Long-acting HIV treatment in people with multiple challenges

When effective HIV treatment (ART) first became available, it involved taking a fistful of pills at least twice daily, often with food and water requirements. Although these early treatments were life-saving, they had many side effects. About 18 years ago, pharmaceutical companies created the first regimen in an entire pill—sold as Atripla. In addition to packing an entire regimen into one pill, Atripla needed to be taken just once daily. Subsequently, other once-daily regimens in a pill were developed. This ensured that for many people with HIV, treatment could be as simple as one pill taken once daily. This development of treatment simplification greatly enhanced adherence for many people.

For ART to be effective, treatment has to be taken daily as directed. According to a team of researchers in San Francisco, daily pill-taking can be difficult for some people for at least the following reasons:

• over the long-term people may become frustrated at having to take pills
• taking pills can remind people that they have HIV
• if pill-taking is observed by others, they can inadvertently disclose that a person has HIV
• some people may not have a place to store pills safely

The first long-acting treatment

In 2020 Health Canada approved a long-acting formulation of ART. This formulation is called Cabenuva and consists of two drugs—cabotegravir + rilpivirine. Cabenuva is meant to replace an existing treatment regimen in people whose viral loads are suppressed. Cabenuva is administered by a healthcare practitioner (usually a nurse) as one injection deep into each buttock (for a total of two injections) monthly for two consecutive months. After this time, it can be injected every two months or once a month.

Cabenuva has the potential to address many of the issues that some people with HIV can face with daily pill-taking. Note that Cabenuva is meant to be used by people who have HIV that is not resistant to it.

Cabenuva does not treat hepatitis B virus (HBV); some people are co-infected with both HIV and HBV. Co-infected people require a daily pill to help keep HBV suppressed. Doctors usually use one of the following pills for this purpose:

• tenofovir DF + FTC – sold as Truvada and available in generic formulations
• tenofovir alafenamide (TAF) + FTC – sold as Descovy

In the everyday world

Cabenuva has been tested in more than 1,000 people with HIV in clinical trials. As with many other studies, the people in clinical trials of Cabenuva were carefully selected. They did not have issues that could affect daily pill-taking, they were willing to undergo the deep intramuscular injections that are required, and they could keep clinic appointments, particularly for repeated injections, and laboratory visits for blood tests.

Researchers at San Francisco General Hospital conducted a small demonstration project to explore the effect of Cabenuva in people with complex lives and adherence issues. They enrolled 39 people with HIV who had adherence challenges due to mental illness, stimulant use and/or insecure housing.

The researchers developed what they called a “patient-centred [Cabenuva] care delivery program in an academic HIV clinic that serves urban [patients] with high levels of psychosocial and economic vulnerability.” Some of these patients had a detectable viral load before initiating Cabenuva. However, over the course of a year, a majority of the 39 patients achieved or maintained a suppressed viral load while on Cabenuva.

The study’s findings are promising and should stimulate other researchers to conduct larger and longer demonstration studies in vulnerable populations. Such studies will require adequate funding to provide the array of services needed by these populations.

Study details

The researchers developed a program to support patients and their care providers and promote adherence to Cabenuva injections.

Researchers did not enroll patients who had mutations, or changes, in HIV’s genetic material that allowed the virus to resist the effect of rilpivirine (this drug is a non-nuke and one of the two medicines in Cabenuva). People who had no or only one mutation associated with resistance to integrase inhibitors (cabotegravir, the other drug in Cabenuva, is an integrase inhibitor) were allowed to enter the program. This is because modern integrase inhibitors are robust drugs that usually require several mutations before HIV can wholly resist them.

People who were co-infected with HBV and who were willing to take HBV treatment were allowed to be considered for entry into the program.

Potential participants were referred to a team pharmacist who checked their lab test results, particularly to ensure that HIV was not resistant to the drugs in Cabenuva. The pharmacist also reviewed other medicines that the patient was taking to ensure that there were likely no unfavourable drug interactions once Cabenuva was injected. As well, the pharmacist also checked their HBV infection status and, if necessary, HBV treatment was initiated or maintained.

Direct to injection

When Cabenuva was initially approved in 2020, patients first had to take several weeks of the oral formulations of cabotegravir and rilpivirine (the drugs in Cabenuva). Once they completed this, and there were no issues, they could then switch to the injectable formulation.

In the past several years, ViiV Healthcare, the developer of Cabenuva, has tested a different approach called “direct to injection.” That is, people whose viral loads were suppressed on oral formulations (of drugs other than cabotegravir or rilpivirine) could simply switch from their oral regimen and go directly to injections of Cabenuva. This direct-to-injection approach has proved successful. Therefore, direct to injection of Cabenuva has been approved as an option for patients by regulatory authorities in Canada, the European Union and the U.S.

The program in San Francisco favoured the direct-to-injection approach. The researchers stated that they felt this approach was necessary because they were concerned about potential problems with pill taking by patients.

The study team developed individualized plans to help patients return to the clinic for future injections of Cabenuva. Such plans included:

• identifying community-based support, such as case managers, nursing services that were available for people at home or for those who were experiencing homelessness, and harm reduction sites
• providing small financial incentives to encourage return visits to the clinic or lab

Every two weeks a multidisciplinary team consisting of a doctor, nurse and pharmacist would meet to review the progress of patients in the program.

During the first week after people had their first injection, pharmacy staff would phone the patient to enquire about their health and any side effects they may have experienced. Subsequently, staff would send reminders about future appointments via text or phone call.

People who entered the study with a detectable viral load underwent viral load testing every four weeks until they developed an undetectable viral load (this is called viral suppression). For this study, an undetectable viral load was less than 30 copies/mL. In cases where the viral load remained detectable, resistance testing was done after the second clinic visit.

Although care providers referred 132 people in the first year of the program, only 51 people initiated Cabenuva injections. In many cases this was because the referral procedure was incomplete or the patients (or their care providers) decided to delay initiation of Cabenuva. Some of the 51 people only had two injections of Cabenuva at the time the report on the study was written. This left the researchers with data on 39 people who had at least several injections of Cabenuva. The researchers decided to focus on these 39 people, as they could provide a fuller report of their experience with multiple injections of Cabenuva.

The average profile of people who initiated Cabenuva was as follows:

• age – 46 years
• 35 were cisgender men, three were cisgender women, and one was a transgender woman
• major ethno-racial groups: White – 39%; Hispanic – 26%; Black – 21%
• 40% had unstable housing or were experiencing homelessness
• 54% were currently using stimulants
• CD4+ counts – among people with detectable viral loads, the CD4+ count was 99 cells/mm³; among people with viral suppression, the CD4+ count was 732 cells/mm³
• five people were also taking long-acting medicines unrelated to HIV, including antipsychotics (four people) and naltrexone (one person)

Commonly used HIV drugs prior to switching to Cabenuva included the following (in decreasing frequency of use):

• Biktarvy – bictegravir + TAF + FTC
• darunavir + cobicistat + TAF + FTC
• Triumeq – dolutegravir + 3TC + abacavir
• Delstrigo – doravirine + TDF + 3TC

Results

Among 24 people who entered the program with an undetectable viral load (prior to initiating Cabenuva), 19 people (almost 80%) subsequently maintained an undetectable viral load over an average of six injections.

There were 15 people who entered the program with a detectable viral load (around 50,000 copies/mL) and a very low CD4+ count (around 99 cells/mm³). In this group, 12 out of 15 people (80%) achieved and maintained an undetectable viral load over an average of six injections. Among the three people who did not achieve this milestone, their viral load fell 100-fold 22 days after they initiated Cabenuva. Data collection from these three people is ongoing, and researchers expect that they will eventually achieve an undetectable viral load.

Side effects

Reactions at the site of injections were generally mild to moderate. None of the participants quit Cabenuva because of such reactions. One person developed a bacterial skin infection at the Cabenuva injection site. This person received oral antibiotics and recovered.

Adherence to clinic visits

Returning to the clinic for continued injections is important so that levels of cabotegravir and rilpivirine remain high in the blood and are able to suppress and keep HIV suppressed. According to ViiV Healthcare, “the date of the first initiation injection becomes the target treatment date going forward. The dose can be given up to 7 days before or 7 days after the target treatment date.”

Thus, there is a window of seven days before and after the appointment for the next dose within which the next injection for Cabenuva must occur—or else levels of the drug can fall below an acceptable level. In cases when people miss this window period (we refer to this as late appointments), they need to switch to oral formulations to ensure that their drug levels are maintained. After a few weeks of oral formulations, they can return to injections. However, repeated missed appointments for injections may flag that there are issues that require attention from patients and their care providers.

Researchers designated certain days at the clinic as “injection days,” whereby patients could drop into the clinic at a time convenient to them to receive their injections.

Thirty-four people (87%) attended the clinic in a timely manner. One person was late for one injection and two others were late for two injections each.

In two cases of late visits for injections, patients had to temporarily take oral formulations of Cabenuva to quickly raise their levels of cabotegravir and rilpivirine in their blood and minimize the chances of HIV developing resistance.

Two other people who were experiencing homelessness had help from street-based nurses and received their Cabenuva injections at a mobile harm reduction van or at a community clinic. Researchers noted that one person even received viral load monitoring through the harm reduction van.

Bear in mind

The present study has found that Cabenuva can be successfully deployed in a patient population experiencing challenges. The researchers found it “striking” that people with detectable viral loads were able to achieve an undetectable viral load once on Cabenuva. In some cases, viral suppression occurred for the first time in their lives.

The researchers cooperated with organizations in the community (nursing services, clinics, harm reduction sites) so that Cabenuva injections could occur, if necessary, outside of the main study clinic. Such cooperation would be essential in the future if Cabenuva can be successfully expanded to people who use drugs or people who are experiencing mental health issues and/or homelessness. Studies of Cabenuva are also needed in rural areas.

The study did not have people who were under the age of 30 and there were a small number of women. The study itself was small, but that is often the case with demonstration projects.

Still, the study’s findings are promising and pave the way for future demonstration projects with larger numbers of people for longer periods. Such studies are important because pharmaceutical companies are developing other long-acting formulations of ART.

—Sean R. Hosein

REFERENCES:

1. Christopoulos KA, Grochowski J, Mayorga-Munoz F, et al. First demonstration project of long-acting injectable antiretroviral therapy for persons with and without detectable HIV viremia in an urban HIV clinic. Clinical Infectious Diseases. 2022 Aug 1:ciac631. 
2. ViiV Healthcare. Vocabria/Cabenuva. Product monograph. 15 June 2022.