Breakthrough Trials Suggest Path to Functional Cure for HIV

Around the world, approximately 40 million people are living with HIV. While advancements in treatment have transformed the virus from a death sentence into a manageable condition, a complete cure has remained elusive. Recent breakthroughs in clinical trials indicate that a functional cure—a method to control HIV in the long term without continuous treatment—may finally be within reach.

In 2025, two independent trials demonstrated promising results using engineered antibodies. Participants in these studies showed sustained health without the need for antiretroviral drugs long after the interventions had concluded.

Key Findings from Landmark Trials

The first trial, known as the FRESH trial, was led by Thumbi Ndung’u, a virologist at the University of KwaZulu-Natal and the Africa Health Research Institute in South Africa. Here, four out of 20 participants maintained undetectable levels of HIV for a median of 1.5 years without taking antiretrovirals. The second trial, the RIO trial, took place in the United Kingdom and Denmark under the leadership of Sarah Fidler, a clinical doctor and HIV research expert at Imperial College London. In this trial, six out of 34 participants achieved viral control for at least two years.

Both trials serve as proof of concept that the immune system can effectively combat HIV. Researchers are now preparing to conduct larger trials to explore whether these antibodies can be optimized for broader application.

Fidler remarked, “I do think that this kind of treatment has the opportunity to really shift the dial, because they are long-acting drugs”—with effects that persist even after the drugs have been metabolized.

Challenges in HIV Treatment and the Search for a Cure

While individuals with HIV can lead long, healthy lives on antiretrovirals, their life expectancy is typically shorter than that of individuals without the virus. Daily medication or bi-monthly injections pose financial, logistical, and social obstacles, including stigma.

The quest for a functional cure has been complicated by the virus’s ability to evolve rapidly. HIV can hide in cells in an inactive state, evading the immune system. This clever evasion has thwarted numerous attempts to find a complete cure. Historically, only a handful of stem-cell transplants have led to successful long-term remissions.

A functional cure represents a significant advancement. Some people with long-term HIV eventually produce broadly neutralizing antibodies, which can target critical parts of HIV proteins. These antibodies recognize a wide range of viral strains and are now the focus of research aimed at engineering a sustainable treatment.

Both the FRESH and RIO trials utilized combinations of antibodies believed to be effective against prevalent HIV strains. The FRESH trial enrolled young women from a high-prevalence community, while the RIO trial primarily included older white men, illustrating the different demographics of HIV infection.

Participants received modified antibodies that were designed to remain active in the body for about six months. Following the infusion, their antiviral medications were paused to see if the antibodies would stimulate an immune response sufficient to control the virus.

Excitingly, results from both trials indicated that the antibodies prompted an ongoing immune response in some participants. In the RIO trial, 22 out of 34 participants did not experience a rise in viral levels after 20 weeks and received another antibody shot. Beyond 96 weeks, six participants maintained low viral levels, allowing them to remain off antiretroviral therapy.

The FRESH trial yielded similar results, with six of 20 participants achieving viral suppression for 48 weeks post-infusion. One participant remained off medication more than two years later, while others resumed treatment for personal reasons.

Researchers have refrained from declaring participants as functionally cured but acknowledge that the antibodies appear to stimulate the immune system’s ability to combat the virus, potentially creating an “immune memory” akin to the rare group of individuals known as elite controllers, who manage HIV without medication.

Continued research aims to determine whether these methods can be applied to a higher percentage of individuals diagnosed with HIV. The RIO trial’s findings suggest that antibodies also influence dormant HIV reservoirs within some cells, which is crucial since these reservoirs are responsible for viral rebound when treatment ceases.

The FRESH trial incorporated a drug called vesatolimod, designed to stimulate immune responses and prompt dormant HIV to become active, allowing the immune system to target those cells.

As researchers analyze the results, Ndung’u plans to secure funding for a larger trial in South Africa, focusing on chronically infected individuals. Meanwhile, Fidler’s team seeks to expand the RIO trial to explore whether longer pauses in antiretroviral treatment enhance immune responses to the antibodies.

The ultimate goal is to combine various strategies to strengthen the immune system’s response to HIV. For the first time since their diagnoses, participants from these trials are living without the daily constraints of antiretroviral treatment, marking a significant milestone in HIV research.