By Monica Gandhi, MD, MPH, as told to Kendall Morgan
Monica Gandhi, MD, MPH, is a professor of medicine and associate division chief of the Division of HIV, Infectious Diseases, and Global Medicine at the University of California San Francisco. She is also the director of the UCSF Center for AIDS Research and education director at the HIV Clinic at Ward 86. She sees patients who have HIV and studies the use of HIV treatments, including long-acting Cabenuva in real-world settings, including in those who are affected by other challenges such as homelessness and housing insecurity. Her studies showed this treatment regimen may benefit people who struggle with treatment adherence. Her published work helped change U.S. treatment guidelines to endorse the expanded use of this long-acting treatment regimen in people with viremia or circulating HIV particles in their bloodstream. Gandhi was not involved in the drug discovery or clinical trials that led to Cabenuva’s approval in January 2021.
The long-acting HIV regimen known as Cabenuva includes two medicines, cabotegravir and rilpivirine. You get them in an injection once every month or two. The two medicines in this regimen work in different ways. Cabotegravir is what’s known as an integrase inhibitor. It blocks an HIV enzyme called integrase that the virus needs to make more copies of itself in infected human cells. Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI). It prevents HIV from making more copies of itself by stopping the virus from converting its RNA into DNA.
When used on its own to treat HIV, Cabenuva can lower the amount of virus in the bloodstream as long as you keep taking it. It also can boost the number of immune cells you have to fight other infections. We spoke with Gandhi to learn more about Cabenuva and who can benefit from this treatment regimen instead of daily pills.
Who typically benefits from this long-acting treatment?
The FDA approved Cabenuva (cabotegravir and rilpivirine) in 2021 as a complete regimen for HIV infection in adults who were already virally suppressed on another daily treatment and had no history of treatment failure. But we see such a low-income population, with a lot of housing insecurity, substance use, and mental health challenges. So, from the beginning, we started using cabotegravir and rilpivirine in those with viremia [who were not virally suppressed and had trouble adhering to other treatment options.] We published a lot on our experience treating patients in San Francisco, and then eventually the guidelines changed to permit the use of this combination in those with viremia, too. This medication can benefit anyone with HIV who would prefer to take a long-acting medicine instead of daily pills.
Can you give more insight into the research and development that led to the approval and current use of this medication?
We’re on the 30th anniversary of highly active antiretroviral therapy. It’s 2026, and 1996 is when it started. We just had two drug therapies at the beginning. They were really hard to take and not very effective. Then we got a three-drug therapy that was really effective, but they were hard to take as well. In 2007, we got the first oral integrase inhibitors, and that was the mainstay. But taking even a single pill once a day can be difficult with all the challenges that can come with life. In urban settings like San Francisco, there are housing insecurity, substance use, and mental health challenges that can stymie the ability to take medications regularly. Many fields have been thinking of long-acting medicines as a way to get around adherence barriers to oral lifelong therapy. Finally, these long-acting injectables for HIV came out in 2021 with the approval of cabotegravir and rilpivirine. But they had only been studied in those with virologic suppression. The clinical trials were in those who were on oral antiretroviral therapy (ART), doing fine, and got switched over to long-acting.
At Ward 86, we take care of such a low-income population, as do many centers. About 38% of our patients have housing instability and 46% have substance use. Right from the very beginning, we wanted to use these medications in those who had a hard time taking the oral ART. We structured a program where we met with patients who were viremic and explained why we would want to use long-acting ART. We worked out how we were going to have them come in to get the medication or how we would go out to find them. We also structured the program so that we would put out data reporting on our outcomes in those with viremia. By doing that, we were able to tell other centers that it’s successful to use long-acting ART in those with viremia and adherence challenges. Based on observational data from centers like ours, they updated the guidelines on the use of long-acting ART in 2024.
What sets Cabenuva apart from HIV medicines that came before it?
I started my infectious disease fellowship in 1999, so I’ve been in HIV care for 25 years. I have found these long-acting injectables to be really remarkable for people who have all these adherence challenges. For the patient population where life is just so difficult, I think it’s really been a revolution to have the long-acting regimen. What makes them work differently is a depot formulation that is injected into muscle. The medicine then releases slowly over time.
When you think about chronic disease management, the World Health Organization has said that we would benefit more from adherence strategies than we would from the development of new drugs. It’s really difficult to take drugs every day when you have chronic disease. With Cabenuva, you put it in and you don’t need it for two months. You don’t have to remember to take that daily pill.
What does this really mean for people you care for?
As an example, I have one patient who is a widow. She got HIV, and it was very distressing for her. She feels very internally stigmatized by her new diagnosis. She’d rather tell her family she has a blood disorder. She got on the long-acting medicine, and it really helped eliminate that stigma of taking a pill every day. I could personally tell you so many success stories. There are people for whom this is the first time they’ve been virologically suppressed. It’s really quite moving to have these medications as an option.
How quickly does it work?
The hallmark of integrase inhibitors from the very beginning is that they drop the viral load really quickly. Cabotegravir is the backbone for both, so they drop the viral load quickly. By the next injection, the virus is usually suppressed. We use it every four weeks until they are virologically suppressed for a couple of months, and then we switch to every eight weeks. We would see the viral load suppressed by the very next visit — within one month — so there is immediate gratification that is motivating for patients to come back for the injectables.
Is this treatment generally considered safe? What are the most common side effects?
It is an injection, and injection site reactions are the main safety concern. The intramuscular injection can cause pain. So it’s not universally acceptable. [Note: Some people have reported side effects including fever, fatigue, headache, and musculoskeletal pain.]
Is there anyone who shouldn’t take this medication?
Some people don’t like needles. But we’ve been surprised, too. Some people will say they never want needles. Then they get on this regimen, and they realize they can take it. They’d rather have this than taking the pill every day. [Note: Cabenuva is contraindicated with several other drugs due to the potential for drug interactions, e.g., anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin; antimycobacterials: rifabutin, rifampin, rifapentine; dexamethasone (more than a single-dose treatment); St. John’s wort (Hypericum perforatum). These medications can decrease the exposure of cabotegravir and/or rilpivirine.]
How much does it cost, and will insurance cover it?
In the U.S., Medicaid has traditionally added every HIV medication that comes out. They’ve added it to their formulary and this was no exception. We have no issues getting it for our low-income patients. High-income people with HIV may have a harder time getting cabotegravir and rilpivirine covered by private insurance companies. They may require you to try an oral medication first. If you have taken other medications and aren’t virologically suppressed, the new guidelines for the treatment of HIV with long-acting ART may help with coverage. It’s always a good idea to talk with your doctor and check with your insurance company to see what they will cover.
What do you recommend for those who are interested in switching to long-acting ART?
I would say reach for it readily if you have HIV or you are a doctor with patients who have adherence challenges on oral medications. In a study from last year, the virologic suppression at 48 weeks is 98%. That is so much better than what we have seen historically. It’s worth it to take the plunge and do this.
Is there still more to learn?
Yes. We’re going to study the pharmacokinetics of the long-acting treatment. We’re also studying the combination of cabotegravir and lenacapavir (Yeztugo), which is another long-acting injectable approved in 2022 for highly treatment-experienced patients. This is for another population of people who had been left behind, which is those with NNRTI resistance. NNRTIs have been the mainstay of therapy but there is a certain rate of resistance. There also is a low genetic barrier to developing resistance. We started using these two together as soon as we got lenacapavir in late 2022. We published the first case report showing individuals started with 47% virologic suppression and went up to 94%. In another study just published, individuals on lenacapavir/cabotegravir have a 100% virologic suppression rate. So I do think this combination could be powerful for some of our patients.
