The coming of lenacapavir for HIV prevention
The drug lenacapavir (Sunlenca) is approved in Canada and other high-income countries for use as part of combination therapy in people who are heavily treatment experienced, who have multidrug-resistant HIV, and whose current regimen is failing. As there are many powerful options for the treatment of HIV, lenacapavir is not commonly used for HIV treatment in Canada. However, it is being studied for another use.
Many drugs used as part of HIV treatment regimens have also been used by people without HIV to prevent infection prior to possible exposure to the virus. This use of HIV medicines is called pre-exposure prophylaxis (PrEP). Drugs approved for PrEP include the following:
- Apretude – cabotegravir
- Truvada – tenofovir DF + FTC and available in generic formulations
- Descovy – tenofovir alafenamide (TAF) + FTC
Lenacapavir works by interfering with an HIV protein called the capsid. This protein is used by HIV to protect its genetic information as it enters and infects a cell. The capsid also protects HIV’s genetic information when the infected cell is making new copies of HIV. Lenacapavir is classed as a capsid inhibitor. As capsid inhibitors are not in widespread use (so far lenacapavir is the only approved one), there is little likelihood of lenacapavir-resistant HIV.
The main advantage of lenacapavir is its dosing. For HIV prevention, in clinical trials, participants first received two injections of lenacapavir. These injections were given subcutaneously (just under the skin) of the abdomen. They also took oral lenacapavir (pills) for two consecutive days. After this, they subsequently received two injections every six months. No further oral doses of lenacapavir were needed unless future injection appointments were significantly delayed. This long duration between injected doses should be attractive to many potential PrEP users.
Ongoing clinical trials
One clinical trial that is still ongoing has released interim results. Researchers found that lenacapavir is highly effective at preventing HIV infection in women and adolescent girls. In this trial, called Discover 1, researchers compared lenacapavir (given by injection every six months) to daily Truvada or Descovy. Lenacapavir provided 100% protection from HIV. In contrast, tenofovir-based regimens were significantly less effective. This reduced effectiveness was likely caused by some participants not taking their pills as directed.
Lenacapavir is generally well tolerated and associated with less risk of nausea and vomiting when compared to tenofovir-based regimens.
What lies ahead?
Gilead Sciences, the developer of lenacapavir, has an extensive research program on the drug. Trials are continuing in women and adolescent girls. There are also prevention trials in gay and bisexual men, transgender women and people who use drugs.
Interim results from a trial in men who have sex with men (MSM), transgender men, transgender women and non-binary people have recently been released (detailed later in this issue of TreatmentUpdate). In this trial, lenacapavir was highly effective.
Complete results from these and other clinical trials will gradually become available in the months and years ahead. Gilead plans to submit a dossier on lenacapavir for prevention to regulatory authorities in the U.S. and then likely in the European Union, followed by other countries and regions. The company will likely seek accelerated approval, given that lenacapavir only needs to be taken twice yearly.
After regulatory agencies approve lenacapavir for prevention, governments will negotiate with Gilead to find a price on which they can agree. All these processes and procedures take time, which is why lenacapavir for prevention may not be approved in Canada until perhaps 2026. It will take at least another year after that before it hopefully ascends to the list of medicines that provincial and territorial governments subsidize for HIV prevention. These lists are called formularies.
In the community
Researchers have found that most people who use PrEP in Canada are gay and bisexual men. Certainly, lenacapavir needs to reach this population. Other populations that bear a disproportionate burden of HIV—such as Indigenous people; transgender and nonbinary people; African, Caribbean and Black people; women; and people who use drugs—also need equitable access to lenacapavir to help reduce their HIV risk.
Understanding the rollout
Pilot studies (demonstration projects) to implement lenacapavir for prevention in the community can be useful, as they help busy clinics understand the best way to manage the flow of patients who require subcutaneous injections. The information from demonstration projects can be used to help integrate lenacapavir into sexual health and other clinics.
Lenacapavir will become an exciting option for many people with HIV. Hopefully Gilead will price it responsibly so that governments can afford to subsidize it. The drug also needs to be equitably distributed.
—Sean R. Hosein
REFERENCES:
- Bekker LG, Das M, Abdool Karim Q, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. New England Journal of Medicine. 2024; in press.
- Gilead Sciences. Gilead’s twice-yearly lenacapavir for HIV prevention reduced HIV infections by 96% and demonstrated superiority to daily Truvada in second pivotal phase 3 trial. Press release. 12 September 2024.
- Bester SM, Wei G, Zhao H, et al. Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020 Oct 16;370(6514):360-364.
- Jang S, Engelman AN. Capsid-host interactions for HIV-1 ingress. Microbiology and Molecular Biology Reviews. 2023 Dec 20;87(4): e0004822.