By Marie Rosenthal, MS
No cisgender woman who received injections of lenacapavir (LEN, Gilead) twice a year as pre-exposure prophylaxis (PrEP) became infected with HIV, according to an interim analysis of the PURPOSE 1 trial, reported at AIDS 2024, in Munich.
“UNAIDS reports that just over 3,000 young women of a similar age to those in PURPOSE 1 became newly infected with HIV every week in sub-Saharan Africa in 2022, with less incidence decline among them compared with their male counterparts,” said Linda-Gail Bekker, MBChB, DTM&H, DCH, FCP(SA), PhD, the director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, and the former president of the International AIDS Society.
“The introduction of oral PrEP has changed the lives of more than 6 million people globally who have accessed it,” she added.
“Despite PrEP's promise, many young women have found uptake, daily adherence and persistence to daily PrEP as a social, emotional and physical challenge. For them, we need new and diverse PrEP options,” Dr. Bekker noted.
LEN, a long-acting, potent inhibitor of the HIV capsid protein, is approved in many countries to treat adults with multidrug-resistant HIV in combination with other antiretrovirals. LEN is currently not indicated for PrEP but is being studied for this indication.
PURPOSE 1 (ClinicalTrials.gov Identifier: NCT04994509) is evaluating the safety and efficacy of twice-yearly, subcutaneous LEN and once-daily oral emtricitabine-tenofovir alafenamide (F/TAF; Descovy, Gilead) as PrEP in cisgender women. (F/TAF is only approved as PrEP for men who have sex with men and transgender women).
Data from the phase 3, multicenter, double-blind, active-controlled, randomized PURPOSE 1 trial were collected from 5,345 HIV-negative, cisgender adolescent girls and young women ages 16 to 26 years at 25 sites in South Africa and three sites in Uganda. Dr. Bekker said she was pleased the study included so many younger women who were sexually active.
PURPOSE 1 is the first HIV prevention trial to intentionally include pregnant and lactating women. There were 510 pregnancies among 487 participants: 193 among women in the LEN group, with no HIV infections; 219 among women in the Descovy group, with four HIV infections; and 98 among women in a once-daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; Truvada, Gilead) group, with one HIV infection. At the time of interim analysis, 54.3% of pregnancies were completed and 45.7% were ongoing. Available pregnancy outcomes were similar to those expected for the population.
LEN and F/TAF were tested in parallel for HIV prevention, with one group receiving twice-yearly injectable LEN and the other group taking once-daily oral F/TAF. A third arm was assigned F/TDF.
Baseline demographics and characteristics were balanced across all groups, according to Dr. Bekker. Trial participants were randomly assigned in a 2:2:1 ratio to LEN, F/TAF and F/TDF, respectively.
Because effective PrEP options already exist, the trial used background HIV (bHIV) as the primary comparator and F/TDF as a secondary comparator. Most of the participants (80.5%) reported prior HIV testing. A small minority (6.3%) reported no prior use of PrEP.
Adherence to LEN and to placebo injections included in the oral PrEP study groups was high: 91.5% of all trial participants received on-time injections at week 26, and 92.8% of participants received on-time injections at one year (within 28 weeks of prior injection), according to Dr. Bekker.
Sixteen incident HIV cases among 1,068 women were observed in the F/TDF group (1.69/100 person-years; 95% CI, 0.96-2.74) and 39 incident HIV cases among 2,136 women occurred in the F/TAF group (2.02/100 person-years; 95% CI, 1.44-2.76).
HIV incidence with F/TAF was not different from bHIV (incidence rate ratio [IRR], 0.84; 95% CI, 0.55-1.28; P=0.21) in the primary efficacy analysis, and no evidence of difference was observed compared with F/TDF (IRR, 1.20; 95% CI, 0.67-2.14) in the secondary efficacy analysis.
Adherence to once-daily oral PrEP was determined by measuring tenofovir levels in blood samples from a subset of patients, which found that adherence was low and declined over the course of the study, according to Dr. Bekker. In addition to the reasons for low adherence to oral PrEP, the size of F/TDF, which is a large pill, could be a factor. The women were more likely to adhere to F/TAF than F/TDF, and more incident HIV infections were associated with low or no detection of TDF.
In the F/TAF group at 26 weeks, 30.2% had high or medium adherence to the drug, and 69.8% had low adherence. At one year in the F/TAF group, 15.9% had high or medium adherence, and 84.1% had low adherence. In the F/TDF group at 26 weeks, 10.9% had high or medium adherence, and 89.1% had low adherence. At one year in the F/TDF group, 7.0% had high or medium adherence, and 93.0% had low adherence.
Injection site reactions were the most frequently reported adverse event with LEN. Other adverse reactions reported for LEN and F/TAF were headache, urinary tract infection, genitourinary chlamydia infection and nausea.
LEN is injected into the subcutaneous layer of fat in the abdomen to form a drug depot, which becomes smaller by the next injection. Four women in the LEN group (0.2%) discontinued the study drug due to injection site reactions, compared with zero women who discontinued due to this condition on placebo.
“So, I conclude by saying zero women receiving twice-yearly LEN acquired HIV in PURPOSE 1,” Dr. Bekker said to resounding applause. “LEN efficacy was superior to both background HIV incidence and to F/TDF PrEP.
“A twice-yearly PrEP choice could overcome some of the adherence and persistence challenges and contribute critically to our quest to reduce HIV infection in women around the world,” Dr. Bekker added.
Several clinical trials of LEN as PrEP in diverse populations are underway around the world, and Dr. Bekker said those results are eagerly awaited. Results from PURPOSE 2 are expected later this year or in early 2025, according to Gilead.
“These data confirm that twice-yearly lenacapavir for HIV prevention is a breakthrough advance with huge public health potential. If approved and delivered-rapidly, affordably and equitably-to those who need or want it, this long-acting tool could help accelerate global progress in HIV prevention,” said Sharon Lewin, MD, the president of the International AIDS Society, AIDS 2024 international co-chair and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne, in Australia.
“Now we eagerly await results from PURPOSE 2, which is assessing twice-yearly lenacapavir for HIV prevention in other populations and countries. In the meantime, all stakeholders must work together to accelerate equitable delivery of existing HIV prevention options, and do more to prepare for future options, such as lenacapavir for PrEP,” Dr. Lewin added.
Gilead said it is developing an access strategy that would enable the most efficient path for the regulatory approval of twice-yearly LEN for PrEP in countries that account for most of the global disease burden.
