New research: High prevention efficacy and “breakthrough infections” on lenacapavir for PrEP

“Breakthrough” HIV infections among people receiving long-acting injectable lenacapavir for PrEP in two major clinical trials were a topic of discussion at 2026 Conference of Retroviruses and Opportunistic Infections (CROI) held this week, in Denver Colorado.

Across two large clinical trials testing long-acting lenacapavir for PrEP, with thousands of cisgender women, men who have sex with men, and gender diverse people who have sex with men, a total of four individuals seroconverted during the study period while receiving on-time medication injections. 

Why did lenacapavir fail to protect a small number of people from acquiring HIV in the study?, questioned one clinician from the University of Colorado during the presentation’s Q&A. “I think patients want to know, and I think we need that information soon. I’ve already had someone who declined to use lenacapavir because of the breakthrough infections.” 

Early results from the PURPOSE I and PURPOSE II studies provided definitive information about the high efficacy of long-acting injectable lenacapavir for HIV prevention–results which went on to inform the FDA’s approval of brand name Yeztugo for injectable PrEP.

At CROI 2026, researchers presented the final results of the entire 52 weeks of the randomized controlled portion of the studies. Both studies indicated that the medication works extremely well to prevent HIV infection. 

Nkosiphile Ndlovu, from the Wits Reproductive Health and HIV Institute, in South Africa, presented results from the PURPOSE I study. This study enrolled cisgender adolescent and young women in sub-Saharan Africa, who were randomly assigned to receive lenacapavir injections twice per year, oral F/TAF (generic for Descovy), or F/TDF (generic for Truvada). More than 5,300 people participated in the study.

The long-acting injectable PrEP option showed incredible efficacy–out of the more than 2,000 who received lenacapavir injections, only two individuals seroconverted during the study period. Among the more than 3,000 people taking oral PrEP, there were 77 seroconversions. The overall HIV incidence among people receiving lenacapavir was 0.07 per 100 person-years (ppy), compared to 1.98 ppy for F/TAF and 1.94 ppy for F/TDF. 

One individual who received lenacapavir injections missed the 26 week injection and ended up transitioning to oral PrEP at week 82 (at which time they were HIV-negative). At 95 weeks, they had seroconverted–over a year after receiving their last lenacapavir injection.

The second individual was diagnosed with HIV at week 52, after receiving all lenacapavir injections on time. 

“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,” said Ndlovu. [Note: Although the researcher described lenacapavir as “low-burden,” the medication is priced at more than $28,00/year in the U.S.] 

Valeria D. Cantos Lucio, from Emory University, shared results from PURPOSE II. This study, which included men who have sex with men and gender diverse individuals who have sex with men, shared similarly high efficacy in HIV prevention.

The double-blind randomized controlled study included 2,179 people who were assigned to take lenacapavir, and 1,086 people who were assigned to F/TDF.

At the end of the randomized blinded phase, which was 52 weeks, there were three HIV infections among people taking lenacapavir and 12 among people taking F/TDF. The overall HIV incidence was 0.11 per 100 person-years for people taking lenacapavir PrEP compared to 0.92 ppy for people taking F/TDF. 

Two of these breakthrough infections had been previously reported, and found to have occurred even with on-time study medication doses. The third case, described by Lucio at CROI, was detected at week 52. The participant did receive all of the medication injections on time and lenacapavir levels measured in the participant’s blood was at target level.

In a separate presentation, Stephanie Cox, from Gilead Sciences, presented information about drug resistance mutations detected among the five individuals who seroconverted while taking lenacapavir. Drug resistance mutations mean that the virus is less susceptible to certain classes, or types, of antiretrovirals. 

Out of the five individuals diagnosed with HIV, four were found to have lenacapavir-associated resistance mutations. Because prior studies have shown that lenacapavir-associated resistant mutations are not circulating widely, the researchers believe that the drug resistance mutations developed as a result of receiving PrEP in the study and were not a transmitted drug resistance mutation. 

In other words, the drug resistance mutation was not the cause of the HIV breakthrough infections. 

“We don’t know why these [HIV infections] occurred,” said Cox, during the Q&A. “You know… only five, well only four, really, out of the two trials and thousands of people. I think the efficacy is very high. We will see certain breakthrough infections, which we have seen, but overall efficacy is extremely high.” 

“This is a major question on the ground,” shared one provider from Nigeria. “We just completed provider training in Nigeria, and the big question across all these sites where we did the training was, ‘Why?’ Why are there breakthrough infections, especially for those who [had medication] on time, on schedule, and had therapeutic doses of LEN [lenacapavir] present at the time when the infection was recorded?” 

When asked to clarify if research is ongoing to determine why breakthrough infections happen with long-acting lenacapavir, Cox clarified that, yes, research is ongoing. 

“There is effort. Unfortunately, nothing obvious or easy to understand has come up. But there is effort to try and understand, but we don’t have an answer right now.” 

“The lenacapavir for PrEP studies presented at CROI 2026 re-affirm that this option has extremely high efficacy for HIV prevention,” said Hyman Scott, MD, MPH, medical director of SFAF. “The breakthrough infections are important to evaluate but are extremely rare among the thousands of study participants. We have observed breakthrough infections in the other forms of oral and injectable PrEP but it doesn’t reduce our enthusiasm and commitment to help get PrEP to everyone who wants it.”