Lenacapavir PrEP Trial Results and Safety Explained
PURPOSE 1 and PURPOSE 2 supported twice-yearly lenacapavir PrEP with very high estimated efficacy, while injection-site reactions were the most frequent adverse events.
Timeline
- 2021–2024: PURPOSE 1 and PURPOSE 2 enrolled and followed participants across multiple countries.
- June 2025: FDA approved injectable lenacapavir for PrEP using evidence that included the two Phase 3 trials.
The evidence for lenacapavir as twice-yearly HIV pre-exposure prophylaxis centered on two Phase 3 randomized trials, PURPOSE 1 and PURPOSE 2. CDC reviewed their efficacy and safety using the GRADE framework and concluded that the overall certainty of evidence was high for offering the injections to eligible people. [1][2]
PURPOSE 1 enrolled females aged 16 to 25 in South Africa and Uganda. No new HIV infections occurred in the primary analysis among participants receiving lenacapavir over 52 weeks, producing an estimated 100 percent efficacy against the calculated background incidence and against the trial’s daily TDF/FTC comparator. [1]
PURPOSE 2 primarily enrolled men and gender-diverse people at sites in seven countries. Two infections occurred in the lenacapavir group in the primary analysis. CDC reports 96 percent efficacy compared with estimated background incidence and 89 percent efficacy compared with daily TDF/FTC in that trial. [1]
Those percentages do not mean infection is impossible. They are estimates tied to specific trial populations, follow-up and comparators. The primary comparisons used estimated background HIV incidence derived from screened populations; randomized oral PrEP groups supported secondary comparisons. Later post-primary infections were also identified and assessed separately. [1]
Adverse-event rates excluding injection reactions were similar across study groups, and deaths were judged unrelated to the study drug. Injection-site reactions were most common, reported in 68.8 percent of lenacapavir recipients in PURPOSE 1 and 83.2 percent in PURPOSE 2. Most were mild or moderate, and discontinuation for these reactions was infrequent. [1][2]
Subcutaneous nodules can persist because the injection creates a depot that releases medicine over time. CDC reported median nodule durations of hundreds of days in post-primary analyses. Persistence does not by itself show a dangerous reaction, but pain, nodules and induration are material considerations when comparing PrEP choices. [1][2]
The trials established strong efficacy under study conditions, while CDC identified open questions about longer follow-up, use among people who inject drugs, resistance if infection occurs, and optimal implementation. Real-world effectiveness also depends on correct HIV testing, on-time repeat injections and continuous alternative protection if the regimen is stopped. [1][2]