Lenacapavir PrEP in cisgender gay men, trans and gender-diverse people: results of the PURPOSE 2 study

9 October 2024. Related: Conference reports, HIV prevention and transmission, R4P 2024 Lima.

Simon Collins, HIV i-Base

Most people expected results from the international phase 3 PURPOSE 2 study comparing 6-monthly lenacapavir to daily oral PrEP to be a highlight at HIVR4P this year.

• Efficacy was still remarkably high, though less than the 100% reported in PURPOSE 1.
• There were also few side effects although injection site nodules led to some discontinuations.
• Key discussions now focus on access and equity of access, including for countries who were included in the study and who still have little access to oral PrEP, despite contributing to the iPrEX study in 2010.

PURPOSE 2 was stopped early in September 2024 following a planned interim analysis after 50% of participants had been followed for 52 weeks. These results were presented in an oral late-breaker at HIVR4P by Colleen Kelley from Emory University, Georgia, US. [1]

A second oral presentation from PURPOSE 2 included a detailed breakdown of how the study successfully achieved its plans to recruit a globally, racially, ethnically, and gender diverse participant population at risk of HIV. [2] 

The study screened more than 4600 potential participants from seven countries: Argentina (7%), Brazil (35%), Mexico (0.4%), Peru (14%), South Africa (11%), Thailand (12%) and the US (20%). Of these, 378 (8.2%) were already HIV positive and 45/378 (11%) were recent infections, providing the background incidence of HIV for the primary efficacy endpoint.

The main study randomised participants (2:1) to either subcutaneous injections of lenacapavir every 6 months or to daily oral TD/FTC PrEP, with matched placebo in both arms. Excluding another six people who were diagnosed on day 1, this left 3265 participants for the second efficacy endpoint comparing lenacapavir against oral PrEP.

The median age of participants was 28 (range: 17 to 74), with roughly one-third aged 16 to 25. Other demographics included 36% Black, 33% white, 13% Asian and 63% were of Hispanic/Latinx ethnicity. Roughly a quarter had never previously tested for HIV and a quarter had previously used oral PrEP. Chemsex was reported by 20%.

Roughly 78% were cisgender gay men, 14.7% transgender women, 1.3% transgender men, and 6.2% gender non-binary individuals.

During the median follow-up of 39 weeks there were two incident HIV diagnoses in the lenacapavir arm compared to nine in the oral PrEP arm. This produced HIV incidence rates (IR) per 100 person years of follow up (PYFU) of 0.10 (95%CI: 0.012 to 0.373) vs 0.93 (95%CI: 0.426 to 1.768) in the lenacapavir vs oral PrEP groups respectively. This compared to background incidence at baseline of 2.37 (95%CI: 1.649 to 3.417).

Table 1: Primary and secondary efficacy results in PURPOSE 2

IRR – incidence rates, PYFU – patient years of follow-up.

In the primary analysis, compared to the background incidence, lenacapavir reduced infections by 96%: IRR 0.04 (95%CI: 0.01 to 0.18), p<0.0001. In the secondary analysis, compared to oral PrEP, lenacapavir reduced infections by 89%: IRR 0.11 (95%CI: 0.02 to 0.51), p=0.0025. In both cases lenacapavir was superior to the control.

No further details were available on the timing, pharmacokinetic, resistance or other information of the incident infections, other than the two infections on lenacapavir were indentified by routine HIV testing.

Side effects were reported as similar in each group, predominantly grade 1 or 2 with only 4% vs 6% reporting grade 3 or higher, in the lenacapavir vs TD/FTC arms respectively, with 3% vs 4% serious adverse events. Excluding injection reactions, 7 participants in each arm discontinued, but only 2 were linked to the study drug (both reductions in creatinine in the TD/FTC arm).

Injection site reactions at any time were also generally similar in the active vs placebo groups and reduced over time although nodules were more common with lenacapavir and led to 26 vs 3 discontinuations.

Nodules (63% vs 39%), pain (56% vs 53%) and redness (17% vs 19%) were reported in the active vs placebo injections respectively, but with less than 5% being grade 2 or higher. Only 4 vs 1 participants reported grade 3 pain and grade 3 redness was only reported by 3 in the lenacapavir group.

comment

These results are of course as impressive as we knew they would be, matching closely those of the PURPOSE 1 study in cisgender women reported at the IAS AIDS 2024 conference in July. [3]

Further information is needed to find explain the two incident cases of HIV which reduced efficacy from the 100% reported in PURPOSE 1.

This includes whether these were due to low drug levels, missed diagnosis at screening (even though baseline testing included PCR viral load) or perhaps (less likely) related to the higher population risk associated with receptive anal sex which was an entry criteria for PURPOSE 2.

Either way, lenacapavir generated levels of protection that surpass expectations of an HIV vaccine, requiring only a subcutaneous injection every six months, and without the difficulties raised by vaccine hesitancy.

Demand for lenacapavir was so high that hundreds of people who were already HIV positive, but untested, volunteered to enrol. This secondary aspect of using lenacapavir as PrEP doubles its ability to help achieve global targets of reducing HIV infections by 2030, by also bringing people not yet diagnosed within care.

More than 40 years of research into an HIV vaccine should have included a plan for rapid access to make any successful vaccine available.

This plan should drive the approach to lenacapavir access now.

Links to the slides from the presentations at R4P together with Gilead press statements on lenacapavir access are available online. Gilead have committed to submitting lenacapavir for global PrEP registration and recently signed licensing agreements to enable generic access in 120 countries. [4]

References

1. Kelly C et al. Twice-yearly lenacapavir for HIV prevention in cisgender gay men, transgender, and gender-diverse people: Interim analysis result from the PURPOSE 2 study. 5th R4P 2024, 6–10 October 2024. Oral abstract 0208.
   https://presentations.gilead.com/item/991a1b1432
2. Gallardo-Cartagena J et al. Global racial, ethnic, and gender diversity among participants enrolled in the PURPOSE-2 trial of lenacapavir for pre-exposure prophylaxis (PrEP). 5th R4P 2024, 6–10 October 2024. Oral abstract 0207.
   https://programme2024.hivr4p.org/Abstract/Abstract/?abstractid=1224
3. HTB. AIDS 2024: Lenacapavir as PrEP is “beyond wonderful” but PURPOSE 1 study tells us so much more. HTB (29 July 2024).
   https://i-base.info/htb/48260
4. Gilead. PURPOSE 2 presentations and press statements.
   https://presentations.gilead.com/item/991a1b1432