Modern antiretroviral therapy (ART) — the term for HIV treatment regimens — has come a long way over the past four decades. Now, many people live full lives with well-controlled HIV, without developing AIDS. However, for some people, ART has drawbacks.

Most therapies come in pill form, which poses problems for people who have trouble taking them. Additionally, all oral ART must be taken daily — sometimes, multiple times per day — and remembering to take the medication can be challenging. In a 2021 retrospective study of more than 200,000 people with HIV in the U.S., researchers found 60 percent had “suboptimal” or “poor” adherence to their prescribed ART treatments.

Being inconsistent with your HIV medications can have serious ramifications: You can develop what’s called drug-resistant HIV, a form of HIV that can’t be controlled by treatments that may have previously worked.

New injectable therapies are promising, long-lasting alternatives that don’t require daily administration. In this article, we’ll look at some of the newer injectable treatments for HIV and how they compare to oral treatments.

Injectable Medication for HIV Treatment

In January 2021, the U.S. Food and Drug Administration (FDA) approved an HIV treatment called Cabenuva. Cabenuva is a combination of cabotegravir and rilpivirine — both extended-release injectable medications. It’s the first injectable treatment for HIV approved by the FDA.

Cabotegravir and rilpivirine lead to viral suppression in someone living with HIV, but in different ways. Cabotegravir is an integrase inhibitor. This means it stops the integrase protein, thereby preventing the virus from integrating into the human DNA and then making more copies of HIV.

Rilpivirine is an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI). Drugs in this class stop an HIV protein called reverse transcriptase. Reverse transcriptase is also necessary for HIV to make copies of itself, and NNRTIs prevent this from occurring.

Cabenuva is designed to be administered once per month as an injection into the muscle of the buttocks. If the monthly injections are working well, sometimes switching to one dose every two months is an option.

Cabenuva is designed to replace the current ART regimen of daily pills for people with well-controlled and stable HIV. People who have well-controlled HIV are considered virologically suppressed or “undetectable.” A person is considered to have well-controlled HIV — and be a possible candidate for Cabenuva — if their viral load (HIV levels in the blood) is less than 50 copies per milliliter for three to six months. People who receive Cabenuva should also have no known drug resistance to either cabotegravir or rilpivirine.

It’s important for anyone taking Cabenuva to get their injections on time to help prevent developing drug-resistant HIV.

Before starting injectable Cabenuva, you may have the option to take the oral formulations of cabotegravir (Vocabria) and rilpivirine (Edurant) for one month. This practice is called oral tablet lead-in. Taking the oral tablets first can establish how well you would tolerate these medications and determine if you would experience any side effects.

The extended-release cabotegravir component of Cabenuva can last up to 12 months in the body. This is why an oral tablet lead-in might be a good idea to assess tolerance and toxicity before receiving the injections that last a lot longer. Not everyone does the oral tablet lead-in before starting Cabenuva. Ask your doctor what approach would be best for you.

If the oral tablet lead-in goes well, you should be able to start monthly injections of Cabenuva. If you plan to miss an injection by more than seven days, you can take cabotegravir and rilpivirine orally until the next injection of Cabenuva. Missing or taking very late doses of Cabenuva can result in resistance to both cabotegravir and rilpivirine.

Injectable Medication for HIV Prevention

In December 2021, the FDA approved Apretude — an extended-release injectable formulation of cabotegravir — as a preventive treatment for adolescents and adults who are HIV-negative but at risk of being infected by HIV. Preventive medication given before possible exposure to HIV is called preexposure prophylaxis (PrEP).

Apretude is administered as an injection into the buttocks initially once a month for two months and then every two months after that. You must have a documented negative HIV test before starting Apretude.

Benefits of Extended-Release Injectables

Sticking to ART or PrEP medicines can be difficult because the pills must be taken at least once daily to control or prevent HIV infection. Sometimes treatment requires several different pills or requires you to take pills taken many times per day. An online survey by pharma company ViiV uncovered some reasons why people struggle with taking pills daily, including:

• Emotional issues, such as anxiety over missing a dose or taking it late
• Privacy concerns, such as fear that carrying around and taking medications every day increases the chances of others learning about their HIV status

Although injections can be painful and require administration by a nurse, Cabenuva and Apretude are only administered every one to two months. The relatively low level of maintenance can be beneficial. Research has shown that people who have difficulty adhering to an oral-medication regimen are more likely to stick to their treatment plan if they switch to long-acting injectables.

More recent research suggests that people who had difficulty sticking to a daily regimen of oral ART could be more likely to achieve viral suppression if they switch to long-acting ART. However, further studies are needed to confirm this.

Cabenuva is just as effective at treating HIV as the oral pill alternatives cabotegravir and rilpivirine. In clinical trials, a higher percentage of participants receiving the injectable therapy maintained well-controlled HIV by the end of each clinical trial, compared to those taking the pills.

In a study with cisgender men and transgender women who have sex with men, long-acting injectable Apretude administered as PrEP was found to be more effective at preventing HIV than emtricitabine/tenofovir disoproxil fumarate (Truvada), a once-daily pill used for PrEP. Although both the oral and injectable drugs were considered “highly effective,” the study authors concluded Apretude was even more effective because it was easier to take consistently.

In clinical trials to date, researchers have found injectable cabotegravir taken either every month or every two months to be well tolerated. Mild injection-site reactions were the most common side effect.

A possible downside to taking injectable Apretude for PrEP is that a person can acquire drug resistance to medications within the integrase inhibitor class. If a person does acquire HIV while taking injectable PrEP with cabotegravir, then treating the HIV may be more difficult.

People starting PrEP with this medicine must be well screened for HIV at the start of therapy, one month into treatment, and then at least every two months while on treatment. If a person waits longer than two months after their most recent injection, they must switch to oral PrEP treatment and/or use condoms or abstinence consistently to avoid developing HIV infection resistant to the integrase class of medicines.

Injectables for Those Who Are Resistant to Other HIV Medications

In addition to the two medications mentioned above, the FDA has approved injectable treatments intended for people who are resistant to other HIV medications. They include a formulation of lenacapavir called Sunlenca and a formulation of ibalizumab-uiyk called Trogarzo. Keep in mind that both of these drugs need to be taken alongside other HIV medications — most often, daily pills — to be effective. This offsets one of the key benefits of taking just one extended-release injectable.

Sunlenca is an HIV capsid inhibitor, approved by the FDA in December 2022. It works by disrupting the assembly and disassembly of HIV capsid (the protein shell of a virus), thereby preventing the virus from infecting cells and forming new viruses. Initially, you’ll need to take an oral version of the drug for up to a week. Taking the oral form helps ensure you can tolerate it. From there, though, only two injections are required per year.

Trogarzo is a laboratory-engineered antibody that specifically targets the CD4 receptor on T cells, a key entry point for HIV to infect these cells. The drug prevents HIV from attaching to and entering T cells, thereby blocking the infection process at a critical stage.

Ibalizumab was first approved in 2018 for administration via an IV infusion, starting with a single loading dose followed by additional doses every two weeks. The FDA approved a new version of the drug in October 2022. It’s also delivered via an IV every two weeks, but the infusion takes 30 seconds instead of 15 minutes.

Side Effects of Injectables

Researchers have observed some side effects from these injectables, some of which they share in common and some of which are unique to each individual drug.

It’s important to remember that every medication has potential side effects, and experiences will vary from person to person. Communicate with your health care provider about any treatment side effects you may experience. They can help you manage them or, if necessary, find an alternative treatment.

Common Side Effects

Common side effects for all four medications include injection site reactions, which can include pain and swelling. Nausea and rash are also commonly reported for these treatments.

More severe but less common side effects shared among these treatments include hypersensitivity reactions, which may manifest as severe rash, fever, or difficulty breathing.

Immune reconstitution syndrome (IRIS) is another potential concern. It occurs when a person's immune system starts to recover, but then has an inflammatory response to a previously acquired infection. IRIS may occur with any ART medication that results in the strengthening of the immune system.

Drug-Specific Side Effects

Uncommon but possible side effects for Cabenuva include fatigue, fever, nausea, depression, and muscle or bone pain. Liver toxicity (damage to the liver) can occur, especially in people previously diagnosed with hepatitis B or hepatitis C.

Rare but serious side effects for Apretude include the risk of drug resistance when it’s used for HIV-1 PrEP by someone with an undiagnosed HIV-1 infection. Other side effects listed on the drug’s label include gas, stomach pain, vomiting, muscle pain, decreased appetite, depression, drowsiness, back pain, and upper respiratory tract infection.

Sunlenca’s prescribing information warns that the drug could remain in a person’s system for 12 months or longer, potentially affecting how the body absorbs and processes other drugs. As with any new medication, a doctor or pharmacist would need to check for any drug interactions.

Trogarzo’s side effects may include diarrhea, dizziness, nausea, and rash. These side effects were all listed as mild to moderate in the studies for drug approval.

For Cabenuva, Apretude, Sunlenca, and Trogarzo, there haven’t been enough studies on the use of these medications during pregnancy to adequately assess a risk of birth defects and miscarriage. If you have questions regarding pregnancy or breastfeeding and these medications, ask your doctor.

Getting the Medications

Finding and paying for any of these medications may pose some challenges. Some Medicare and Medicaid plans may cover Cabenuva or Apretude. Contact your insurance company to ask about coverage.

Medications such as Trogarzo and Sunlenca may also be covered, but they will likely require a special letter from your doctor to the insurance company. These medications will likely also need to be obtained from a specialty pharmacy and will take more time and effort to get. Your doctor’s office, pharmacist, and insurance company will be your best source of information.

U=U Campaign

The U=U campaign is spreading awareness about the power of HIV therapy. “U=U” stands for “undetectable equals untransmittable.” The name of the campaign refers to the fact that people who are HIV-positive and maintain undetectable viral loads are unable to spread the virus through sexual activity.

The campaign is based on three large clinical trials — from The New England Journal of Medicine, JAMA, and The Lancet HIV — that determined that HIV-positive individuals didn’t pass HIV to their partners sexually if their HIV was undetectable for a certain period of time. These studies illustrate the importance of becoming undetectable. The new injectables for HIV treatment and prevention may be the key to remaining undetectable and therefore helping prevent the spread of HIV.

Injectables and myHIVteam Members

Although new injectable HIV medications may not be the best choice for everyone, they offer a promising way for many to gain better viral control — and therefore improved quality of life. Many myHIVteam members are excited about the possibilities of these formulations.

“For me it was a game changer!” one member shared. “Not having to take a pill every day, especially while on vacation. … Mine were a piece of cake. I highly recommend, but I know everyone’s different.”

“I’m currently on a once-a-month injectable study. I love it,” shared another member. “I do experience soreness at the injection site, but that lasts maybe two days at most. Sometimes, not at all.”

Research into injectable HIV therapies is ongoing, and the future looks bright for people living with HIV. If you think injectables are a good fit for your goals while living with HIV, contact your health care provider.

Talk With Others Who Understand

On myHIVteam, the social support network for those diagnosed with HIV, you can connect with others. Members come together to ask questions, give advice, and share their stories with others who understand.

Are you interested in injectables for HIV treatment? Have you tried them? Share your insights in the comments below, or start a conversation by posting on myHIVteam.