Twice-yearly injections are 100% effective in preventing new infections, according to the final results from the PURPOSE 1 trial of lenacapavir.
For weeks, the HIV community has been talking about this highly anticipated clinical trial and whether the strong — and to many, surprising — interim results would hold at final presentation at the International AIDS Conference 2024 in Munich, Germany.
Presenting the results, Linda-Gail Bekker, MD, director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, reported zero new infections in those who got the shots in the study of about 5000 young women. In the group given daily oral preexposure prophylaxis (PrEP), roughly 2% contracted HIV from infected partners.
"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," Bekker said about the results, which were published simultaneously in The New England Journal of Medicine.
PURPOSE 1 confirmed that lenacapavir is a "breakthrough" for HIV prevention, said International AIDS Society president Sharon Lewin, PhD, MBBS. It has "huge public health potential," said Lewin, who is also the AIDS 2024 conference co-chair and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne in Australia.
Lenacapavir is a novel, first-in-class multistage HIV-1 capsid inhibitor with a long half-life, which enables the twice-yearly dosing.
PURPOSE 1 enrolled women aged 15-25 years who were at risk for HIV in South Africa and Uganda, with a primary endpoint of HIV infection. Because of the previously announced interim results, which showed the injection was preventing infections, study sponsor Gilead Sciences discontinued the randomized phase of the trial and shifted to an open-label design for lenacapavir.
"One hundred percent efficacy is more that we could ever have hoped for a potential prevention efficacy," said Christoph Spinner, MD, MBA, an infectious disease specialist at the University Hospital of the Technical University of Munich and AIDS 2024 conference co-chair.
Spinner added that while this is the first study of lenacapavir for PrEP, it's also the first to explore outcomes of emtricitabine-tenofovir in cisgender women.
Strong Adherence Rates
The twice-yearly injection demonstrated adherence rates above 90% in the trial for both the 6- and 12-month injection intervals.
"Adherence was 91.5% at week 26 and 92.8% at week 52," Bekker reported.
The trial compared three PrEP options including the lenacapavir injection to once-daily oral emtricitabine 200 mg and tenofovir-alafenamide 25 mg (F/TAF) and once-daily emtricitabine 200 mg and tenofovir–disoproxil fumarate 300 mg (F/TDF).
"Most participants in both the F/TAF and F/TDF groups had low adherence, and this declined over time," Bekker reported. At 52 weeks, the vast majority of patients on both oral therapies had low adherence with dosing, defined at less than two doses a week.
Bekker called the adherence to the oral agents in this trial "disappointing."
Findings from the trial underscore the challenges of adherence to a daily oral medication, said Rochelle Walensky, MD, and Lindsey Baden, MD, from the Harvard Kennedy School of Government and Harvard Business School in Cambridge, Massachusetts, in an editorial accompanying the published results.
With almost 92% attendance for the twice-yearly lenacapavir injections, the "well-done," large, randomized, controlled trial "exemplifies not only that women can dependably adhere to this administration schedule, but also that levels of an HIV-1 capsid inhibitor can remain high enough over a period of 6 months to reliably prevent infection," they added.
Another key focus of the presentation was adverse events. The rate of adverse events grade 3 or more in the lenacapavir arm was 4.1%, Bekker said, which is slightly lower than the rates in the oral arms. The rates of serious adverse events were 2.8% for lenacapavir, 4% for F/TAF and 3.3% for F/TDF.
Injection Site Reactions
Injection site reactions occurred in 68% of the lenacapavir group, including 63% with subcutaneous nodules.
The injection can form "a drug depot which may be palpable as a nodule," Bekker said. In the placebo group, 34% of patients had injection-site reactions and 16% had nodules. Nearly all injection-site reactions were grade 1 or 2, she said. "Higher grade injection-site reactions were rare and not serious and occurred in a similar percentage in lenacapavir and placebo," she said.
Overall, more than 25,000 injections of lenacapavir have been given, Bekker said, and four patients discontinued treatment because of injection-site reactions. "Reporting of injection-site reactions, including nodules, decreased with subsequent doses," she said.
Contraception was not a requirement for enrollment in the study, Bekker pointed out, and pregnancy outcomes across the treatment arms were similar to the general population.
First in a Series of Trials
This is the first in a series of PURPOSE trials, Bekker reported. The phase 3 PURPOSE 2 trial, enrolling 3000 gay men, transgender women, transgender men and gender nonbinary people who have sex with male partners, is the second pivotal trial now underway.
Three other smaller trials are in the clinic in the United States and Europe.
PURPOSE 1 participants will continue to access lenacapavir until the product is available in South Africa and Uganda, Bekker said. Trial sponsor Gilead Sciences is also developing a direct licensing program to expedite generic access to the drug in high-incidence, resource-limited countries, she said.
Walensky and Baden report that lenacapavir currently costs about $43,000 annually in the United States. "But the results of the PURPOSE 1 trial have now created a moral imperative to make lenacapavir broadly accessible and affordable as PrEP" to people who were enrolled, as well as all those who are similarly eligible and could benefit.
So now we have a PrEP product with high efficacy, they added. "That is great news for science but not (yet) great for women."
Given the high pregnancy rate among participants in the PURPOSE 1 trial, Walensky and Baden point out the assessment of lenacapavir safety is a priority. They are also interested in learning more about drug resistance with this new option.
"I f 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," Lewin said.
Now, she added, "we eagerly await results from PURPOSE 2."