The FRESH Study Tests New HIV Remission Strategy in South African Women

Thumbi Ndung'u, BVM, PhD, scientific director of the HIV Pathogenesis Programme and professor of HIV/TB Research at the University of KwaZulu-Natal presented results from the FRESH study at CROI 2025, a phase 2a trial exploring a combination regimen of two broadly neutralizing antibodies (bNAbs), VRC07-523LS and CAP256V2LS, alongside the TLR7 agonist vesatolimod (VES) for HIV remission in South African women. The study aimed to assess the safety and virologic control of the regimen during an analytical treatment interruption (ATI), testing potential HIV remission strategies.

The FRESH study enrolled 20 women with acute HIV-1 infection, all of whom had been on antiretroviral therapy (ART) for at least 12 months. The participants were given a regimen that included oral doses of vesatolimod and intravenous infusions of VRC07-523LS and CAP256V2LS. The study included an ATI beginning on day 35, where ART was interrupted until viral rebound or predefined restart criteria were met. The primary endpoint was the safety of the regimen, with secondary endpoints assessing viral rebound, time to ART restart, and pharmacokinetic parameters.

Safety and Virologic Control Findings

As of January 16, 2025, all participants had completed the study. The regimen was well tolerated with no serious treatment-related adverse events. However, one participant experienced grade 1 cytokine release syndrome, leading to discontinuation of vesatolimod. Eighteen participants had mild infusion-related reactions that resolved within two days.

Thumbi Ndung’u said, "Overall, the regimen was mostly very safe in the women. No serious side effects were observed."

Six participants maintained ART interruption through Week 48, with four continuing without ART for the full 55 weeks. Eight participants showed partial virologic control, with periods of undetectable viral load alternating with viral rebound.

Implications for HIV Remission Strategies

Thumbi Ndung’u emphasized that the study’s focus on women in South Africa is significant, as women are often underrepresented in clinical trials. "This is the first HIV cure trial in Africa, and it’s crucial to involve women because they are disproportionately affected by HIV," he noted.

While the study showed that the combination of bNAbs and vesatolimod was not fully efficacious in all participants, it demonstrated that a subset of women could achieve partial virologic control without ART. "Six of the women did not meet the criteria for restarting ART for up to 48 weeks. Four of them are still controlling the virus without ART," said Ndung’u.

The study’s findings point to the potential of bNAbs and vesatolimod as part of an HIV cure strategy. "Broadly neutralizing antibodies have shown promise in controlling HIV long-term, and vesatolimod, a TLR7 agonist, helps boost immune responses," explained Ndung’u.

Next Steps in HIV Cure Research

Following these results, Ndung’u and his team are continuing to investigate the mechanisms underlying the observed virologic control. "We are currently exploring why some women could control the virus without ART and are looking for immune mechanisms that might explain the remission," he added.

Further studies are underway to understand how this combination therapy could be refined to offer more patients a path to HIV remission.

Looking Forward: Clinical and Regional Impact

The FRESH study highlights the feasibility of conducting complex HIV cure research in resource-limited settings, a critical factor for countries most affected by the HIV epidemic. "We are demonstrating that it is possible to conduct HIV cure studies in settings with limited resources, which is vital for regions like sub-Saharan Africa," Ndung’u said.

Looking ahead, the results of this study could influence HIV treatment strategies, particularly in regions with high unmet need. "Our goal is to reduce reliance on daily ART, especially in regions where access to treatment can be a challenge," Ndung’u explained.

Reference:
Ndung'u T, et. al. FRESH Trial: Broadly Neutralizing Antibodies and Vesatolimod in HIV Remission in South African Women. Presented at: CROI 2025; March 9-12, 2025; San Francisco, California.