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Predictors of virological failure with Cabenuva

Clinical trials have found that the use of Cabenuva is generally safe and effective in people with HIV. A very small proportion of people—less than 2%—have developed confirmed virological failure during these trials.

A team of researchers reviewed information collected from three pivotal trials of Cabenuva to better understand factors at the start of the study that could be used to explain why some people experienced virological failure. This information would also be useful for doctors who screen patients for possible use of Cabenuva.

The review encompassed data from more than 1,000 people who had never used Cabenuva prior to entering the trials.

In these three pivotal phase III studies (code-named Atlas, Atlas-2M and Flair), researchers found that the presence of at least two of the following factors at the start of the studies was associated with an increased risk of virological failure:

  • two mutations in HIV’s genetic material that are associated with resistance to rilpivirine
  • subtypes of HIV labelled A1 or A6
  • having a body mass index (BMI) of at least 30 kg/m2

Study details

Researchers pooled data from the three clinical trials for their analysis. No patient profile was provided.

Results

There were 13 people (1.3%) who had confirmed virological failure—defined as two consecutive viral load measures of 200 copies/mL or greater.

After performing extensive statistical and other analyses, researchers found the following possible factors (which were present when some participants entered the study) associated with an increased risk of virological failure:

  • two mutations in HIV’s genetic material that are associated with resistance to rilpivirine
  • subtypes of HIV labelled A1 or A6
  • having a body mass index (BMI) of at least 30 kg/m2

Most participants in the pooled analysis from the three trials had either none of these risk factors (71% or 732 people) or just one of them (26% or 272 people). In the entire study, only a relatively small proportion of people had two of these risk factors (3.4% or 35 people).

However, among people with confirmed virological failure, having two risk factors was relatively common. This was found in 9 out of 13 people (nearly 70%). Only one participant had all three risk factors at the start of the study.

Most people who developed virological failure had concentrations of cabotegravir and rilpivirine in their blood that were less than ideal at the eighth week of the study (9 of 13 participants). This happened whether or not participants were being injected every four or eight weeks. People with a high BMI (30 or greater) tended to have less-than-ideal levels of study drugs at week eight.

Why these risk factors at baseline?

The analysis of more than 1,000 participants was not pre-planned but was done after the study was completed to try to explain something that happened. Such analyses, which are called “post-hoc” analyses by researchers, are not ideal. However, nothing can be done about this because the problem of virological failure apparently was not anticipated and pooling data from several studies was the only way to get enough virological failures to be useful in a statistical analysis.

Mutations associated with resistance to rilpivirine

Rilpivirine belongs to a group of drugs commonly called “non-nukes” (NNRTIs, non-nucleoside reverse transcriptase inhibitors). Some people who developed virological failure in the three pivotal studies had HIV that was at least partially resistant to rilpivirine (and possibly other non-nukes). This problem may have arisen because they had used non-nukes in the past and developed partial resistance to this class of drug or because they were infected with a strain of HIV that had acquired at least partial resistance to non-nukes. This underscores the importance of obtaining HIV resistance testing to assess the possibility of resistance prior to initiating treatment with Cabenuva.

HIV subtypes A1 and A6

There are two main types of HIV: HIV-1 and HIV-2. HIV-1 is the virus found in most of the world; it is the most common form of the virus. HIV-2 is most commonly found in parts of West Africa. HIV-1 can be divided into subtypes (A, B, C and so on) based on its genetic information. Subtypes can sometimes be further subdivided, such as A1, A6 and so on. Note that although some subtypes are relatively common in some regions, these can spread due to migration and tourism.

Subtype A appeared to have originated in Central Africa and subsequently spread to other parts of that continent. Later it spread to Eastern Europe, the former Soviet Union and adjoining countries. Subtype A6 appears to have arisen from subtype A1 (itself an offshoot of subtype A). Some scientists think that subtype A6 originated in the former Soviet Union and adjoining countries. Indeed, all but one of the participants with virological failure who had subtype A1 or A6 were from Russia. However, one of the people with these subtypes who developed virological failure was from Canada.

It is plausible that subtypes A1 and A6 somehow have reduced susceptibility to cabotegravir and/or rilpivirine.

Body mass index

People who were obese or very obese had an increased risk for virological failure. Previous research showed that after intramuscular injection in the buttocks, cabotegravir is initially released more slowly into the blood of people whose BMI is 30 or greater than in people whose BMI is less than 30 kg/m2. The same research found that 20 to 24 weeks after initiating cabotegravir injections and continuing to inject the drug at regular intervals, concentrations of cabotegravir in the blood are similar in people with or without obesity. BMI does not appear to have an impact on rilpivirine concentrations.

In the three pivotal studies that were analyzed for virological failure, participants with a BMI of 30 kg/m2 or greater who experienced virological failure had received intramuscular injections of Cabenuva with standard-length needles. At the time of Cabenuva’s approval by regulatory authorities, ViiV encouraged healthcare providers to use needles at least two inches long when administering Cabenuva in people with obesity to ensure that Cabenuva gets injected into muscle rather than fat.

Bear in mind

This analysis of data from people who developed virological failure found that at least two of the above risk factors are needed for failure to likely occur. All of these risk factors can be assessed prior to initiating Cabenuva and can help healthcare providers in their screening of patients for whom Cabenuva may be beneficial.

—Sean R. Hosein

REFERENCE:

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