A novel combination of the long-acting injectable medication lenacapavir with two broadly neutralizing antibodies has shown promising results as a potential twice-yearly HIV treatment regimen, according to research presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) in San Francisco.
The phase II clinical trial evaluated the efficacy of lenacapavir (Sunlenca) combined with two broadly neutralizing antibodies (bnAbs) – teropavimab and zinlirvimab – in people with suppressed HIV viral loads. This combination, dubbed "LTZ," could represent a significant advancement in HIV treatment by eliminating the need for daily oral medications.
"We believe that the high efficacy of viral suppression and the safety data support continuing our study and support the clinical development of what we think is an exciting six-monthly HIV regimen," said Dr. Onyema Ogbuagu of Yale University, who presented the findings.
The Challenge of Long-Acting HIV Treatment
Lenacapavir, the only approved HIV capsid inhibitor, is currently administered by injection every six months but lacks equally durable partner medications to create a complete twice-yearly regimen. This means patients must still take daily oral antiretrovirals alongside the injection.
Broadly neutralizing antibodies offer a potential solution to this challenge. Unlike typical HIV antibodies that target variable parts of the virus, bnAbs target conserved regions that change little over time. Teropavimab (GS-5423) targets the CD4 binding site that HIV uses to enter cells, while zinlirvimab (GS-2872) binds to the V3 loop of HIV's envelope. Both antibodies have been modified to extend their half-life, enabling less frequent dosing.
Study Design and Participant Demographics
The phase II trial enrolled 80 participants with viral suppression who were highly susceptible to both teropavimab and zinlirvimab based on phenotypic resistance assays. Approximately half of those screened demonstrated sensitivity to both antibodies, while 24% were sensitive to teropavimab only, 16% to zinlirvimab only, and 12% showed no sensitivity to either antibody.
The study population was diverse, with about 80% of participants from the United States. While 85% were men, more than a third were Black and a quarter were Latino. The median age was approximately 51 years, and participants had well-preserved immune function with a mean baseline CD4 count of 749 cells/mm³.
After screening, 53 participants were randomly assigned to switch to the LTZ regimen, while 27 remained on their daily oral treatment. The LTZ group received:
- A loading dose of oral lenacapavir on the first two days
- Subcutaneous injections of lenacapavir (927mg) every six months
- Intravenous infusions of teropavimab (2550mg) and zinlirvimab (2550mg) every six months
Impressive Efficacy Results
The primary endpoint was the proportion of participants maintaining viral suppression at week 26. The results were highly encouraging, with 96% of participants in both treatment groups maintaining undetectable viral loads. Additionally, CD4 counts increased on average, with no significant difference between the groups.
Only one participant in the LTZ group experienced virological failure, with viral rebound occurring around week 24. This individual subsequently resumed their previous regimen of Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) and regained viral suppression. Analysis revealed that while this participant maintained average levels of both antibodies, their lenacapavir concentration fell below the mean. The person developed resistance to lenacapavir (Q67H mutation) and lost susceptibility to zinlirvimab.
Safety Profile
The LTZ regimen demonstrated a favorable safety profile with no severe drug-related adverse events, serious treatment-emergent adverse events, or withdrawals due to adverse events. The most common side effect was mild injection site reactions from lenacapavir, with approximately 40% of participants developing nodules due to the formation of a 'depot' of medication under the skin. Pain and other injection site reactions were less common and generally mild. Notably, no participants experienced infusion-related reactions to the antibody components.
Building on Previous Research
These findings build upon earlier research presented at CROI 2023 and published in The Lancet HIV from a smaller phase I trial that showed the LTZ combination maintained viral suppression for six months in people highly susceptible to both antibodies. Additional data presented at CROI 2024 and the HIV Drug Therapy Glasgow meeting demonstrated that the combination could be effective for people sensitive to at least one of the antibodies if they received a high enough dose of zinlirvimab.
The current phase II study is ongoing and plans to extend follow-up to 52 weeks. Earlier this year, the US Food and Drug Administration granted a Breakthrough Therapy Designation for the LTZ regimen, intended to accelerate development of this promising approach.
Implications for HIV Treatment
Dr. Ogbuagu described the twice-yearly LTZ regimen as a "huge advance" and "the longest-acting complete regimen in advanced development." He highlighted the practical advantage that all components can be administered together, improving treatment logistics.
If successful in larger trials, this approach could transform HIV care by offering a complete treatment regimen requiring only two clinic visits per year. This could significantly improve treatment adherence, reduce stigma associated with daily medication, and enhance quality of life for people living with HIV.
The importance of pre-treatment screening for viral sensitivity to the antibodies remains a critical consideration, as effectiveness appears highest in those with susceptibility to both antibodies, though high-dose regimens may still benefit those with partial sensitivity.
As research continues, the LTZ regimen represents a promising step toward simplified, long-acting HIV treatment that maintains the high efficacy standards of current daily oral regimens while potentially offering substantial quality-of-life improvements for patients.
