Lenacapavir, a twice-yearly injectable antiretroviral, demonstrated 100% effectiveness for preventing HIV acquisition in a large study of young cisgender women in Africa, Gilead Sciences announced June 20.
The PURPOSE 1 trial showed that lenacapavir PrEP administered every six months reduced HIV incidence compared with the background infection rate and daily Truvada PrEP pills. There were zero new infections among women randomly assigned to receive lenacapavir. The trial's independent data monitoring committee recommended that this part of the study should be stopped early and all participants should be offered lenacapavir.
Another trial, PURPOSE 2, is testing lenacapavir PrEP for gay and bisexual men, transgender men, and women and nonbinary people. Results are expected in late 2024 or early 2025, Dr. Jared Baeten, Gilead's vice president of HIV clinical development, told the Bay Area Reporter. Data from both trials will be used to support an application for U.S. Food and Drug Administration approval.
Clinicians and advocates lauded the news about a potential new prevention option.
"While we know traditional HIV prevention options are highly effective when taken as prescribed, twice-yearly lenacapavir for PrEP could help address the stigma and discrimination some people may face when taking or storing oral PrEP pills, as well as potentially help increase PrEP adherence and persistence given its twice-yearly dosing schedule," said Dr. Linda-Gail Bekker of the Desmond Tutu HIV Center at the University of Cape Town in South Africa.
Multiple options needed
While oral PrEP is very effective, additional options are still needed. Some people have trouble remembering to take a pill every day, some do not want to constantly be reminded about HIV, and some are hesitant to have pill bottles that could be lost or stolen or reveal they are at risk for HIV.
"Adding additional HIV prevention options means more people may find an option that is right for them," AVAC Executive Director Mitchell Warren said in a statement. "Beyond expanded choice, a twice-yearly injection has the potential to transform the way we deliver HIV prevention to people who need and want it most — from an easier to follow regimen for individuals to a decreased burden on healthcare systems that are stretched to the limit."
Truvada (tenofovir disoproxil fumarate/emtricitabine), also from Gilead, was approved for HIV prevention in 2012, but it has still not reached its full potential. While urban white gay and bisexual men have eagerly adopted PrEP, uptake has been slower among cisgender women and Black and Latino men who have sex with men. The Centers for Disease Control and Prevention estimates that only about a third of the 1.2 million people in the United States who could benefit from PrEP are using it.
The FDA approved a second oral PrEP option, Gilead's Descovy (tenofovir alafenamide/emtricitabine), for certain populations in 2019. ViiV Healthcare's Apretude (cabotegravir), an injection administered by a health care provider every other month, is currently the longest-acting PrEP option. ViiV is working on an ultra-long-acting formulation that could be administered once every four months.
Lenacapavir, the first HIV capsid inhibitor, extends the PrEP dosing interval to once every six months. In 2022, the FDA approved lenacapavir (sold as Sunlenca) as part of a combination treatment regimen for people with multidrug-resistant HIV. Like other antiretrovirals, lenacapavir prevents HIV replication. Despite its long dosing interval, it is not a vaccine that trains the immune systems to fight HIV. After four decades of effort and many failures, there are still no effective HIV vaccines.
No new infections
When the FDA approved Descovy for PrEP, the indication did not include people who are at risk for acquiring HIV from vaginal sex, due to a lack of clinical trial data for cisgender women, trans men, and nonbinary people. But Gilead did not make the same mistake again, including all relevant populations in its lenacapavir PrEP studies.
PURPOSE 1 enrolled more than 5,300 cisgender women ages 16 to 25 in South Africa and Uganda. PURPOSE 2 has enrolled more than 3,000 cisgender and transgender men, trans men and women, and nonbinary people who have sex with men in the United States and six other countries. The two trials are running in parallel, but PURPOSE 1 had an earlier data read-out because it enrolled faster, according to Baeten. Two smaller studies, PURPOSE 3 and PURPOSE 4, are evaluating lenacapavir and Truvada PrEP for cisgender women and people who inject drugs in the United States.
PURPOSE 1 is actually two studies in one, evaluating both lenacapavir and Descovy. Thus, it helps fill the data gap that has held up approval of Descovy PrEP for cisgender women. Participants were randomly assigned to receive lenacapavir, Descovy, or Truvada.
Lenacapavir and Descovy were separately compared against the background HIV incidence rate among people in the same population who do not use PrEP and against Truvada. Now that oral and injectable PrEP have proved effective and are widely available, it would be unethical to compare new prevention methods against a placebo.
There were zero new infections among the 2,134 women who received lenacapavir, 16 new infections among the 1,068 participants assigned to Truvada and 39 new infections among the 2,136 women who used Descovy. The corresponding HIV incidence rates were 0.00, 1.69 and 2.02 per 100 person-years, respectively, while the background incidence rate was 2.41 per 100 person-years. The study therefore demonstrated the statistical superiority of lenacapavir over the background incidence rate and over Truvada.
"More than 2,000 women were randomized to receive lenacapavir, and none of them acquired HIV," Baeten told the B.A.R. "That has never been seen before in a phase 3 trial of any HIV prevention intervention."
Descovy, on the other hand, did not provide superior protection compared with the background HIV incidence rate or Truvada. Previous studies of oral PrEP for cisgender women have found challenges with adherence to daily pills, and this may be the problem here as well. Adherence analyses, including measurement of drug levels in blood to see how often women took the pills, are currently underway.
All three PrEP methods were generally well tolerated, and no new safety concerns were identified. The most common side effects of lenacapavir are nausea and injection site reactions such as pain, swelling, or nodules. Some experts have expressed concern that lenacapavir could potentially interact with other drugs including fentanyl, oxycodone, steroids, and Viagra.
But the biggest concern is that lenacapavir PrEP might not be accessible to the people who need it most in the United States and worldwide. This is already the case for Apretude, which is more effective than daily oral PrEP for both gay men and cisgender women but is not yet widely used. Lenacapavir for HIV treatment is priced at around $3,000 per month, while generic versions of Truvada can cost as little as $30 per month.
The full range of PrEP products "must be made feasible choices for all people who need and want HIV prevention options," Warren stated. "Since oral PrEP was first shown to be safe and effective 14 years ago, the global health community has failed in delivering PrEP at scale and with equity, and we have, therefore, not seen the impact that we need. ... There can be no excuses and no delays."
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