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Lenacapavir PrEP Toolbox
Where Lenacapavir Might Fit in the PrEP Toolbox

Released: August 08, 2025

Colleen F. Kelley
Colleen F. Kelley, MD, MPH
Raphael J. Landovitz
Raphael J. Landovitz, MD, MSc
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Key Takeaways
  • FDA approval of lenacapavir for HIV PrEP is a major step towards ending the HIV epidemic, but it comes with many practical considerations for implementation, such as new recommendations for HIV testing, coordination of prescriptions for initiation doses, and managing injection-site reactions.  

On June 18, 2025, lenacapavir (LEN) was approved by the Food and Drug Administration for HIV pre-exposure prophylaxis (PrEP) in men and women as a long-acting injectable agent given every 6 months. This approval makes it the second long-acting PrEP option, in addition to cabotegravir (CAB). Read on to learn what experts had to say with regards to integrating this new drug into the current field of HIV prevention. 

How frequently should individuals be monitored for HIV infection while on LEN for HIV PrEP? Which tests do you recommend using?

Colleen F. Kelley, MD, MPH:
The prescribing information recommends screening all individuals for HIV-1 before initiating LEN for PrEP. Screen with an antigen/antibody test and an RNA test; the results of the RNA test do not need to be available prior to initiation as long as the antigen/antibody result is negative.

After LEN initiation, individuals should be screened at least before each subsequent injection (or more frequently if they show symptoms consistent with acute HIV-1 infection or are diagnosed with another sexually transmitted infection), using an FDA-approved test for diagnosis of acute or primary HIV-1 infection. If using a rapid, point-of-care antigen/antibody test, negative results should be confirmed using a more sensitive assay.

The 2-day initiation doses of LEN consist of 2 subcutaneous (SC) injections and 2 oral tablets on Day 1 and 2 oral tablets on Day 2. Do you recommend that patients take the oral initiation doses of LEN in clinic as directly observed therapy? 

Colleen F. Kelley, MD, MPH:
Although some healthcare professionals may prefer this approach, the logistics may be a barrier. My understanding is that the oral loading doses and the subcutaneous initiation doses will require 2 separate prescriptions. So, in order to have the patient take the oral LEN in clinic, they may have to fill the prescription at the pharmacy and bring it to the clinic, which might be logistically challenging. Therefore, it may not be possible to have the oral loading doses on hand for all first injections.  

In the PURPOSE 2 clinical trial, participants took the first set of 2 pills in clinic on Day 1, and then the second set of 2 pills were taken at home. So, I don’t think there’s any reason to require that the oral initiation doses be conducted as directly observed therapy. But if you feel that it is necessary and you have a close, collaborative working relationship with your pharmacy, you might be able to work that out.. 

Injection-site nodules are potential adverse reactions to SC LEN. Are there available publications with pictures of nodules in a broad range of skin colors and types? Typically, how big are the nodules and how long do they last?

Raphael J. Landovitz, MD, MSc:
I have not seen any such images or publications, but I think it’s a really important question that we will need to think about going forward. We will need to know if there are differences in the way those nodules present in people whose skin has different levels of melanin content.

According to the prescribing information, the median size of these nodules was approximately 3 cm in both PURPOSE 1 and 2. Some of them can be quite long-lasting. In PURPOSE 1, the median duration of nodules associated with initial injections of LEN was 350 days, while in PURPOSE 2, the median duration was 297 days. 

How does the pharmacokinetic tail of LEN compare to that of CAB? If an individual acquires HIV within the pharmacokinetic tail, is the concern for drug resistance greater with LEN than CAB? 

Raphael J. Landovitz, MD, MSc:
Personally, pharmacokinetic tails aren’t a major concern for me, with either LEN or CAB, except for potential drug–drug interactions. My reasoning is that even if someone halts an injectable product, if there is still an ongoing risk that they are going to be exposed to HIV, they will need a different form of HIV prevention. In such cases, healthcare professionals should consider an alternative PrEP agent.

I don’t worry much about drug resistance with either CAB or LEN for infection acquired during the tail period. You’ll remember with clinical trials of CAB, no resistance mutations were found when HIV acquisition occurred during the tail phase of HPTN 083 (that is, 6 months or more after the last injection), and no resistance mutations were observed among the 4 HIV infections during HPTN 084. With LEN, it seems like a large proportion of the breakthroughs in PURPOSE 2 (but not PURPOSE 1) had capsid inhibitor resistance, but I think this is less of a concern because capsid inhibitors are not currently part of most first-line HIV treatment regimens.         

How does LEN change the landscape of PrEP for you? 

Colleen F. Kelley, MD, MPH:
I think we are all aware of the potential for long-acting agents to end the HIV epidemic, to prevent HIV for a broad range of people. I think how well this potential is realized is going to come down to the logistics, cost and insurance coverage, global access, and infrastructure. With all of these things currently under threat, it remains to be seen what will happen. 

Raphael J. Landovitz, MD, MSc:
I think the opportunity to have less frequent healthcare system contacts for people who are at increased risk of exposure to HIV is really powerful at this time, when resources are being cut down both in the United States and globally for HIV prevention.

Furthermore, the tremendously high levels of efficacy (driven by better “coverage” of sex acts with the long-acting injectable preparation) are also notable and really exciting. I think, as clinics start implementing this, it’s going to be really important to think about who’s going to help patients navigate the payer approval process, and who’s going to be a champion for patients in your clinics to make sure that people come in for the required visits.

Finally, looking to the future, there is a once-yearly formulation of LEN that is beginning phase III clinical trials that could be even more impactful if it gains FDA approval as well.

Your Thoughts
How do you anticipate LEN changing your approach to HIV prevention? Leave a comment to join the discussion!

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