CROI 2026: Only three new HIV cases on lenacapavir PrEP: updates from PURPOSE-1 and -2
19 April 2026. Related: Conference reports, HIV prevention and transmission, CROI 33 (Retrovirus) 2026.
Simon Collins, HIV i-Base
Three presentations covered extended follow-up for lenacapavir PrEP in the large, randomised, phase 3 PURPOSE-1 and -2 studies, including details on new cases of HIV acquisition. All abstracts, posters and webcasts for the studies reported below are now available online and hyperlinked in the references.
Although no transmissions were previously reported in the PURPOSE-1 study in cisgender women in southern Africa, two new cases were reported in the LEN arm out to week 52. This makes a total of two case overall compared to 52 incident infections in the F/TAF arm and 25 in the F/TDF. [1]
There was only one new infection in the LEN arm of the PURPOSE-2 study in gay, bisexual, trans and non-binary men, compared to two new cases in the F/TAF arm, with totals of 3 vs 12 overall to the end of week-52. [2]
These results showed very high levels of continued protection from LEN.
The new analysis included week-52 data for all participants and open-label extension results.
In PURPOSE-1, plasma levels of LEN were within the target range for the case who had all injections on time (44.6 ng/mL on diagnosis at week 65, with IQ target of >15.5 ng/mL based on 4x protein adjusted 95% EC in vitro). The second case had had their last LEN injection more than 16 months earlier (with LEN levels at 0.65 ng/mL on diagnosis at week-95 after having switched to oral PrEP at week-82).
No new safety concerns were reported with very few grade-3 injection site reactions relating to either pain or nodules (<0.1% over total follow-up).
The new HIV acquisition in PURPOSE-2 was diagnoses at week-52 and had received all injections on time, with the most recent injection 25 weeks earlier. Plasma levels of LEN on diagnosis were only slightly below target (14.2 ng/mL). This person had a viral load of 2 million copies/mL on diagnosis due to seroconversion.
Tolerability was similar to the primary analysis, with no new discontinuations due to side-effects, including from injection site reactions.
The third oral presentation at CROI 2026, presented resistance test results for all incident infections, including the two new cases of breakthrough infections despite receiving all injections on time. The participant in PURPOSE-1 who was diagnosed at week-52 could only be genotyped at weel-79 due to a low viral load, showing the N74D mutation. The participant in PURPOSE-2 who had very high viral load at baseline showed Q67H and K70R in capsid.
N74D was previously reported in the two earlier incident cases in PURPOSE-2 and also in 4/8 cases where HIV infection had been missed at baseline (2/4 in each study). These cases of N74D were all explained by resistance developing while on LEN monotherapy, rather than from a concern about transmitted drug resistance.
comment
Together, both cases of incident HIV with good drug levels of lenacapavir might just reflect contact with partners who were themselves undergoing serocpnversion.
It would be interesting to know the exposure levels used to calculate 95% EC in the in vitro studies and to what degree this might cover seroconversion. This might also explain other rare cases of people who become HIV positive despite excellent adherence on oral PrEP.
Also, if appropriate to the participants circumstances, whether contract tracing was able to look at partners in these cases.
References
- Ndlovu et al. Twice-Yearly Subcutaneous Lenacapavir for PrEP: Updated HIV-1 Incidence and Safety Data in PURPOSE 1. CROI 2026, Denver. Oral abstract 128.
https://www.croiconference.org/abstract/557-2026 (abstract)
https://www.croiwebcasts.org/console/player/55041 (webcast) - Lenacapavir for PrEP: HIV-1 Incidence and Safety From PURPOSE 2 at End of Randomized Blinded Phase. CROI 2026, Denver. Oral abstract 129.
https://www.croiconference.org/abstract/545-2026 (abstract)
https://www.croiwebcasts.org/console/player/55042 (webcast) - Cox S et al. Resistance Analyses of the PURPOSE Studies Through the End of the Randomized Blinded Phase. CROI 2026, Denver. Oral abstract 130.
https://www.croiconference.org/abstract/362-2026 (abstract)
https://www.croiwebcasts.org/console/player/55043 (webcast)