Twice-Yearly HIV Injections Show High Efficacy in Phase 2 Trial

A significant step forward in HIV treatment has emerged from a Phase 2 study published in The Lancet Microbe, revealing a twice-yearly injectable regimen—combining lenacapavir, teropavimab, and zinlirvimab—demonstrated high rates of viral suppression and a favorable safety profile over 26 weeks. The findings, led by Dr. Joe Eron of the UNC Institute for Global Health and Infectious Diseases, suggest a potential future where individuals living with HIV could significantly reduce the frequency of treatment, moving away from daily oral medication.

Easing the Burden of Daily Treatment

For decades, managing HIV has largely relied on daily antiretroviral therapy (ART). While highly effective at suppressing the virus, this regimen presents challenges for some individuals, including adherence difficulties and potential side effects. The prospect of a twice-yearly injection offers a compelling alternative, potentially improving quality of life and simplifying treatment for those who struggle with daily pills. The study enrolled adults already on effective oral ART, switching them to the injectable combination, and comparing outcomes to those who continued their existing regimen.

The Phase 2 trial, conducted across 34 clinical sites in the U.S., Canada, Australia, and Puerto Rico, included the UNC Clinical Trials Unit in Chapel Hill. Participants were chosen because their virus was highly susceptible to the two broadly neutralizing antibodies (bNAbs) – teropavimab and zinlirvimab – included in the combination. This susceptibility is a key factor, as broadly neutralizing antibodies work by targeting parts of the virus that remain consistent even as the virus mutates, offering a broader defense than some traditional ART drugs.

Robust Viral Suppression and Tolerability

At the 26-week mark, an impressive 96% of participants receiving the twice-yearly injections maintained viral suppression – a result comparable to the 96% suppression rate observed in the group continuing daily oral ART. This indicates the injectable regimen is as effective as the standard of care in keeping the virus under control. Notably, only one participant in the injectable group experienced a temporary rebound in viral load, but was able to regain suppression without altering their treatment plan, highlighting the regimen’s overall resilience.

The combination was similarly well-tolerated. Researchers reported no drug-related serious adverse events, and no participants discontinued treatment due to safety concerns. The most common side effects were mild reactions at the injection site, which is typical for long-acting injectable medications. No infusion-related reactions were observed with the antibody components, teropavimab and zinlirvimab.

Patient Preference and Quality of Life

Beyond clinical efficacy, the study also assessed patient perspectives. A significant 84% of participants expressed a preference for the injectable regimen over their daily pills. This strong preference underscores the potential for improved treatment satisfaction and adherence with a less frequent dosing schedule. Participants also reported improvements in their overall quality of life, suggesting that reducing the daily burden of medication can have a positive impact on well-being.

Building on Previous Research

Dr. Eron emphasized the significance of this combination approach, noting that while lenacapavir has been studied for prevention and multidrug-resistant HIV, and broadly neutralizing antibodies have been explored in smaller trials, this is the first complete regimen suitable for maintenance therapy with twice-yearly dosing to reach Phase 2 evaluation. This builds on a growing body of research exploring long-acting HIV treatments, including monthly injectable options already available, and represents a further step towards simplifying HIV management.

What’s Next: Phase 3 Trials and Broader Access

The investigational combination, representing the longest-acting HIV treatment regimen tested to date, will continue to be evaluated in ongoing and future Phase 3 studies. These larger trials will be crucial for confirming the findings from the Phase 2 study and assessing the long-term safety and efficacy of the regimen. The Phase 2 trial was funded by Gilead Sciences and is registered at ClinicalTrials.gov (NCT05729568).

The ultimate goal is to provide a more convenient and effective treatment option for people living with HIV, potentially reducing the burden of daily medication and improving overall health outcomes. While further research is needed, this Phase 2 study offers a promising glimpse into the future of HIV treatment, where long-acting injectables could become a cornerstone of care. The UNC Institute for Global Health and Infectious Diseases, under Dr. Eron’s leadership, continues to play a pivotal role in advancing HIV research and improving the lives of those affected by the virus.

Study Details: The study published in The Lancet Microbe was authored by Onyema Ogbuagu and colleagues. The research team evaluated the efficacy and safety of lenacapavir, teropavimab, and zinlirvimab in a multicentre, open-label, randomised, active-controlled, phase 2 study. The DOI for the publication is 10.1016/j.lanmic.2025.101283.