Who is at risk of injectable treatment failure?

Three factors present before starting the combination strongly predict virologic failure of injectable antiretroviral treatment with cabotegravir and rilpivirine, Professor Chloe Orkin of Queen Mary University of London reported at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) last week. These factors can be used to identify people with HIV at higher risk of experiencing the failure of this regimen.

Although failure of the injectable cabotegravir/rilpivirine regimen was rare in clinical trials, affecting only 1.4% of participants, predicting who is less likely to benefit from the regimen can prevent treatment failure and the development of resistance. This is especially important in the case of injectable cabotegravir/rilpivirine, because these long-acting formulations remain in the blood for a long time, potentially reinforcing the emergence of resistance.

Investigators on the phase III clinical trials that led to the licensing of injectable cabotegravir/rilpivirine carried out an analysis of trial data from three studies to identify risk factors for virological failure throughout the study periods.

The analysis pooled data from the ATLAS study (to week 96), the FLAIR study (to week 124) and the ATLAS-2M study (to week 152). Two sets of factors were analysed: variables measure both before starting the regimen and during treatment (in 1224 participants with complete study data) and variables present before starting the regimen (in 1363 participants).

During the three studies, the pooled rate of viral failure was 1.4% or 0.54 per 100 person-years of follow-up. There was no significant difference in viral failure between dosing regimens: receiving cabotegravir/rilpivirine injections every eight weeks rather than every four weeks was not associated with a higher risk of viral failure.

Five factors emerged as significant predictors of viral failure: the presence of rilpivirine resistant mutations; HIV-1 A6 or A1 subtype; predicted cabotegravir trough concentration four weeks after starting treatment and predicted cabotegravir and rilpivirine concentrations 44 weeks after starting treatment.

People with rilpivirine resistance mutations had a 25-times greater risk of viral failure than those without rilpivirine resistance. People with the HIV-1 A6 subtype, the most common form of HIV in Russia and eastern Europe, or A1, a subtype originally from east Africa, had a 15-times higher risk of viral failure (nearly 15% of participants had one of these subtypes). In comparison, low drug concentrations had a much smaller impact on the risk of viral failure. Body mass index did not emerge as a significant factor in this analysis, but Orkin noted that it is highly correlated with cabotegravir concentrations.

Looking only at factors identified before starting treatment, the presence of rilpivirine resistant mutations, HIV-1 A6 or A1 subtype and greater body mass index predicted viral failure. 

After identifying the significant factors associated with viral rebound or viral failure, the investigators assessed which combinations of factors best predicted viral failure.

In 1431 people who received cabotegravir and rilpivirine during the three studies, 970 people had no baseline risk factors. Four people (0.4%) experienced viral failure in this group.

One baseline risk factor was present in 404 people and eight people (2%) experienced viral failure in this group.

Two or more baseline factors were present in 57 people and 11 people (19%) in this group experienced viral failure.

Using these predictors in clinical practice will require attention to a patient’s clinical history, in particular any history of NNRTI use, as sequencing of HIV proviral DNA to detect archived NNRTI drug resistance mutations is not carried out routinely.

Professor Orkin highlighted the importance of looking carefully for the presence of multiple factors and stressed that one factor alone did not confer a higher risk of viral failure than the absence of predictive factors.