PHARMACOLOGY

Discussion concerning the follow-up and pharmacological management of HIV-infected patients treated with the combination abotegravir/Rilpivirine administered intramuscularly every 2 months (long-acting) outside the clinical research protocol.
Therapeutic Drug Monitoring (TDM) of antiretroviral drugs (ARV) is officially recommended in France in a certain number of indications, because of a significant inter-individual pharmacokinetic variability and pharmacokinetic-pharmacodynamic relationships (virological efficacy and/or toxicity) established for most ARVs (1).
In the context of the upcoming availability of the long-acting injectable combination of cabotegravir and rilpivirine, we propose the following modalities for the implementation of TDM for these two compounds.

1. Level of evidence

These recommendations are based on:

– pharmacokinetic data from phase 3 trials (Flair and Atlas pooled data) at week 48 reporting significant inter-individual variability in trough plasma concentrations (Cmin) of cabotegravir and rilpivirine with values below the respective geometric mean for patients with virologic failure (2).

– results of the multivariate analysis of virologic failures in the phase 3 Flair and Atlas trials (3) identifying trough plasma rilpivirine concentration at S8 (i.e., 4 weeks after the initiation injection) as a risk factor for virologic failure. The analysis reported that the presence of at least two of the risk factors at initiation among the A1/A6 viral subtype, the presence of archived rilpivirine resistance mutations, or a BMI >30 kg/m2 was associated with a higher risk of failure (25.7%). A lower trough cabotegravir plasma concentration at S8 (i.e. 4 weeks after the initiation injection) was also associated with a higher BMI (4). However, although related to virological failure, trough cabotegravir concentration was no longer predictive in the multivariate analysis but should remain a point of vigilance in the real-life setting. Indeed, recent data from the Flair trial at week 124 reported a new virologic failure between S96 and S124 in a patient presenting two of the identified risk factors: viral subtype A6 and a rilpivirine Cmin below 32 ng/mL (i.e 24.6 ng/mL) and a cabotegravir Cmin below 1,120 ng/mL (i.e 1005 ng/mL). An additional failure in an obese patient who received direct injection (without the oral lead-in) was also reported with low W4 Cmin (cabotegravir 349 ng/mL; rilpivirine 16.4 ng/mL). Week 152 ATLAS-2M results also reported ≥2 baseline factors associated with increased risk of failure in 6/10 (60%) patients failing by Week 48 and at least one risk factor in 2 of 3 failures post-W48 (11).

For information, a recent French study conducted in 3 university hospitals in Paris reported a prevalence of 10.1% of A6/A1 viral subtype OR resistant to rilpivirine (i.e with 1 of the 2 virological risk factors for failure) and a prevalence < 0.5% of A6/A1 viral subtype AND resistant to rilpivirine (i.e with the 2 virological risk factors for failure) (5).

– the French transparency commission, recommending pharmacological monitoring, particularly in obese subjects (6) :

« Caution is further recommended in the presence of archived resistance to rilpivirine, BMI ≥ 30 kg/m2, or HIV-1 subtype A6/A1, factors associated with the risk of virological failure in studies. In addition, the trough plasma concentration of rilpivirine at 4 weeks after the initiation injection was associated with the risk of failure, so performing therapeutic drug monitoringof the 2 molecules is worth discussing especially in obese patients. »

2. Indications and modalities of TDM

The sample is collected on a gel-free lithium heparinate tube or EDTA, which is compatible with samples collected for plasma HIV-1 RNA), as currently recommended for the TDM of ARV: 

• At the end of the oral lead-in phase (W4-Peros), in residual period (T>20h), if treatment with oral lead-in phase.
• At 1 month, i.e. 4 weeks after the 1^st IM injection (W4-IM), before the new administration, whatever the treatment, with or without oral lead-in phase.
• A minima, in the following indications:
  • in case of missed or delayed injection(s), and before resuming the treatment as defined in the Summary of Products Characteristics (SPCs)
  • in case of occurrence of adverse events
  • in case of virological failure (including low viremia)
  • in case of pregnancy occurring during treatment*
  • in case of drug-drug interaction that may significantly alter the exposure of cabotegravir and/or rilpivirine (**see list below)
  • along with viral load monitoring in patients with a BMI > 30 kg/m2 and/or A1/A6 viral subtype.

TDM should be performed preferentially either prior to the next injection or before re-starting treatment as recommended in the SPCs for missed injections (specify the estimated time of interruption) (7,8).

*In case of pregnancy occurring during treatment, monitoring plasma of concentrations is recommended whether the treatment is maintained (documentation and follow-up with bodyweight changes) or stopped (monitoring of the decrease in plasma concentrations, given the long elimination half-life of the two compounds). The frequency of the pharmacological follow-up will be determined on a case-by-case basis according to the context and discussed in a multidisciplinary staff.

3. TDM interprétation

To date, no specific target value are officially validated for maintenance treatment and IM administration.

To date, TDM is therefore proposed in accordance with the expected values published in the respective SPCs, with an alert threshold corresponding to the 1^st quartile of trough plasma concentrations presented in the multivariate analysis of failures (3, 7-8,10).

In case of a Cmin below this threshold, close virological monitoring is recommended along with a new pharmacological control after checking the absence of other factors associated with virological failure (viral sub-type, resistance profile, BMI).