What do we know about injectable HIV medication?

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This page is about injectables used for HIV treatment, rather than prevention of infection (PrEP). We have another page on injectable cabotegravir for PrEP.

Which medications can be taken by injection?

The first complete HIV treatment provided by long-acting injections is a combination of two medications. Cabotegravir belongs to the same class of medication – integrase inhibitors – as the widely used HIV medication dolutegravir. The second medication is called rilpivirine and is already used for HIV treatment in tablet form. It is from a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs).

 

In Europe, the brand name for injectable cabotegravir is Vocabria, while the brand name for injectable rilpivirine is Rekambys. In North America and Australia, the two drugs are packaged together, with the brand name of Cabenuva.

Cabotegravir and rilpivirine can be taken either once a month or every two months. For more information on this, see How frequent are the injections? on this page.

Pharmaceutical companies are researching other long-acting medications. See the last question on this page for more information.

You can find out more about cabotegravir and rilpivirine in our factsheet and in our detailed page in the A-Z of antiretroviral medications.

Is injectable treatment available?

The injectable combination has been approved by drug regulators in the European Union, United Kingdom, United States, Canada and Australia. In many countries however, the injections are not yet available in clinics and decisions on reimbursement still need to be made.

In the United Kingdom, NHS clinics are expected to begin providing the injections in the spring of 2022. Elsewhere in Europe, countries with access include France, Germany, Sweden, Norway, Finland, Denmark, Belgium and The Netherlands.

They are not yet available in the global south but the pharmaceutical companies say they are preparing for regulatory submissions in a number of low- and middle-income countries. They will also need to come to agreements on licensing and patents that would make the injections affordable.

Are the injections better than tablets? 

No, their efficacy is comparable. The cabotegravir and rilpivirine injectable regimen was approved by drug regulators based on the results of three randomised control trials:

  • The first study involved people who hadn’t taken HIV treatment before. All started with daily pills for around four and a half months (20 weeks to be precise). Half then continued with daily pills, while half switched to monthly injections.
  • The second study recruited people who were already taking HIV treatment and had an undetectable viral load. Half continued with their daily pills, while half switched to monthly injections.
  • As a follow-on from the second study, the third study compared injections once a month with injections once every two months.

Each of the studies assessed the success of treatment in terms of how many people had an undetectable viral load after just under a year. Pooling the results of the three studies, this was the case for 94% of people given the injections. The first two studies found that the monthly injections were as effective as daily pills. (In research terminology, they were ‘non-inferior’.) Similarly, the third study found that injections every two months were non-inferior to monthly injections.

Visit the A-Z of antiretroviral medications to find out more about these research studies.

Does injectable treatment help with adherence?

We don’t know yet, but long-acting technologies are already used for other health issues, such as contraception, osteoporosis and psychiatric treatment. This experience suggests that long-acting medications may help people miss fewer doses and it is plausible that this could also be true for HIV. However, the studies which led drug regulators to approve cabotegravir and rilpivirine only gave the injections to people who had already had good adherence to daily pills.

Glossary

antiretroviral (ARV)

A substance that acts against retroviruses such as HIV. There are several classes of antiretrovirals, which are defined by what step of viral replication they target: nucleoside reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; entry inhibitors; integrase (strand transfer) inhibitors.

adherence

The act of taking a treatment exactly as prescribed. This involves not missing doses, taking doses at the right time, taking the correct amount, and following any instructions about food.

long-acting

In pharmacology, a medication which maintains its effects over a long period of time, such as an injection or implant.

oral

Refers to the mouth, for example a medicine taken by mouth.

middle income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. There are around 50 lower-middle income countries (mostly in Africa and Asia) and around 60 upper-middle income countries (in Africa, Eastern Europe, Asia, Latin America and the Caribbean).

Given that the injectables are thought to have advantages for people who struggle with adherence to daily pills, this research gap may seem surprising. One US study is now investigating whether the injectables are a good option for people who struggle with adherence or whose current HIV treatment is not working well.

Rather than adherence to daily pills, cabotegravir and rilpivirine require adherence to healthcare appointments once a month or once every two months. We don’t yet know how well people will stick to this when injections are provided in regular healthcare settings, rather than in research studies.

What are the side effects?

Around three-quarters of people who take cabotegravir and rilpivirine have injection site reactions such as pain, bumps and swelling. They typically last a few days, and tend to become easier to tolerate after the first few injections. Very few participants dropped out of the studies due to these reactions.

Other common side effects are headache, raised temperature and feeling hot.

There’s more information about side effects in our factsheet and in our detailed page in the A-Z of antiretroviral medications.

Where are the injections given?

Both injections are given into the muscle of the buttocks, a few minutes apart, by a healthcare professional. As cabotegravir and rilpivirine must be injected into a muscle large enough to take the required volume of medication, the buttocks are considered to be the only feasible site. Self-injection is not currently an option.

How frequent are the injections?

Injectable cabotegravir and rilpivirine can be taken either once a month or every two months.

When taking standard HIV treatment, you need to take your tablets every 24 hours to have enough levels of the medications in your blood. Injectable cabotegravir and rilpivirine have long half-lives, meaning they can stay in the body for much longer than the tablets. This makes long-acting treatment possible: injections every one or two months are enough to maintain high enough blood levels of the medication to suppress HIV.

Your doctor will tell you whether you need to attend each month, or every two months, for your injections. The frequency of injections may depend on your country. For example, the pharmaceutical company has decided that in Europe it will only sell the dosage required for the every-two-months regimen. (Depending on whether the injection is every one or two months, different doses are given.)

Is it necessary to take daily tablets before having the injections?

It’s often recommended to start by taking cabotegravir and rilpivirine pills once a day for a month, before beginning the injections. This is known as an ‘oral lead-in’.

The rationale is to ensure that the medications are well tolerated since the content of an injection cannot be removed if it causes problems. Nonetheless, safety concerns have not emerged from the trials so far, and there are some data suggesting the oral lead-in is not necessary. European regulators have now approved provision without an oral lead-in.

What happens if you are late for an injection?

The injections do require people to attend injection appointments regularly. Nonetheless, there is a 14 day dosing window – it’s OK to have the injection up to seven days before or up to seven days after the regular date.  Having the injections on time is particularly important for those using the every-other-month regimen. The once-monthly schedule may be more forgiving.

If you know you won’t be able to attend an injection appointment (for example, if you are travelling), you will be given a supply of cabotegravir and rilpivirine tablets to take each day until you can go back for more injections.

How long do the drugs stay in the body after an injection?

The injectable medications persist in the body for several weeks or months after a last injection, slowly declining over time. It is estimated that the ‘half life’ (how long it takes for the drug concentration in blood to be reduced by 50%) of cabotegravir is between five and 12 weeks, while that of rilpivirine is between 13 and 28 weeks. In some people, traces of the drugs can still be found one year after their last injection.

This raises concerns about drug resistance. If you stop receiving the injections and do not switch to another HIV treatment, there will be a lengthy period during which resistance could develop. Drug resistance can only develop in situations like this when there is some HIV medication in the blood but not enough to fully suppress the virus.

For this reason, if you stop the injections, it is essential to switch to an alternative HIV treatment regimen. If you have been having the injections once a month, you should switch to your new treatment within one month of your final injection. If you have been having them once every two months, you should switch within two months.

Who can take them?

Injectable cabotegravir and rilpivirine are licensed for adults with a viral load under 50 on a stable oral antiretroviral regimen, and without any evidence of resistance to integrase inhibitors (like cabotegravir) or NNRTIs (like rilpivirine). That could potentially be a large number of people currently taking HIV treatment.

However, they are not currently licensed for people who have difficulties with adherence to daily pills or whose current HIV treatment is not working well.

Also, they cannot be used for someone starting HIV treatment. If someone new to HIV treatment does want to use them, they would need to take an oral antiretroviral regimen for a few months first and achieve viral suppression on that, before switching to the injections.

They are not licensed for children, adolescents, or during pregnancy or breastfeeding, as they have not been studied in these groups. They are not suitable for people who have hepatitis B co-infection (who should take a drug combination that includes medications that are active against both HIV and hepatitis B).

Who might get the most benefit from injectable treatment?

Surveys suggest that large numbers of people living with HIV would be interested in trying injectable treatment. Nonetheless, providing injections requires extra staff and resources, so they won’t necessarily be made available to all people living with HIV, but may be prioritised for individuals who are most likely to benefit.

Many people with HIV are fed up with taking pills every day or find it a constant reminder of their HIV status. For people who wish to keep their HIV status private, switching to injections may increase confidentiality and privacy. For example, they could help people who live in shared accommodation and currently feel the need to hide their medication. There could be advantages for people who are homeless, in prison or who use drugs. Injectable HIV treatment will suit people who are able to stick to clinic appointments, even if they struggle with daily pills. However, cabotegravir and rilpivirine is not yet approved for people with adherence challenges.

The injections may be practical for people who are travelling, especially to countries which restrict entry to people living with HIV. They may also provide an option for people who have specific challenges such as swallowing difficulties, drug malabsorption or gastrointestinal conditions.

For some other people living with HIV, the disadvantages may outweigh the benefits. Patients who may currently only visit their clinic twice a year will need to come in six or 12 times a year, which could be inconvenient. The need to take time away from work or personal responsibilities could lead to unwanted disclosure of HIV status for some. Some people dislike injections or the pain they can cause. Many people living with HIV feel comfortable and confident taking pills every day, and would still need to have daily medication for other health conditions even if their HIV treatment was less frequent. Some people feel uncomfortable with the idea of having an active medication in their body for several weeks or months at a time, and being unable to change that once it has been administered.

People who have taken injectable treatment as part of research studies have generally been very satisfied with it. Some more ambivalent views have been expressed by other people with HIV in studies in France and the United States.

How will health services adapt?

Arrangements for providing the injections are likely to vary considerably between countries, due to different health systems, policy challenges and funding arrangements. In many places, the injections will probably be initially provided at specialist HIV services; it may take some time for more convenient community-based services to be put into place.

HIV services will need to make some adjustments to their clinics. Patients who may currently only visit their clinic twice a year will be attending six or 12 times a year. Administration of injections is resource-intensive, requiring more staff time and clinic space than oral therapy. Clinics must establish a system to schedule and track injection appointments, send reminders, and trigger intervention for people who are late for a dose. Staff need to be trained in the injection technique and on how to support patients.

You can read about early adopters’ experience implementing injections in our news reports, here, here and here.

Will injectable HIV treatment be practical in low- and middle-income countries?

So far, long-acting antiretrovirals have primarily been studied in mostly men from higher income countries, which is not representative of the global HIV epidemic. Research in more diverse settings is needed.

The cost of cabotegravir and rilpivirine could be a significant barrier to provision in low- and middle-income countries. Highly effective and safe oral antiretroviral therapies already exist, at a cost of less than US$80 a year, and the injectables’ price will need to be competitive against this. The work processes of already over-burdened clinics will need to be rethought, or alternative service providers identified.

Several African countries do already have large programmes providing contraceptive injections, suggesting it may be feasible to administer injectable HIV treatment too. However, there may be extra challenges. Rilpivirine needs to be stored in a fridge (whereas the contraceptive injection does not); cabotegravir and rilpivirine is not suitable for people with HIV and hepatitis B co-infection (which is common in many African and Asian countries); and they should not be used at the same time as some tuberculosis medications (rifampicin and rifapentine).

Will other injectable medications be available in the future?

Developing new long-acting medications is currently a major focus of pharmaceutical companies’ research. As many of the daily pills for HIV treatment are highly effective and well tolerated, creating simpler treatment options is seen as the main way to make progress. Various companies are trying to develop intramuscular injections, subcutaneous injections, infusions, implants, patches and pills.

This process is not smooth, with many potential products failing for one reason or another. For example, several clinical trials of islatravir, which had been considered to be one of the most promising new antiretrovirals, were halted in December 2021 due to declines in immune system cells in some people taking the medication. It had been hoped that islatravir could be given as a weekly or monthly pill, or as an implant lasting a year.

The new agent lenacapavir also shows promise. It is a capsid inhibitor that is being trialled as subcutaneous (under the skin) injection in the belly, once every six months. Initial results in people with extensive drug resistance are encouraging, and there are also early results from people using the drug as part of their first HIV treatment. However, for treatment every six months to become a reality, researchers will need to find a second medication which also only needs to be taken every few months.

Several broadly neutralising antibodies (bNAbs) are being studied for HIV treatment, prevention and long-term viral remission. One phase II study is pairing VRC07-523LS (a bNAb, given as an infusion every two months) with cabotegravir (given as an injection every month). Another is pairing 3BNC117 (a bNAb, given as an infusion every two or four weeks) with albuvirtide (a fusion inhibitor, given as a weekly injection).

Other medications in development include leronlimab (PRO 140, a CCR5 antagonist, given as a weekly subcutaneous injection) and UB-421 (a CD4 attachment inhibitor, given as an infusion every two weeks).

It’s also worth noting that one long-acting infusion is already available: ibalizumab is a post-attachment inhibitor, taken every two weeks for treatment of multidrug-resistant HIV. However, it must be taken in combination with daily tablets.

Next review date