Long-Acting Injection Better for PrEP in Men, Gender-Diverse Groups

Twice-yearly lenacapavir (Sunlenca) substantially reduced HIV infection when used for preexposure prophylaxis (PrEP) in cisgender men and transgender or gender-nonbinary persons in the pivotal PURPOSE 2 trial.

Injections every 26 weeks cut the rate of HIV infections by a relative 89% compared with daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF, Truvada), with rates of 0.10 versus 0.93 per 100 person-years (incidence rate ratio 0.11, 95% CI 0.02-0.51, P=0.002).

There was also a 96% reduction in risk compared with background HIV incidence of 2.37 per 100 person-years among individuals screened for enrollment without any PrEP or HIV screening in the prior 3 months (IRR 0.04, 95% CI 0.01-0.18, P

And no safety concerns arose, researchers led by Moupali Das, MD, MPH, of drug manufacturer Gilead Sciences in Foster City, California, reported in the New England Journal of Medicine.

“Twice-yearly lenacapavir offers an efficacious choice for prevention of HIV infection, which may increase PrEP uptake,” the group concluded.

The findings were consistent with those of the PURPOSE 1 trial that showed a similar advantage to twice-yearly lenacapavir among cisgender women in high-risk countries. Before being stopped early for efficacy, the trial found a 100% reduction in HIV incidence compared with daily F/TDF or background HIV incidence (P

While cheap PrEP with F/TDF has been available, adherence with a daily medication has been seen as contributing to breakthrough infections. In PURPOSE 2, the daily oral PrEP adherence started off high (82% taking at least four pills a week at week 8) but declined to 67% at week 26 and 62% at week 52. The breakthrough infections were associated with low adherence to F/TDF.

The phase III trial aimed for enrollment of individuals age 16 and older from “demographic subpopulations that are disproportionately affected by HIV and have historically been underrepresented in HIV clinical trials” — cisgender gay, bisexual, and other men, transgender women, transgender men, and gender nonbinary persons who have condomless receptive anal sex with partners assigned male at birth.

Trial sites were in areas with evidence of substantial ongoing HIV transmission, most in the United States (61), along with nine in Brazil, seven in Thailand, six in South Africa, five in Peru, three in Argentina, and one in Mexico.

Overall, 3,265 participants were randomized 2:1 to double-blind treatment with lenacapavir or F/TDF and included in the modified intention-to-treat analysis that excluded persons adjudicated as having HIV infection at randomization. The trial was stopped early after an interim analysis suggested superior efficacy of lenacapavir.

Two cases of HIV infection in the lenacapavir group occurred during the trial period and had emergence of capsid resistance resulting from lenacapavir monotherapy.

“We’re at a crossroads in the HIV epidemic, and a twice-yearly choice for HIV prevention, if approved, could be transformative as we work toward achieving the UNAIDS 2030 targets around the world,” according to a statement by PURPOSE 2 principal investigator Onyema Ogbuagu, MBBCh, of Yale School of Medicine in New Haven, Connecticut. “Lenacapavir for PrEP could provide an important alternative to existing preventative medications that require more frequent dosing, and could help transform the HIV prevention landscape by addressing a range of unmet needs for individuals who need or want PrEP globally.”

Lenacapavir is approved for the treatment of HIV in combination with other antiretrovirals among heavily treatment-experienced adults with multidrug resistant HIV-1 infections. Gilead has said that it will seek expanded approval for use as PrEP and noted that the drug has been granted expedited review by the FDA through both Breakthrough Therapy Designation and a rolling review.

One question has been how to achieve equitable access to the more effective treatment given that F/TDF is available for less than $50 per year in South Africa whereas lenacapavir currently costs $43,000 per year in the U.S., severely limiting access in low- to middle-income countries where HIV risk is highest.

Editorialists for the PURPOSE 1 trial argued that the findings had “created a moral imperative to make lenacapavir broadly accessible and affordable as PrEP.”

Gilead has announced “non-exclusive, royalty-free voluntary licensing agreements with six pharmaceutical companies to manufacture and supply high-quality, low-cost versions of lenacapavir for 120 high-incidence, resource-limited countries, which are primarily low- and lower-middle income countries.”

One limitation of the trial was use of recency assays and the recent infection testing algorithm to estimate the incidence of HIV infection in the screening cohort, which “avoids the ethical issues associated with a placebo group, given that effective options exist” but may give a conservative estimate of background HIV incidence.