Michael Gwarisa
As more African countries begin to introduce lenacapavir into their HIV prevention programmes, scientists are examining new data showing that a small number of people became infected with HIV while using the medication.
The drug’s rollout now extends beyond just one or two nations. Countries that have started distributing the twice-yearly injectable or have regulatory approval in place include Zimbabwe, Zambia, Eswatini, Uganda and Kenya. Others where approval has been granted or rollout plans are advancing, include South Africa, Botswana, Mozambique, Namibia, Malawi, Rwanda, among others. These moves represent a significant expansion of access to long-acting HIV prevention options for communities most affected by the epidemic across sub-Saharan Africa.
According to findings from updated results of two large clinical trials, which were presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2026) in Denver, United States, researchers say the rare cases of infection, sometimes referred to as “breakthrough infections,” have prompted further investigation even as the drug continues to demonstrate extremely high effectiveness.
Lenacapavir is a long-acting antiretroviral injection administered every six months as pre-exposure prophylaxis, or PrEP. The drug has generated significant excitement among scientists and public health experts because it provides an alternative to daily oral pills and offers long-term, discreet protection for people at risk of HIV infection.
Updated results presented at the conference came from the phase 3 PURPOSE 1 and PURPOSE 2 trials, two large studies evaluating the safety and effectiveness of lenacapavir in different populations.
Presenting findings from the PURPOSE 1 trial was Nkosiphile Ndlovu, MBChB, from the University of the Witwatersrand in Johannesburg, South Africa. The study focused primarily on adolescent girls and young women aged 16 to 25 in South Africa and Uganda, groups that continue to face a disproportionately high risk of HIV infection.
Through the end of the randomized blinded phase of the study, researchers recorded two HIV infections among the 2,134 participants who received subcutaneous lenacapavir injections every 26 weeks. By comparison, 77 infections occurred among 3,204 participants who used a daily oral PrEP pill.
“For [lenacapavir], this corresponds with an updated HIV incidence of 0.07 per 100 person-years, consistent with high efficacy and a very low number of infections,” said Ndlovu.
The study also examined the circumstances surrounding the two infections in the lenacapavir group. One participant had received all injections on schedule and was diagnosed with chlamydia at week 52 before later testing positive for HIV at week 65. The second participant became infected after discontinuing lenacapavir and transitioning to an open-label tenofovir disoproxil fumarate and emtricitabine regimen, with the HIV diagnosis occurring 16 months after their last injection.
Despite these rare cases, researchers emphasized that the overall results strongly support the effectiveness of this long-acting prevention approach.
“This finding still positions twice-yearly subcutaneous lenacapavir as a powerful, durable, low-burden HIV prevention option for one of the populations most urgently needing innovation,” Ndlovu concluded.
Similar findings were presented from the PURPOSE 2 trial, which primarily enrolled cisgender men and gender-diverse individuals who have sex with men. The study results were presented by Valeria D. Cantos, MD, an associate professor in the Department of Medicine at Emory University in the United States.
In the PURPOSE 2 trial, a total of 2,179 participants received lenacapavir injections every 26 weeks, while 1,086 participants used the daily oral F/TDF regimen. Researchers reported that three participants in the lenacapavir arm contracted HIV through the end of the randomized blinded phase. In comparison, 12 infections were recorded among participants taking the daily oral medication.
This translated to an HIV incidence rate of about 0.11 per 100 person-years among those receiving the twice-yearly injection. One of the infections occurred in a participant who had received all scheduled injections on time. The participant had previously been diagnosed with rectal chlamydia at the start of the study and again at week 26, and also had a diagnosis of rectal gonorrhea during the same period.
“In this extended analysis, twice-yearly subcutaneous lenacapavir for PrEP remained highly efficacious and well-tolerated among cisgender men and gender-diverse people who have sex with men through the end of the randomized blinded phase of the PURPOSE 2 study,” Cantos concluded.
While the results highlight the remarkable protective effect of lenacapavir, scientists say the few breakthrough infections underline the importance of continued monitoring and research. Experts are now exploring possible explanations for why infection occurred in these cases despite adequate drug levels in the body. Potential factors under investigation include individual biological differences, immune responses, and the interaction between HIV and the medication.
Public health specialists stress that the findings should be viewed in context. Across both trials, only a handful of infections occurred among thousands of participants who received the injection. Researchers say the results continue to demonstrate that long-acting PrEP could play a transformative role in expanding HIV prevention, particularly among populations that face challenges taking daily medication consistently.
As countries across Africa and the world prepare to introduce this new prevention option, scientists say ongoing surveillance and research will remain important to ensure the benefits of this breakthrough approach are fully realized.
For now, the evidence presented at CROI reinforces a clear message. Lenacapavir remains one of the most promising tools yet developed in the global effort to reduce new HIV infections and offer more accessible prevention options for populations at highest risk.
