HIV-free after twice-yearly PREP

The HIV-1 capsid inhibitor lenacapavir, administered as a twice-yearly injection, was 100% effective in preventing HIV infection in women at high risk of infection, according to an interim analysis of a Phase 3 clinical trial. Objective 1 Test.

The results were so promising that an independent data monitoring committee recommended that Gilead Sciences stop the blinded phase of the trial and offer open-label lenacapavir to all participants.

The results were unexpected and exciting: “I've been involved in HIV research for a long time, and I've never seen anything like it in the Phase 3 PREP trial with zero transmission,” said Moopali Das, MD, PhD, executive director of clinical development at Gilead Sciences in Foster City, California.

Objective 1 is to evaluate the safety and effectiveness of two regimens for pre-exposure prophylaxis in women and girls aged 16 to 25 years: twice-yearly subcutaneous lenacapavir and once-daily oral Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg). The two agents will be compared with the standard once-daily oral Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg).

There were no cases of HIV infection among the more than 2,000 women in the lenacapavir group. In contrast, the HIV incidence rate was 2.02 per 100 person-years in the Descovy group and 1.69 per 100 person-years in the Truvada group.

One of the trial's primary endpoints, the background incidence of HIV, was 2.41 cases per 100 person-years for those taking lenacapavir. All drugs have been shown to be safe and well-tolerated, Das said, and full interim data from the trial will be presented at an upcoming conference.

No new infections

The medical community is “overjoyed” with the results so far, said Monica Gandhi, M.D., director of the Gladstone Center for AIDS Research at the University of California, San Francisco. “We'll have to wait until the full data is in, but so far this treatment is 100 percent effective and far superior to other treatments.”

Gandhi said he wants to wait for more details about side effects, tolerability, and the trial's dropout rates and reasons. For example, lenacapavir tends to form nodules under the skin, which are reservoirs from which the drug is released over a six-month period. Gandhi said he's interested to see whether participants found it bothersome enough to stop treatment.

The global HIV epidemic remains ongoing, with 1.3 million new infections expected in 2022. Existing oral PREP options and even the long-acting injectable cabotegravir have so far not been as effective at reducing infection rates as hoped, Gandhi said. “We've been waiting for another option.”

Twice-yearly lenacapavir injections are easier and more convenient to administer than oral PREP, and many people, especially younger people like those in PURPOSE 1, tend to forget to take their medication every day.

Individual options

Many trial participants said they are uncomfortable with the stigma that can come with HIV PREP — they don't want people to see pill bottles around their homes or rattling around in their purses — so getting an injection just twice a year at a clinic is appealing.

“It's a discreet option, and people are excited about the privacy and the fact that they don't have to take a pill every day,” Das said. “PREP only works if you take it.”

Higher adherence to the treatment regimen is likely one reason why lenacapavir was superior to oral PREP. But lenacapavir also has a unique mechanism of action as a multistage viral capsid inhibitor, Das said. It targets the capsid both before and after the virus is integrated into the nucleus, which could be another reason for lenacapavir's efficacy.

While the results are promising, concerns remain about how accessible the drug will be, especially in low- and middle-income countries where the HIV burden is highest. “No one has any idea how Gilead plans to make this accessible,” Gandhi said.

Access issues

The company: Pharmaceutical Patent Pool Gandhi recommended that state legislators allow companies to manufacture generic formulations of lenacapavir, a move he said was traditionally made to provide cheaper alternatives to poorer countries. He said the “disastrous” rollout of injectable cabotegravir, which is still not widely available in low-income countries, set a worrying precedent.

Gilead Sciences confirmed that all 5,300 participants in the PURPOSE 1 study will have the option to continue receiving lenacapavir until the drug becomes publicly available in their countries. The company has committed to ensuring exclusive Gilead Sciences supply in countries with the highest demand until its sole licensing partners are able to supply high-quality, low-cost lenacapavir.

Gilead Sciences also negotiates voluntary licensing programs directly with other partners to supply generic drugs to poor countries, rather than going through a third-party MPP.

Lenacapavir is already approved to treat multidrug-resistant HIV, but not yet for HIV prevention. A sister study, PURPOSE 2, is ongoing and is testing lenacapavir in men who have sex with men, and transgender men, transgender women, and non-binary individuals who have sex with partners assigned male at birth. If results, expected by the end of 2024 or early 2025, are positive, the company plans to move forward with a regulatory filing for lenacapavir PREP.

Three other trials are also underway: PURPOSE 3 and PURPOSE 4 are small U.S.-based studies of women and people who inject drugs, and PURPOSE 5 will enroll people at high risk of HIV infection in France and the United Kingdom to provide European data for European regulators.