Study confirms that long-acting injectable HIV treatment can work in people with multiple challenges

• Injectable HIV treatment has been found to be highly effective in clinical trials
• Researchers reported results with injectable treatment in 133 people with adherence challenges
• Rates of virological success were high and similar to those reported from large clinical trials

HIV treatment or antiretroviral therapy (ART) is highly effective when used as directed. This occurs because ART can suppress HIV levels in the blood and continued adherence (taking ART as directed) helps to keep HIV suppressed. As a result, the immune system can sufficiently repair itself so that the risk of AIDS-related infections becomes extremely rare. The power of ART is so transformative that researchers increasingly expect that many ART users will have near-normal life expectancy.

In addition to its effect on health, a suppressed viral load has another benefit. Clinical trials have found that people who initiate ART and achieve and maintain a suppressed viral load do not pass on HIV to their sexual partners.

The challenge of adherence

Although many ART users can adhere to treatment, large studies in Canada and the U.S. from the years 2010 to 2020 found that a significant proportion of people are not filling their prescriptions for ART on time. That is, there are gaps in their supply of ART. This would lead to non-adherence and an increased risk for HIV developing the ability to resist treatment. The reason(s) for non-adherence in these studies is not clear and requires investigation.

Some small studies have explored possible reasons for non-adherence and suggest that at least the following issues can play a role:

• stigma associated with HIV
• experiencing homelessness
• not having sufficient food
• unrecognized, untreated or poorly managed mental illness
• drug dependency

Long-acting HIV treatment

In late 2020, regulatory authorities in Canada and subsequently other high-income countries approved a long-acting injectable HIV treatment called Cabenuva. This is a combination of two drugs—cabotegravir + rilpivirine. Cabenuva is meant as a complete treatment for people whose HIV is already suppressed on an oral regimen and who would like to switch to injectable treatment. The drugs in Cabenuva are injected deep into the buttocks, one injection per buttock. These deep injections ensure that the drugs are released slowly into the blood. Cabenuva is injected by a healthcare provider.

Initial regulatory approval was for patients to first take cabotegravir and rilpivirine in pill form (the oral lead-in) and then switch to an injectable formulation. The injections were meant to be given every four weeks.

Subsequent data from clinical trials found that many people could go directly from their previous oral regimen to injectable treatment, bypassing the use of oral formulations of cabotegravir and rilpivirine. Also, clinical trials found that injections could be given every eight weeks. As a result, regulatory agencies revised their approval and allowed Cabenuva to be given without an oral lead-in. And, if the doctor and patient agreed, injections could ultimately be given every eight weeks.

The drugs in Cabenuva do not have activity against hepatitis B virus (HBV), so people co-infected with HBV need to take a pill daily to keep that virus suppressed.

Cabenuva is not meant for use by people who have HIV that is resistant to cabotegravir or rilpivirine.

Analysis of 1,651 people who have used Cabenuva in clinical trials found that 1.4% developed virological failure. Factors associated with an increased risk of virological failure included the following:

• having HIV that was resistant to rilpivirine
• having a variant of HIV-1 called subtype A1 or A6
• having a body mass index (BMI) of 30 mg/kg² or greater

Demonstration project in San Francisco

A team of researchers in San Francisco set up a demonstration project to find out if Cabenuva could successfully be used in patients with HIV who had one or more challenges, particularly the following: unstable housing, major mental illness, drug use (mostly methamphetamine) and insufficient access to food. Furthermore, some of the patients the researchers sought to serve had never been able to suppress HIV on oral regimens.

The team developed a support program and educated patients about the importance of adherence, regular clinic visits and other issues.

Initially, people who had HIV with a minor degree of resistance to rilpivirine or cabotegravir were allowed entry to the demonstration project. However, the researchers subsequently made entry criteria more restrictive and did not allow people into the project with any degree of resistance to these drugs.

The researchers analysed data from 133 people—76 entered the project already suppressed on an oral regimen and 57 were not suppressed.

All participants who entered the study suppressed on a pre-study regimen remained suppressed after they switched to Cabenuva. And 54 out of 57 people who entered the study with an unsuppressed viral load subsequently became suppressed after switching to Cabenuva.

Overall, 1.5% of participants developed virological failure. This is similar to the figure (1.4%) that has been found in clinical trials.

The demonstration project has found that a regimen of injectable ART can help the majority of people who are unsuppressed become virologically suppressed despite having one or more life challenges. It also found that people who were virologically suppressed prior to initiating injectable ART continued to be suppressed after switching to Cabenuva.

Long-term monitoring is needed to confirm and extend the promising findings reported from San Francisco.

Study details

Researchers assembled a team of staff who met regularly to develop and monitor the demonstration project, including doctors, nurses, a pharmacy supervisor, a pharmacy technician and so on. The team developed a protocol for who would be eligible for referral to the project, how injections would be administered, monitoring of patients, and other issues associated with the project.

Doctors and nurses outside of the project could refer patients to it. The pharmacy supervisor reviewed the medical records of referred patients and, if they were eligible, met with them. At these meetings, education and counselling about the importance of adherence was provided. Participants could come to a drop-in clinic for injections. Those who were more than seven days late for an injection appointment first had to take oral formulations of rilpivirine and cabotegravir to ensure that the levels of these drugs were adequate before they could resume injections.

People who had a BMI that was 30 kg/m² or greater got injections with longer needles to ensure that the drug penetrated deep into the buttocks.

The average profile of participants upon study entry was as follows:

• age – 45 years
• cisgender men – 88%
• cisgender women – 8%
• transgender women – 4%
• major ethno-racial groups: White – 38%; Hispanic – 32%; Black – 16%
• housing status: experiencing homelessness – 7%; unstable housing – 47%; stable housing – 58%
• current stimulant use – 34% (note that nearly 50% of people who had detectable viral loads at the start of the study were using stimulants)
• other long-term injections (of antipsychotics, naltrexone or hormones) were used by 12% of participants
• HIV-related test results: people whose viral load was suppressed (“undetectable”) by their pre-study regimen had a CD4+ count of 615 cells/mm³; people whose viral load was unsuppressed had a CD4+ count of 215 cells/mm³ and a viral load of 16,000 copies/mL

Results

As mentioned previously, 76 people had viral suppression on their pre-study regimen. All of these people maintained a suppressed viral load after switching to injectable ART. Five of these people subsequently chose to stop taking injectable ART and resume oral ART because they had injection site reactions. Three other people chose to return to oral ART because they found it difficult to visit the study clinic every four or eight weeks.

Among the 57 people who entered the study with an unsuppressed viral load, 54 (95%) were able to achieve a suppressed viral load on average 33 days after they first received injections. The researchers stated that for 19% of the 57 people, viral suppression was achieved for the first time in their lives thanks to the use of injectable ART. This is an important point because for some vulnerable populations barriers to adherence can be profound.

Virological failure or persistent low-level viral load

Two people had early virological failure. Another person was initially able to suppress HIV, but the virus subsequently became detectable. A fourth person had persistent low-level HIV after initiation of injectable ART. Here is what happened with all four people:

Patient 1

This person’s viral load decreased from 215,000 copies/mL to 39,000 copies/mL after initiation of injections. Analysis of their blood revealed HIV that was resistant to rilpivirine at the start of the study (prior to use of Cabenuva), and two weeks before injections, they had received an antibiotic (rifabutin) that can significantly reduce levels of cabotegravir in the blood. Injections were discontinued, and at the time the data were published, the patient had chosen not to initiate oral ART.

Patient 2

After initiation of injections, this person’s viral load fell from 137,000 copies/mL to about 4,000 copies/mL. At the time of the third series of injections, their viral load fell to less than 30 copies/mL (this was considered “undetectable”). Analysis of their blood samples found that HIV had developed resistance to both cabotegravir and rilpivirine. Injections were stopped and the patient was offered oral ART. However, at the time of the study’s publication, the patient had chosen not to initiate oral ART.

Patient 3

This person was initially able to suppress HIV after initiation of injectable ART. However, HIV subsequently became detectable. As a result, he stopped receiving injections and was given an oral regimen (consisting of darunavir + cobicistat + TAF + FTC) that was able to re-suppress HIV. This patient had a BMI of 32 kg/m² and healthcare providers forgot to use longer needles when injecting him with Cabenuva. He therefore developed less-than-ideal levels of cabotegravir and rilpivirine in his blood. Analysis of his blood samples did not find HIV that was resistant to these drugs.

Patient 4

This person had persistent low-level HIV (182 copies/mL) despite five rounds of injections of Cabenuva. Doctors then added another drug—lenacapavir (sold as Sunlenca)—to the regimen. After lenacapavir is taken in oral form for about a week, it is then given by injection just under the skin every six months.

Timeliness

Patients need to return to clinics every four or eight weeks for injections. Nearly 75% of all participants returned to the clinic on time. The researchers stated that some patients were highly motivated to continue injections. They also stated that strong relationships that formed between the clinic staff and patients helped many to stay in the demonstration project.

When patients were unable to get to the clinic in time, they were provided with oral formulations of ART to maintain HIV suppression.

Bear in mind

According to the researchers, “the main finding [of the demonstration project] showed that injectable ART maintained virological suppression in those who were receiving suppressive oral ART before switching, and nearly all patients who did not have virological suppression and were not using oral ART before [Cabenuva] initiation achieved suppression.”

In addition, the researchers stated that injectable ART has the potential to help people struggling with adherence in at least the following ways:

• It can minimize concerns about privacy that can arise when taking “oral ART regimens in group settings, such as shelters.”
• It can integrate the treatment of HIV and mental illness (for example, 8% of participants were taking long-acting antipsychotics, which can be injected at the same visit).

Although the report from the demonstration project is very promising, the researchers stated that long-term data are needed to confirm their findings.

—Sean R. Hosein

Resource

Researchers find that some Canadians with HIV have low levels of adherence to treatment — CATIE news

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