The promise of once-yearly lenacapavir
Clinical trials have found that lenacapavir, when used every six months (given by subcutaneous injection into the belly), reduces the risk of HIV infection between 96% and 100%, depending on the study. In these trials, an oral formulation of lenacapavir is initially taken in the first two days of therapy to quickly raise levels of the drug in the blood so that protection is obtained.
Lenacapavir for the prevention of HIV is now approved in the U.S. and will hopefully be approved in Canada in mid-2026.
Lenacapavir as part of combination therapy for HIV is already approved in Canada and many countries. This use of lenacapavir is meant for people living with HIV who have few treatment options. However, only a very small number of people with HIV in Canada use it for this purpose.
Once yearly
Gilead Sciences is the developer of lenacapavir. Scientists with the pharmaceutical company have developed new liquid formulations of lenacapavir that are long lasting. These new formulations are meant for clinical trials where the drug is injected deep into the muscles on the sides of the hip.
A relatively small clinical trial designed to assess the safety of lenacapavir and monitor the levels of lenacapavir in the blood up to a year after one intramuscular dose has been completed.
This trial found that lenacapavir levels were, for the most part, higher with the once-yearly dose than seen in historical data with the twice-yearly dose. Overall, the drug was safe, and participants reported temporary pain at the injection site.
Study details
Researchers randomly assigned 40 participants to receive one of the following formulations of lenacapavir:
- formulation 1 – lenacapavir 5,000 mg containing 5% ethanol
- formulation 2 – lenacapavir 5,000 mg containing 10% ethanol
Participants were in their mid-30s and did not have HIV; 65% were assigned male at birth and 35% were assigned female at birth. On average, their body mass index (BMI) was 27 kg/m2.
The formulations were administered by healthcare providers deep into muscles at the sides of the hips in two injections containing 5 mL of fluid each. Half of the participants who received formulation 2 had an ice pack placed on the side of their hip 10 minutes prior to the lenacapavir injections.
Over the course of the study, study personnel collected blood samples and conducted physical examinations from time to time, and participants completed surveys.
Results
In general, the level of lenacapavir in the blood of participants was higher than has been reported in past studies (where the drug was given subcutaneously rather than via intra-muscular injection). Furthermore, in the present study, high levels of lenacapavir in the blood were maintained for one year after injection.
Participants given intramuscular injections took longer to achieve high levels of lenacapavir in the blood (compared to people who got subcutaneous injections in past studies). However, people who took lenacapavir via subcutaneous injection in past studies also received a loading dose of an oral formulation of lenacapavir for the first two days when the drug was initiated. This rapidly raised levels of lenacapavir in the blood to protective levels.
Side effects
Intramuscular injections are used to administer many medications and cause temporary discomfort and pain.
About 80% of people who received formulation 1 of lenacapavir and 75% who received formulation 2 reported pain at the injection site. This was generally mild to moderate in intensity. Injection site pain persisted between three and four days.
Four people who received formulation 2 had temporary difficulty walking because of pain in their hip muscle.
Four people who received formulation 1 reported swelling at the injection site; this was not a problem in people who received the formulation 2.
According to Gilead, pre-treating the injection site with an ice pack for 10 minutes prior to the injections reduced the intensity of pain.
Four people with pre-existing high levels of LDL-C (so-called bad cholesterol) had levels of this protein increase further, peaking more than six months after injection in three of the four people. However, after this time, their LDL-C levels gradually returned to their pre-study level.
For the future
Gilead scientists need to refine their intramuscular formulations; perhaps the high dose used in the current study is necessary. Initially, oral doses of lenacapavir will be needed to ensure that levels of the drug rise rapidly once it is initiated.
Although no one became HIV positive during the study, participants were at low risk for HIV infection, according to the researchers.
Future studies will be needed with populations that reflect people who might use lenacapavir once yearly in the future. This will mean recruiting people who are age- and gender-diverse. As well, participants from the present study were from the U.S. A future study of intramuscular lenacapavir should include people from different regions of the world.
—Sean R. Hosein
REFERENCES:
- Jogiraju V, Pawar P, Yager J, et al. Pharmacokinetics and safety of once-yearly lenacapavir: a phase 1, open-label study. Lancet. 2025 Apr 5;405(10485):1147-1154.
- Ogbuagu OE, Avihingsanon A, Segal-Maurer S, et al. Efficacy, safety, and pharmacokinetics of lenacapavir oral bridging when subcutaneous lenacapavir cannot be administered. AIDS. 2025 May 1;39(6):639-648.