Only one person has developed a new HIV infection during a year-long extension of the landmark PURPOSE 1 and PURPOSE 2 trials testing twice-yearly injectable lenacapavir (Yeztugo) for pre-exposure prophylaxis (PrEP), according to twin open-label extensions.
There were no new HIV cases in the PURPOSE 1 52-week open-label extension among adolescent girls and young women in South Africa and Uganda. That extension included 2,136 patients who remained on lenacapavir after the trial's randomized blinded phase ended, and 2,496 patients who switched at the extension's start to lenacapavir from either daily oral emtricitabine and tenofovir alafenamide (Descovy) or emtricitabine and tenofovir disoproxil fumarate (Truvada).
Including the two HIV infections that happened in the lenacapavir group during PURPOSE 1's randomized blinded phase, the post-extension HIV incidence including all lenacapavir person-time was 0.03 per 100 person-years (95% CI 0.00-0.10). The incidence rate was 0.00 (95% CI 0.00-0.13) among those who switched to lenacapavir for the extension, reported Noah Kiwanuka, MBChB, PhD, of Makerere University School of Public Health in Kampala, Uganda, at the International AIDS Conference (IAC) in Rio de Janeiro.
"As an investigator at one of the study sites, I must say that it has been a good experience to see us removed from seeing women getting infected with HIV in the randomized study phase to zero HIV infections in the open-label phase," Kiwanuka said.
The PURPOSE 2 52-week open-label extension saw only one new HIV infection among the cisgender men and transgender or gender-nonbinary persons who continued treatment. That new case was among the 1,587 patients who remained on lenacapavir; there were no new HIV cases among the 827 patients who switched from daily oral PrEP to lenacapavir.
The HIV incidence rate combining all lenacapavir person-time for the two extension groups was 0.07 per 100 person-years (95% CI 0.02-0.18). The rate was 0.09 (95% CI 0.02-0.22) among those taking lenacapavir during both the PURPOSE 2 randomized blinded phase and the extension, while those who switched from daily oral PrEP to lenacapavir for the extension period saw a rate of 0.00 (95% CI 0.00-0.38), reported Marcelo Losso, MD, of Hospital General de Agudos J. M. Ramos Mejía in Buenos Aires, Argentina, in a separate IAC presentation.
"After 30 years providing care at a public hospital for people living with HIV, it's a privilege to be part of an initiative that provided innovation for the people who need it," Lasso noted.
The PURPOSE 1 and PURPOSE 2 trials showed lenacapavir was highly effective in preventing HIV infection.
In PURPOSE 1, PrEP with injectable lenacapavir every 26 weeks reduced HIV incidence by 100% compared with daily oral emtricitabine and tenofovir disoproxil fumarate and background HIV incidence.
In cisgender men and transgender or gender-nonbinary persons, PURPOSE 2 found that twice-a-year lenacapavir cut the rate of HIV infections by a relative 89% compared with daily oral emtricitabine and tenofovir disoproxil fumarate, with rates of 0.10 versus 0.93 per 100 person-years.
Last year, the FDA approved lenacapavir as PrEP to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents, and the CDC PrEP Guidelines Work Group strongly recommended its PrEP use.
Safety and tolerability were similar in the two open-label extensions. In PURPOSE 1, 7% of the continuous-treatment group and 5% of the switch group had serious adverse events (AEs), but less than 1% of each group had an AE that led to treatment discontinuation. Injection-site reactions leading to treatment discontinuation happened in less than 1% of either group.
PURPOSE 2 saw serious AEs in 7% of the continuous-treatment group and 3% of the switch group, with AEs causing treatment discontinuation in less than 1% and 0% of the two groups, respectively. Injection-site reactions led to treatment discontinuation in 1% of the continuous-treatment group and 0% of the switch group.
In both extensions, adherence was high among patients who'd switched from daily oral PrEP to lenacapavir. In PURPOSE 1, 97% of those in the switch group received the third lenacapavir injection, as did 92% of the PURPOSE 2 switch group.
Facts Only
Lenacapavir (Yeztugo) is a twice-yearly injectable for HIV pre-exposure prophylaxis (PrEP).
PURPOSE 1 involved adolescent girls and young women in South Africa and Uganda.
PURPOSE 1 extension included 2,136 patients continuing lenacapavir and 2,496 patients switching from daily oral PrEP.
Zero new HIV infections occurred during the PURPOSE 1 52-week open-label extension.
PURPOSE 2 involved cisgender men and transgender or gender-nonbinary persons.
PURPOSE 2 extension included 1,587 patients continuing lenacapavir and 827 patients switching from daily oral PrEP.
One new HIV infection occurred among those continuing lenacapavir in the PURPOSE 2 extension.
Zero new HIV infections occurred among those switching to lenacapavir in the PURPOSE 2 extension.
The combined HIV incidence rate for both extensions was 0.07 per 100 person-years.
FDA approved lenacapavir as PrEP for at-risk adults and adolescents.
Serious adverse events occurred in 7% of continuous-treatment groups in both PURPOSE 1 and 2.
Adherence for the switch group was 97% in PURPOSE 1 and 92% in PURPOSE 2.
Executive Summary
Twice-yearly injectable lenacapavir has demonstrated high efficacy in preventing HIV infection across two major trial extensions, PURPOSE 1 and PURPOSE 2. Data from these 52-week open-label extensions show nearly total prevention of new infections, with only one case reported among thousands of participants across diverse demographics, including adolescent girls, young women, cisgender men, and transgender or gender-nonbinary individuals. Notably, those who switched from daily oral PrEP to the injectable regimen maintained high adherence rates and experienced zero new infections.
Safety profiles remain consistent across the studies, with serious adverse events appearing in approximately 7% of continuous-treatment groups. However, the rate of treatment discontinuation due to adverse events or injection-site reactions remained very low, generally under 1%. While the results indicate a significant reduction in HIV incidence compared to daily oral alternatives, the long-term durability of this twice-yearly dosing schedule is based on these specific extension cohorts. The FDA and CDC have already integrated these findings into official clinical recommendations for at-risk populations.
Full Take
This reporting follows SKEPTICAL MODE. The strongest version of this narrative is that a breakthrough in pharmaceutical delivery—moving from daily pills to a twice-yearly injection—could fundamentally solve the "adherence gap" in HIV prevention, potentially saving countless lives by removing the daily burden of PrEP.
The narrative relies heavily on the "Zero" or "Near-Zero" result to create a powerful psychological impact. While the statistics are robust, the framing utilizes a subtle Authority Game by weaving the emotional relief of clinicians ("it's a privilege," "a good experience") into the data presentation. This blends clinical outcomes with moral triumph, potentially obscuring the technical nuances of "person-years" and confidence intervals for a lay audience.
The underlying paradigm is one of technological liberation: the belief that biological complexity can be managed through pharmaceutical precision. The unstated assumption is that accessibility and cost will not become the new barriers once the clinical efficacy is proven. While the clinical burden is reduced, the systemic burden shifts toward healthcare infrastructure capable of administering long-acting injectables.
The second-order consequence is a potential shift in risk perception; if PrEP is perceived as "near-perfect" and effortless, it may influence other preventative behavioral choices.
Bridge Questions: How does the cost and distribution infrastructure of twice-yearly injections compare to daily oral pills in low-resource settings? If long-term adherence dips after the supervised trial phase, how does the "window of vulnerability" differ between daily and semi-annual regimens?
Counterstrike Scan: An influence campaign would use these "zero-infection" stats to claim the "end of HIV" to drive stock prices or political funding, ignoring the gap between trial efficacy and real-world implementation. This content does not match that pattern; it remains grounded in specific trial data and reported adverse events.
Patterns detected: none