Long-acting HIV treatment – a major change begins

Until there is a safe, effective and simple-to-administer cure for HIV, treatment with a combination of anti-HIV drugs (ART) will remain vital. In the past 35 years, HIV treatments have become more effective and better tolerated. Furthermore, ART has become simpler—an entire regimen in one pill taken once daily for the average person initiating treatment. Now, a long-acting injectable regimen has become available. This treatment is called Cabenuva and consists of two drugs—cabotegravir and rilpivirine.

Why long-acting formulations?

People with chronic health conditions, including HIV, have to take pills every day. This means there is the possibility that people might inadvertently forget to take their pills. Some people with complex lives and competing issues may also find it difficult to engage in regular pill taking. Missing doses can result in less-than-ideal levels of HIV drugs in the body. If pill taking becomes intermittent, the concentration of medicine can fall to low levels repeatedly, which can give HIV the chance to adapt and overcome the effects of treatment.

Other issues

A survey of nearly 2,400 people with HIV enquired about issues related to daily dosing of medicines. People surveyed lived in North and South America, Europe, South Africa and East Asia. Researchers found that a significant proportion of people reported different issues, including the following:

  • 31% had difficulty swallowing pills every day
  • 33% felt stressed by the need to take HIV medicines every day
  • 35% disclosed that the need to take HIV pills every day caused them to have a bad feeling about their medicines and recall bad memories from their past
  • 38% worried that the need to take pills daily could inadvertently expose their HIV status to others

Some people said that having to take an HIV pill every day gave them control over the virus and their lives. However, not everyone surveyed felt this way.

Long-acting ART has the potential to address some of the psycho-social burdens of living with HIV. Another potential advantage is that Cabenuva consists of two drugs rather than the usual three drugs. As HIV treatment is lifelong, Cabenuva may offer the possibility of reduced long-term toxicity from taking medicine for decades.


In 2020 in Canada, then subsequently in the European Union and the U.S., a major change in HIV treatment began. Regulatory agencies approved the first long-acting injectable regimen for the treatment of HIV: Cabenuva, which contains cabotegravir and rilpivirine. Cabotegravir belongs to a class of drug called integrase inhibitors and rilpivirine belongs to a class called non-nukes (NNRTIs, non-nucleoside reverse transcriptase inhibitors).

Cabenuva is meant to be used as part of what is called a switch strategy. Prior to initiating Cabenuva, patients must already be on oral ART and virologically suppressed. If there are no potential barriers—such as the presence of HIV that is resistant to cabotegravir or rilpivirine, or if the person has a strain of HIV called A1 or A6 (which are less susceptible to cabotegravir and rilpivirine), or other issues—then an oral lead-in regimen can be initiated. That is, the person’s existing regimen is switched to a combination of oral formulations of cabotegravir and rilpivirine. This combination is taken for four weeks to ensure that the drugs are tolerated and that there are no problems. At the end of this time, the patient changes from oral formulations to injectable formulations of cabotegravir and rilpivirine. The drugs are injected deep into the muscles of the buttocks, one injection of cabotegravir in one buttock and one injection of rilpivirine in the other buttock. Initially the injections are given once monthly, but after a couple of months of injections to raise levels of cabotegravir and rilpivirine in the blood, patients can change to a regimen of injections every two months.

Results from a recent clinical trial (detailed later in this issue of TreatmentUpdate) have found that in people on a dolutegravir pill-based regimen, it is possible to avoid the oral lead-in with pills of cabotegravir and rilpivirine and go directly to injecting these drugs. As a result, regulatory authorities in the European Union have made the oral lead-in optional. Regulatory agencies in Canada and the U.S. are reviewing the possibility of making the oral lead-in optional. We will have more information about research on direct-to-injection strategies later in this issue of TreatmentUpdate.

HIV prevention

In the U.S., the long-acting injectable formulation of cabotegravir has been approved for use to reduce the risk of getting HIV. Taking medicines to reduce the risk of getting HIV is called pre-exposure prophylaxis (PrEP). This formulation of cabotegravir is sold under the brand name Apretude. Regulatory authorities in the U.S. have advised that patients can initiate Apretude with or without a four-week oral lead-in with cabotegravir pills. An injection of the drug is given deep into muscles in the buttocks once a month for two consecutive months. After this, the drug can be injected every two months.

The manufacturer of cabotegravir, ViiV Healthcare, is planning to seek approval for Apretude in Canada and the European Union for HIV prevention.

In the current era

Although much anticipated by doctors and their patients, regulatory approval of long-acting HIV treatment has been met with a somewhat muted reception. The approvals occurred during the midst of a worldwide respiratory pandemic—COVID-19. Many people were concerned with maintaining their health and well-being because of this pandemic. Initially, Cabenuva was only subsidized by private insurance. However, recently it has been listed on some public formularies in Canada (for information about formulary access consult your local pharmacist).

A patient support program is available

In Canada, ViiV has facilitated a third-party support program that helps patients navigate public/private insurance and arrange injection appointments. Patients first discuss with their doctor if Cabenuva is right for them. Once the doctor and patient agree about using Cabenuva, they can discuss options for injecting. If they agree that injections should be administered away from the clinic, then the doctor can contact their ViiV representative about enrolling the patient in the support program. The program then contacts the patient, asks some questions and provides general information about Cabenuva. It also provides help in navigating private insurance or public reimbursement mechanisms in their province/territory. The program liaises with the patient’s pharmacy and also helps the patient choose a location for the injection that is convenient (injections are not done at the patient’s residence). The program also runs sites with dedicated nurses skilled at administering intramuscular injections.

Revolutionary but imperfect

Long-acting cabotegravir and rilpivirine have the potential to become widely used. The advent of these formulations is revolutionary because they ultimately only need to be taken every two months. In comparison, when potent combination HIV treatment was first introduced in 1996, and for years after, it was only available in pill form and had to be taken two or three times daily. Furthermore, some patients in that early treatment era had to take large quantities of pills daily.

In the future, it is likely that more people will choose to have injections every two months (vs. monthly). However, long-acting regimens, like all forms of ART, are imperfect and may not be for everyone.

Here are some issues that patients and doctors will likely need to consider when it comes to the use of long-acting regimens such as Cabenuva and other long-acting ART formulations in development:

Hepatitis B virus (HBV)

Some people with HIV are co-infected with HBV. Many oral regimens for HIV treatment contain a combination of antiviral drugs, which are effective not only against HIV but also, in some cases, against HBV. Cabenuva does not work against HBV. Therefore, people co-infected with HBV need to take daily oral treatment (a pill or pills) for this virus. Commonly used combinations that work against both HIV and HBV include the following:

  • TDF (tenofovir disoproxil fumarate) + FTC
  • TDF + 3TC (lamivudine)
  • TAF (tenofovir alafenamide) + FTC


Cabenuva has not been studied in large numbers of pregnant people. As a result, doctors are not sure about the potential effects of Cabenuva on the risk of miscarriage or birth defects. A clinical trial of Cabenuva is underway in pregnant people.


Cabenuva is injected deep into muscle tissue in the buttocks, and from there it is slowly released into circulation. Although the levels of cabotegravir and rilpivirine decrease over time (hence the need for regular injections), the drugs can remain in the body for a long time even after a person stops taking them. For instance, in early studies of cabotegravir, levels of this drug remained at low but detectable levels for up to a year after the last injection. In the case of rilpivirine, levels of the drug remained at low but detectable levels more than a year after the last injection.

These findings about drug levels have implications for potential treatment interruptions; in general, unsupervised treatment interruptions are not a good idea. Furthermore, in people who are using Cabenuva, such interruptions are fraught with the risk that HIV could develop resistance not only to cabotegravir and rilpivirine but to other related drugs as well. This could greatly reduce future treatment options.

Potential drug interactions

The prescribing information for Cabenuva lists a relatively small number of clinically significant drug interactions compared to older HIV drugs. However, as Cabenuva becomes more widely used, it is possible that some unexpected drug interactions may occur. These may be difficult to manage because it is virtually impossible to quickly remove cabotegravir and rilpivirine from the body once they have been injected deep into muscle. Therefore, consultation with a pharmacist is important both before initiating treatment with Cabenuva, and, if currently taking Cabenuva, before taking other prescription medicines, over-the-counter medicines and supplements.

Is one dose right for everyone?

As people age, their organs become less efficient at breaking down medicines. Research needs to be done with older people with HIV and Cabenuva to find out if different doses are needed. The doses of cabotegravir and rilpivirine are the same regardless of a person’s weight or body mass index (BMI). Research also needs to be done to better understand if people with a high BMI require a larger dose of long-acting cabotegravir or rilpivirine. Doctors in Switzerland plan to assess blood samples from a diverse range of people who are taking Cabenuva to try to find answers to some of these questions.

Other populations

Long-acting formulations of cabotegravir and rilpivirine have largely been tested in highly motivated adults who did not have competing issues and health conditions in their lives. These people were virologically suppressed prior to initiating Cabenuva and had a history of good adherence. However, Cabenuva’s long intervals between dosing may make it attractive for people who have complex lives and for whom adherence to daily pill taking has been difficult. The U.S. National Institute of Allergy and Infectious Diseases is sponsoring a clinical trial called Latitude. Potential participants will have a history of difficulty with adherence to oral ART.

Other injection sites

Currently Cabenuva is approved for injection deep into the buttocks. However, such injections are only possible with the help of healthcare personnel. Studies need to be done to explore other parts of the body, such as the thighs, that could be potential injection sites. It is possible that if the thigh muscle could be shown to be a depot for injectable treatment, then people who want the option of being able to self-inject Cabenuva could do so. This would add convenience and remove the need for visits to a healthcare provider just to get the drug injected.

About injecting

In multiple clinical trials, Cabenuva has been found to be generally safe and effective. The most common side effect involved reactions at the injection site. Data from clinical trials suggest that injection site reactions included redness, swelling and/or pain. In general, these side effects were mostly mild and resolved within a few days without intervention. Over time, injection site reactions became less common and less bothersome for many people.

The participants who were drawn to clinical trials of Cabenuva would have likely wanted long-acting treatment and were largely willing to tolerate discomfort and any pain that they would have experienced. Outside of clinical trials, it is likely that people who are interested in Cabenuva would also be willing to undergo regular intramuscular injections every month or two.

For the future

Cabenuva is the first long-acting regimen for HIV; several more will likely be developed in the years ahead. Doctors, patients, scientists and health policy analysts will be closely watching the deployment of Cabenuva. This scrutiny will help inform ways of improving access to Cabenuva and future formulations of long-acting HIV treatment.

—Sean R. Hosein


  1. Thoueille P, Choong E, Cavassini M, et al. Long-acting antiretrovirals: a new era for the management and prevention of HIV infection. Journal of Antimicrobial Chemotherapy. 2022; in press.
  2. de Los Rios P, Okoli C, Castellanos E, et al. Physical, emotional, and psychosocial challenges associated with daily dosing of HIV medications and their impact on indicators of quality of life: Findings from the Positive Perspectives Study. AIDS and Behavior. 2021 Mar;25(3):961-972. 
  3. Bares SH, Scarsi KK. A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV. Current Opinion in HIV/AIDS. 2022 Jan 1;17(1):22-31. 
  4. Hodge D, Back DJ, Gibbons S, et al. Pharmacokinetics and drug-drug interactions of long-acting intramuscular cabotegravir and rilpivirine. Clinical Pharmacokinetics. 2021 Jul;60(7):835-853. 
  5. Gulick RM, Flexner C. Long-acting HIV drugs for treatment and prevention. Annual Review of Medicine. 2019; 70:137-150.