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Is measuring drug levels in the blood necessary with long-acting HIV treatment?

Due to its infrequent administration, long-acting HIV treatment has the potential to lead to improvements in adherence and better quality of life.

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The previous article in this issue of TreatmentUpdate reports on a study from French researchers on the use of long-acting cabotegravir + rilpivirine (sold as Cabenuva in Canada, the U.S., Australia and some other countries). That study of 736 people with HIV found some variation in levels of the study drugs in the blood of participants. Less-than-ideal levels of anti-HIV drugs can lead to the virus developing the ability to partially or wholly resist the drugs. Furthermore, it can also lead to the virus acquiring the ability to resist drugs that were not being taken but that are structurally related (such as within classes of drugs). 

In the French study, between 20% and 30% of participants had suboptimal levels of cabotegravir and/or rilpivirine. However, virological failure (persistently detectable HIV) occurred in a much smaller proportion of participants (2.5%). The risk of virological failure increased when study participants had at least two of the following factors:   

  • obesity
  • less-than-optimal levels of medicines in the blood
  • a CD4+ count that fell below the 200-cell mark prior to the initiation of HIV treatment (ART; antiretroviral therapy) 

Why might suboptimal drug levels occur?

The long-acting formulations of cabotegravir and rilpivirine are injected by a healthcare provider deep into the muscles of the buttocks. Over time, the drugs are slowly released from the buttocks into the blood. 

However, each person is different. According to pharmacologist Catie Marzolini (from the University Hospital in Lausanne, Switzerland), an expert in studying drug levels in people with HIV, variations in levels of cabotegravir and rilpivirine can occur because of factors such as the following:

  • sometimes there is an inflammatory reaction related to intramuscular injection
  • intense physical activity

Marzolini noted that females tend to have more fat in their buttocks than males, which might explain the slower absorption and the persistence of drugs that are injected into the buttocks. She stated that “thicker [fatty] layers increase the risk of unintended [injection of the drugs into the upper layers of the skin rather than deeper into the buttocks]. This can lead to lower drug concentrations after the initial injection.”

To overcome this hurdle, she noted that healthcare providers are encouraged to use longer needles in patients with obesity who are using long-acting cabotegravir + rilpivirine.

Therapeutic drug monitoring

In theory, therapeutic drug monitoring (TDM) could be useful in alerting doctors about the low concentration of drugs in the blood. But Marzolini notes that clinical trials have found that not everyone with a low level of cabotegravir and/or rilpivirine will develop virological failure. Also, some studies have found that people with adequate levels of these drugs can still develop virological failure, perhaps because of the subtype of HIV-1 that they have or because they have a large burden of HIV-infected cells (referred to as “the reservoir” by scientists). 

In an editorial in the journal Clinical Infectious Diseases, Marzolini stated that measurement of drug levels in people who are using long-acting cabotegravir + rilpivirine can be useful “in individuals with one risk factor for virological failure, as TDM can potentially prevent virological failure by optimizing the timing of dosing, for instance, in obese or morbidly obese individuals, pregnant people, or any other special population understudied during drug development.” 

She added that measuring blood levels of cabotegravir and rilpivirine “may also be useful to monitor drug interactions with inducers or [drugs] that can enhance the release of cabotegravir + rilpivirine from the depot (for example, anabolic steroids) to prevent virological failure because of [reduced levels of cabotegravir + rilpivirine].” 

Marzolini states that “continuous research efforts are needed to better understand factors leading to low concentrations [of cabotegravir and/or rilpivirine].”  More studies will lead to more data that can then be used in computer simulations to help set target concentrations of these drugs in the blood.

—Sean R. Hosein

REFERENCE:

Marzolini C. Is therapeutic drug monitoring of long-acting cabotegravir and rilpivirine of clinical utility? Clinical Infectious Diseases. 2025; in press.