said. Twelve participants exhibited typical viral rebound dynamics once rebound occurred with exponential growth of viraemia.

The remaining eight exhibited atypical dynamics, including oscillation (ie, re-suppression after initial rebound) and nonexponential growth. The viral load went down to undetectable levels and either remained so following a brief period of viraemia, or there was a bit of oscillation before the viral load increased, necessitating treatment restart, he explained.

First HIV cure study in Africa

African women bear a disproportionate burden of the global HIV epidemic, yet they are rarely included in clinical trials. “Our study is unique because all participants were women; most [HIV] studies have been done in men … It is also the first HIV cure study in Africa, and all started treatment while in hyperacute HIV infection, mostly Fiebig stage 1 (n=17) … Those we identified as having acute HIV infection were put on ART immediately,” said Ndung’u.

“[This] trial suggests that complex cure studies can be successfully conducted in resource-limited settings with great unmet need via partnership with community and multisector collaborators,” he said.

Only four women achieved durable ART-free viral control with the regimen, but ongoing analyses may inform the development of future cure approaches, Ndung’u said. “Insights from an integrated sociobehavioural study within this cohort will also help design future studies.”