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No Pain, No Gain? Why Injection-Site Reactions Should Not Deter Us From Appropriate Use of Long-Acting ART

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Released: August 11, 2026

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Injection-site reactions (ISRs) with long-acting (LA) antiretroviral therapy (ART) for HIV are common and expected, but manageable, and they should be considered in the context of the overall benefit of LA ART for treatment or prevention. Here’s how I counsel patients on what to expect and why I consider effective counseling to be the most important intervention for improving tolerability of ISRs with LA ART.

Monica Gandhi
Monica Gandhi, MD, MPH
Managing ISRs with LA ART


Having cared for people living with HIV since beginning my infectious disease fellowship in 1999, I have watched antiretroviral therapy (ART) evolve tremendously. Moving from complex, multidrug “cocktails” to single-tablet regimens has greatly simplified treatment. But even a tolerable, single-pill regimen does not solve every problem. There are still barriers to taking a pill every day, especially for people who are experiencing life challenges, like substance use, housing insecurity, and mental illness. For others, taking an HIV pill every day can be very stigmatizing and serve as an unwanted daily reminder of their diagnosis. 

The data show that many people prefer long-acting (LA) ART and that, for some, getting injections in the clinic instead of taking a daily pill can overcome important adherence barriers. We have so many stories from the Ward 86 HIV Clinic that show the power of LA ART.I had one person with long-standing HIV tell me that every time she put a pill in her mouth, she would vomit because taking it reminded her that she had HIV. We tried every regimen in the book to find one she could tolerate, without success, until a LA option became available. Another person with unstable housing told me that carrying pills in their backpack simply was not realistic because they would get stolen.

Experiences like these are why I believe we need to discuss LA therapy with our patients proactively. For many people, LA ART agents represent a life- and practice-changing advance in HIV treatment and prevention, but they do introduce a different set of considerations compared with oral ART, specifically, injection-site reactions (ISRs). These reactions are common and expected, and generally mild, but they can sometimes lead to discontinuation.

To empower people to make informed decisions and support persistence on LA ART, we must be well-informed and prepared to discuss ISRs.

ISR Impact
In my opinion, 2 real-world studies have really demonstrated how ISRs can contribute to discontinuation of LA ART. The first comes from the Ward 86 cohort in San Francisco, where approximately 16% of participants discontinued LA cabotegravir plus rilpivirine (CAB + RPV), mainly because of ISRs. Similarly, in the OPERA cohort, approximately 6% of discontinuations were because of ISRs with LA CAB + RPV.

Although similar real-world evidence for lenacapavir (LEN) is lacking, we do have data from clinical trials on treatment discontinuation because of ISRs with LEN. In CAPELLA, up to approximately 3% of participants discontinued LEN for HIV treatment because of ISRs, whereas 0.2% to 1.2% of participants discontinued LEN for HIV prevention because of ISRs in PURPOSE 1 and PURPOSE 2.

Setting Expectations
These findings raise the question of what we can do to minimize these reactions.

With intramuscular administration of LA CAB + RPV, I talk patients through the injections and ask which injection they would prefer to receive first. I tell patients that RPV is more viscous, so it can be more painful than CAB. Then, I warm up the medication rather than injecting it cold. Although icing the area prior to injection is usually not helpful for such a deep intramuscular injection, I find that the patient rubbing the area can help. I also vary the site of administration when appropriate. Of importance, the data show that intramuscular ISRs generally decrease over time, and these injections are generally well tolerated.

Subcutaneous injections with LEN are a different story. Pain may occur, but it can be mitigated by ice because this is a subcutaneous injection. Administration technique also matters. I have been surprised by how much using a 90-degree angle helps. The goal is to ensure that the medication reaches the subcutaneous space rather than the dermal space, which is not where the medication should go and will increase pain. 

Nodule formation with LEN is another important consideration. In my experience, nodules are almost universal and can persist for months. They represent a foreign-body inflammatory reaction and gradually diminish with time.

For me, the most important intervention to improve tolerability of ISRs is counseling. I find that if patients know beforehand that they may experience pain or nodules, they are much less bothered by the experience. Setting expectations can ease anxieties and help patients understand that ISRs are normal.

When I discuss LA agents with patients, I explain the practical differences between an intramuscular injection, which goes deep into the muscle, and a subcutaneous injection, which goes just under the skin. I also ask them to consider whether nodules would bother them and whether the interval between injections would help with acceptability. A patient may decide that some pain or a persistent nodule is an acceptable tradeoff for receiving an injection only twice a year rather than taking an oral pill every day.

The Future
With many new LA ART agents in the development pipeline, I think it behooves us as healthcare professionals and researchers to consider tolerability, even in phase I studies. How large are the injection volumes? Is administration subcutaneous or intramuscular, and does one route hurt more than the other? How might ISRs affect adherence and persistence? I think these are crucial questions to ask as we look ahead to new formulations.

Your Thoughts
What strategies have helped improve your patients’ comfort with LA therapy? Leave a comment to join the discussion!