More long-acting PrEP options on the way

More widespread and consistent use of pre-exposure prophylaxis (PrEP) has the potential to dramatically reduce the incidence of HIV in the U.S., but substantial barriers to PrEP remain, particularly access, stigma, and non-HIV specialist physicians’ knowledge of the growing slate of options.

New PrEP options on the horizon may help alleviate some of these barriers as physician awareness also increases.

“There’s data from contraception [studies] that if you have more choice, the uptake is higher overall,” Matthew Spinelli, MD, of the University of California San Francisco, told MedPage Today. “PrEP is highly effective, and if the populations that need it had access to it, we would see the end of the HIV epidemic.”

A 2022 study modeled HIV transmission in 32 U.S. urban areas and used it to project incidence among men who have sex with men from 2020 to 2030 under a variety of different strategies aimed at increasing use of PrEP. With no intervention, HIV incidence would fall an estimated 19% across the cities studied, the researchers calculated. But boosting long-acting PrEP uptake by just 10% would bump the decline to a 36% reduction in incidence by 2030. The effect varied by city, from a 22% reduction in Atlanta to a 51% reduction in San Francisco. If long-acting PrEP uptake increased by 25%, however, new infections could be cut by more than half, with a 54% reduction across the cities studied.

Current PrEP Options

FDA has approved three PrEP options and is likely to approve a fourth — long-acting lenacapavir (branded as Sunlenca for HIV treatment) — this year. Any licensed prescriber can prescribe PrEP, so physicians in family medicine, internal medicine, and pediatrics, for example, can prescribe it without specializing in HIV or infectious disease. Patients should receive an HIV test to ensure it’s negative and undergo baseline assessments for kidney function, hepatitis B infection, and lipids before beginning PrEP.

One daily oral PrEP option is emtricitabine with tenofovir disoproxil fumarate (Truvada). This combination, dubbed F/TDF or TDF-FTC, is available to any adolescent or adult who weighs at least 77 pounds whether they have known risk factors for HIV or not.

Emtricitabine with tenofovir alafenamide (F/TAF or TAF-FTC, Descovy) is another daily oral PrEP option, but it’s not approved for those whose risk for HIV is via receptive vaginal sex. Although the pharmacokinetics would suggest it’s just as effective as any other PrEP option, F/TAF is not approved for those assigned female at birth because studies haven’t been done in this population, Spinelli said. Its effectiveness also has not been studied for insertive vaginal sex.

In 2021, approval of cabotegravir (Apretude) as the first long-acting PrEP option provided patients an option to move from daily oral therapy with two medications to every 2 month injection with a single agent for prevention.

The arrival of cabotegravir has increased uptake of PrEP, Spinelli said, but less than hoped, partly because of the drug’s cost and partly because of logistical challenges in how the drug is purchased. Also, the unique side effects of injectables can be a reason some patients stick with oral PrEP.

Still, long-acting injectable PrEP is particularly ideal for several populations, Spinelli said.

“Anyone who struggles with adherence to oral medication, anyone who has stigma or who would have a risk of disclosure from taking an oral pill associated with HIV, people who travel, people who have chaotic schedules, people with substance use, or anyone with a degree of life chaos that makes it hard” to take a daily pill are all ideal candidates, Spinelli said. He added that he takes care of a lot of patients experiencing homelessness, and “their meds are constantly getting stolen or lost in sweeps of encampments, so long-acting is really amazing for that population.”

Barriers to PrEP

Those best suited for long-acting PrEP, however, may also be among those who struggle most to access it.

“It’s definitely true that the populations that are at highest risk of HIV tend to be the most vulnerable,” Spinelli said. “There’s a lot of barriers to uptake, because clinics need to purchase the drug, have space to give the drug, and have nurses trained to give the injection,” for example. Many of these logistical hurdles are unique to the U.S. healthcare system and drive up costs, he said.

“When it’s available and patient-centered and easy to access, the uptake is high and it’s highly effective. It’s just that we, unfortunately, don’t live in that world in the U.S., and it’s getting worse,” Spinelli said. “The access is much better to orals than it is to injectables for all the logistical reasons.”

Another barrier is awareness among the populations that would benefit from using PrEP.

“Knowledge is insufficient, particularly of the long-acting PrEP,” Spinelli said. “Outside of white gay men, the awareness is relatively low. It’s improving, but there’s definitely a lot of inequity in who has access to it, who has the information, and who has healthcare access.”

Though infection rates have declined, they have gone down less so in Black and Latino gay men, he said. Other high-priority populations for PrEP access include transgender women, Black women in the southeast U.S., and people who inject drugs, he said.

“PrEP was really marketed as this thing for gay men, and that is the group that has the most HIV diagnoses in the U.S., so it wasn’t wrong to do a population-specific approach, but I think we’re a victim of that success,” Spinelli said. “Women don’t see this as something for them and don’t perceive themselves at risk.” Women are also more likely to perceive stigma with use of PrEP, he said.

“The primary determinants of low PrEP uptake and adherence are really structural factors, including stigma, mental health, and substance use,” he said.

PrEP Options on the Way

Aside from the existing menu of PrEP options, companies are continuing to develop new ones with a special focus on long-acting agents.

Following the results of the PURPOSE1 trial and PURPOSE2 trials, a twice-yearly lenacapavir formulation is currently under priority review with the FDA, with a decision expected this month. The data on lenacapavir suggest it is superior to oral options in prevention primarily because of adherence challenges with daily oral PrEP, Spinelli said. A once-yearly lenacapavir option was also recently tested in a phase I study.

A registration study is underway to look at extending injectable cabotegravir from administration every 2 months to administration every 4 months, according to a spokesperson for drugmaker ViiV Healthcare.

Merck had been developing islatravir as long-acting PrEP, either as an implant or a monthly oral pill. A phase I study assessing the implant for 12 weeks seemed promising, and two phase III studies had been enrolling candidates for once-monthly oral islatravir, but the FDA halted the studies in 2021 due to safety concerns related to reduced CD4 counts. Merck has since decided to abandonopens in a new tab or window islatravir for PrEP, though it’s continuing to pursue the drug for treatment.

A newer Merck attempt for long-acting PrEP is the agent MK-8527, also a nucleoside reverse transcriptase translocation inhibitor (NRTTI) like islatravir. The company presented data from two phase I trials at the 2024 Conference on Retroviruses and Opportunistic Infections and recently completed a phase IIa study from which results have not been reported yet.

A 2024 CDC study in macaques suggested once-weekly oral PrEP with tenofovir alafenamide is worth exploring, and preliminary evidence suggests that even taking just two pills a week of TDF-FTC can reduce risk of infection by 89%.

A dapivirine vaginal ring for PrEP available in Africa will not be reviewed by the FDA, Spinelli said, because the efficacy data was not as impressive as other PrEP options.

By Tara Haelle