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A large study assesses levels of medicines in long-acting HIV treatment

The first complete regimen of long-acting HIV treatment is a combination of two drugs—cabotegravir + rilpivirine. These may initially be taken orally and after a few weeks they are injected. However, many doctors and patients agree to bypass the use of oral formulations of these drugs and go directly to injections. The injections are administered deep into the buttocks, initially once a month and then every two months. In Canada, the U.S., Australia and some other countries, the long-acting formulation of these drugs has been approved and is called Cabenuva.

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In clinical trials, the long-acting formulation of cabotegravir + rilpivirine is highly effective at suppressing HIV and is generally well tolerated. Some people develop injection site reactions such as pain, redness and swelling, but these are usually temporary and resolve within a day or two.

Although Cabenuva is the first long-acting combination approved for HIV treatment, pharmaceutical companies are working on developing other such formulations. In the meantime, additional research with long-acting cabotegravir + rilpivirine continues.

In France

Researchers in France conducted a study with 736 people with HIV who used long-acting cabotegravir + rilpivirine. The researchers primarily focused on analyzing blood samples to measure the concentration of these drugs at different points up to 18 months after participants entered the study. They found that body mass index (BMI), specifically obesity, was linked to lower-than-normal levels of the study drugs; this, in turn, was linked to an increased risk for virological failure (persistently detectable HIV). The researchers stated that their findings underscore the importance of therapeutic drug monitoring (TDM), particularly in people with obesity. 

Study details

In 2022, researchers in 14 clinics across France recruited participants for this study. Most were assigned male at birth (79%). Before entering the study, participants had been on other regimens and were largely virally suppressed. 

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

  • age – 41
  • BMI – 24.5 kg/m2 for most participants (54%). However, 33% were overweight (having a BMI between 25 and 30), and 11% were classified as obese (having a BMI of 30 or greater). 
  • time since HIV diagnosis – 11 years
  • CD4+ count – 762 cells/mm3
  • lowest-ever CD4+ count – 332 cells/mm3
  • suppressed viral load (less than 50 copies/mL) – 97% 
  • most participants (nearly 60%) were infected with HIV subtype B and six participants had subtype A6/A1; information on the HIV subtypes of the rest of the participants was not available

For the most part, people were in the study for one year, but some were in the study for 18 months.

Results

On average, researchers obtained three blood samples from participants at different times over the course of the study.

After injections in the first month, researchers found that people who were overweight and obese tended to have lower levels of cabotegravir in their blood than people with lower BMIs, as follows:

  • normal BMI – 2,052 ng/mL
  • overweight BMI – 1,726 ng/mL
  • obese BMI – 1,421 ng/mL

These differences were statistically significant. 

Rilpivirine levels in the first month were lower only in participants with obesity (39 ng/mL) vs. 50 ng/mL in non-obese people. This difference was statistically significant. 

However, by the third month of the study, these differences in drug levels among participants with varying BMIs were not found.

During the first month, the following factors were statistically linked to having an increased risk for lower-than-normal levels of cabotegravir in the blood:

  • being female
  • having excess weight (being overweight or obese)

Being female and obese were risk factors for suboptimal rilpivirine levels. 

The risk of virological failure

Over the course of the study, 18 participants (2.5%) developed virological failure (persistently detectable viral loads; more than 50 copies/mL). Another 31 participants developed intermittently detectable viral loads (between 50 and 200 copies/mL). 

On average, it took about five months before virological failure occurred.

Past clinical trials of long-acting cabotegravir + rilpivirine identified several factors that were associated with virological failure:

  • obesity
  • HIV-1 subtypes A6/A1
  • pre-existing mutations associated with resistance to rilpivirine
  • low concentrations of cabotegravir or rilpivirine after the first injection

The presence of two or more of these risk factors has been found to significantly increase the chance that virological failure can occur.

In the present study, the risk factors for virological failure by the sixth month were as follows:

  • the presence of at least two risk factors that had been found in previous clinical trials 
  • less-than-ideal levels of study medicines in the blood
  • a CD4+ count that fell below the 200-cell mark prior to initiation of HIV treatment

According to the researchers, among the 18 participants who developed virological failure, 67% had less-than-ideal blood levels of cabotegravir or rilpivirine at months one and three of the study; 28% had less-than-ideal levels of both drugs.

Also, half the participants who developed virological failure in the present study “had at least two risk factors” at months one or three, including obesity or less-than-ideal cabotegravir levels.

Other findings

Although the present study was largely focused on the levels of drugs in the blood of participants, researchers collected some other data. For instance, 96 participants discontinued long-acting therapy during the study. However, only 37 people (about 5%) discontinued due to adverse events. Among them, the most common adverse events were:

  • injection site pain – 27%
  • neuropsychiatric issues – 27%
  • skin reactions – 16%
  • gastrointestinal issues – 11%

Other reasons for participants leaving the study included: 

  • virological failure
  • decision by doctor or participant
  • unspecified participant decision (no details were available)
  • pregnancy
  • participants simply stopped returning for study visits

Two participants died during the study from causes unrelated to HIV treatment. 

Bear in mind

The study was a good first step in trying to understand the relationship between drug levels of cabotegravir and rilpivirine and the risk of virological failure. However, some critical data (such as viral subtype) were missing. Additionally, the study was retrospective in design. That is, data were collected for one purpose at a time in the past and then later reanalyzed for another purpose. This could lead to important data not being available for the purposes of a future analysis. 

The researchers stated that suboptimal levels of cabotegravir and/or rilpivirine during the first three months of treatment “particularly in patients with a high BMI, appears to increase the risk of virological failure.” The researchers encourage doctors to consider the use of therapeutic drug monitoring in this subgroup of patients.

The researchers noted that further study is needed to better define ideal levels of cabotegravir and rilpivirine in the blood. This is important because between 20% and 30% of participants had suboptimal levels of cabotegravir and/or rilpivirine, yet only 2.5% ultimately developed virological failure. 

—Sean R. Hosein

REFERENCE:

Néant N, Lê MP, Bouchet S, et al. Therapeutic drug monitoring of long-acting cabotegravir and rilpivirine in a national cohort of people with human immunodeficiency virus type 1: first results from the ANRS-MIE CARLAPOP study. Clinical Infectious Diseases. 2025; in press.