The global effort to combat HIV has reached a significant milestone with the announcement of groundbreaking results from a pioneering clinical trial conducted in South Africa. This study, the first of its kind on the African continent, has explored the possibility of achieving long-term HIV remission. The virus is controlled in this state without requiring daily antiretroviral therapy (ART). The findings, presented at the prestigious CROI 2025 conference, have ignited a renewed sense of optimism in the scientific community and among individuals living with HIV, suggesting a potential future where the burden of daily medication could be lifted for many.

Imagine Life Without the Daily Reminder of HIV

For millions around the world, living with HIV means adhering to a strict daily regimen of antiretroviral medications. While ART has been incredibly successful in suppressing the virus and allowing people with HIV to live long and healthy lives, the need for lifelong treatment presents its own set of challenges. These can include adherence difficulties, potential long-term side effects, and the constant reminder of living with a chronic condition. It is this reality that makes the concept of HIV remission so profoundly appealing. 

Imagine a future where individuals could manage their HIV without the daily reliance on medication, offering the potential for an improved quality of life and a reduced psychological burden. “Imagine if someone could take medication for two or five years — and then stop ART completely. That’s the vision,”  Professor Thumbi Ndung’u said. 

The “FRESH” Study

The innovative approach tested in this South African trial, known as the “FRESH” study, centers around combination immunotherapy. This strategy aims to tackle the persistent challenge of HIV – its ability to hide in the body – by employing a two-pronged attack. The researchers combined two exceptionally potent broadly neutralizing antibodies (bNAbs), specifically VRC07-523LS and CAP256V2LS, alongside an immune system stimulant called vesatolimod (VES). Vesatolimod acts as a toll-like receptor 7 (TLR7) agonist, which essentially means it’s designed to activate and boost the body’s natural immune responses. The rationale behind this combination was to first “wake up” the dormant HIV lurking in its cellular reservoirs and then simultaneously empower the immune system to effectively target and control the reactivated virus, ideally without the ongoing need for ART.

Addressing a Critical Gap in HIV Research

A particularly significant aspect of the “FRESH” study is its focus on South African women. Women are disproportionately affected by the HIV epidemic in sub-Saharan Africa, yet they are often underrepresented in clinical trials aimed at finding a cure or remission strategies. In regions like KwaZulu-Natal, where this study took place, HIV prevalence rates among women aged 25 to 44 can reach alarmingly high levels, underscoring the urgent need for effective and accessible treatment options tailored to this population. Professor Kirsta Dong, a key collaborator in this research, has long been a vocal advocate for ensuring that research findings are relevant and applicable to women in sub-Saharan Africa, recognizing the unique challenges they face in the context of the HIV epidemic. 

How the Trial Worked

The “FRESH” study enrolled 20 women living with acute HIV-1 infection, all of whom had been successfully maintained on antiretroviral therapy (ART) for at least 12 months before participating. The trial involved an experimental treatment phase where participants received intravenous infusions of the two broadly neutralizing antibodies and oral doses of vesatolimod. Following this treatment period, the participants underwent what is known as an analytical treatment interruption (ATI). This is a carefully monitored process where individuals temporarily stop taking their ART under strict medical supervision. The purpose of the ATI was to observe whether the experimental treatment had enabled their bodies to control the virus on their own. It’s crucial to understand that ATI is not simply a “drug holiday”; it is a closely regulated phase of research designed to assess the effectiveness of novel interventions while ensuring the safety and well-being of the participants. Researchers meticulously monitored the participants’ viral loads and overall health during this interruption period.

A Significant Percentage Achieved ART-Free Virus Control

While described as mixed, the results of the “FRESH” study offer a significant glimmer of hope. A notable percentage of the women who participated demonstrated the remarkable ability to control the HIV without the need for ongoing ART. Specifically, the findings revealed that 30% of the participants, which equates to six out of the 20 women enrolled, were able to stay off HIV treatment for nearly a year without experiencing a viral rebound that necessitated restarting ART. Even more impressively, 20% of the participants, or four women, remained off treatment until the trial concluded at 55 weeks. Perhaps the most compelling outcome is the case of one individual who has continued to maintain control of the virus without any ART for an astounding 2.5 years even after the formal end of the trial. “We cannot say that this is a definitive cure, but it is a significant step toward understanding how we can achieve remission for people living with HIV,” Ndung’u explained.”

The Treatment Regimen Was Generally Well-Tolerated

Alongside the encouraging findings regarding virologic control, the study also demonstrated a generally favorable safety profile for the experimental treatment regimen. The researchers reported that the combination of broadly neutralizing antibodies and vesatolimod was well-tolerated by the participants, with no serious treatment-related adverse events observed. While some participants experienced mild and manageable side effects, such as infusion-related reactions that typically resolved within a couple of days, and one participant discontinued vesatolimod due to a mild case of cytokine release syndrome, the overall safety data suggest that this therapeutic approach is potentially viable for further investigation.

Why Did It Work for Some?

Despite the promising outcomes in a subset of participants, the reality is that the treatment approach did not yield the same results for everyone involved in the “FRESH” study. This highlights a crucial area of ongoing research: understanding the underlying mechanisms that contributed to the virologic control observed in some women. Professor Ndung’u and his team are now exploring why some participants responded more effectively to the combination therapy than others. Their investigations focus on identifying specific immune responses and other biological factors that might explain the sustained remission in these individuals. 

A Landmark Achievement for HIV Research in Africa

The “FRESH” study holds particular significance as it represents the first HIV cure trial ever conducted on African soil. This milestone is significant considering that sub-Saharan Africa remains the region most heavily affected by the HIV epidemic. Professor Ndung’u emphasized the importance of conducting such complex research in resource-limited settings, demonstrating that it is possible to undertake cutting-edge scientific investigations in communities where the need for effective HIV treatments and potential cures is most urgent. This achievement not only contributes valuable scientific knowledge to the global fight against HIV but also underscores the growing capacity for advanced medical research within Africa itself.

Refining Strategies for Broader Impact

The findings suggest that the combination of broadly neutralizing antibodies and immune stimulants holds promise as part of a multi-faceted strategy to achieve long-term virus control without daily ART. Professor Ndung’u and his team, and other researchers in the field, are now focused on building upon these findings to refine the treatment approach, explore different combinations of antibodies and immune modulators, and identify biomarkers that can predict which individuals are most likely to benefit from such therapies.

From Eradication to Remission: A More Accessible Goal

In the context of HIV research, it’s important to distinguish between two distinct goals: complete eradication of the virus from the body and functional remission. While complete eradication, often referred to as a “cure,” has been achieved in only a handful of individuals through complex and usually risky procedures like bone marrow transplants, functional remission offers a more attainable and potentially more widely applicable goal. Remission, in the context of HIV, refers to a state where an individual can control the virus at undetectable levels without the need for ongoing antiretroviral therapy. 

Teamwork Makes the Dream Work

The success of the “FRESH” study is a testament to the power of collaboration and the crucial role of community involvement in scientific research. Professor Ndung’u emphasized that this complex undertaking required strong partnerships between researchers, the local community, and various stakeholders. 

The researchers also faced significant challenges during the study, including political unrest, devastating floods, and the global COVID-19 pandemic, which temporarily disrupted clinical operations. Despite these obstacles, the dedicated research team persevered, demonstrating remarkable resilience and commitment to their mission. 

A New Era of HIV Treatment on the Horizon?

The research presented at the recent HIV/AIDS conference offers a renewed sense of hope in the ongoing quest for an HIV cure. The advancements in long-acting PrEP promise to revolutionize prevention efforts, but it is the progress in antibody research that holds the most tantalizing possibility of a future free from daily medication for people living with HIV. As Ole Schmeltz Søgaard aptly stated, “It’s not just one mechanism that’s maintaining control” against HIV after treatment is stopped. 

He believes that the immune system remains the most promising avenue for achieving a cure, emphasizing the focus on “enhancing immunity” as the most promising path forward for the time being. While there is still much work to be done to understand the mechanisms at play fully and to develop broadly effective and accessible antibody-based therapies, these new findings represent a significant step forward on the long and challenging road toward an HIV cure, offering a glimmer of light and renewed optimism for the millions of people living with the virus worldwide. “This is not just about curing HIV for one person,” Dong said. “It’s about making a global impact, helping people across the world, and ensuring that the next generation of scientists, particularly from Africa, will lead the way.”