Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV‐infected patients

Abstract

The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine. Methods: A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration. Results: Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%). Conclusions: This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.

Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the dolutegravir/rilpivirine two‐drug regimen in SWORD‐1/‐2 phase 3 studies

“…These steady‐state values (C0 at all timepoints and C0avg) were above the pharmacologically active concentrations 11–13 (DTG PA‐IC90 = 0.064 μg mL −1 as well as the clinical target C0 of 0.3 μg mL −1 ; RPV PA‐IC90 = 12 ng mL −1 ) at all timepoints in both the overall population and the NNRTI subset (Figure 2). RPV C0 and Cavg were also at or above 70 ng mL −1 (the lowest C0 value of 68.91 ng mL −1 occurred at week 4 in the early‐switch group of the NNRTI subset), which was recently proposed by others as the clinical target from an observational cohort of treatment‐naive and treatment‐experienced people with HIV‐1 14 . The categorical analysis exploring the effect of age (≥50 and <50 years) on PK did not reveal any clinically meaningful differences in the DTG or RPV C0avg between the two age groups (Table 1).…”

“…12 those with virologic suppression after 6 months (72 vs 97 ng mL À1 , P = .03) and 12 months (68 vs 103 ng mL À1 , P = .006), which could have been in part related to suboptimal adherence, but RPV C0 levels remained well above PA-IC90 regardless of virologic suppression status. 14 The absence of a PK/PD relationship was also the case for the NNRTI subset, despite the slightly lower C0 values in the immediate post-switch period due to residual enzyme induction by EFV or NVP taken prior to the switch, supporting a direct switch to the 2DR DTG + RPV from any antiretroviral regimen without dose adjustment, lending more support for the approved doses that are efficacious when administered as part of a two-or three-drug regimen. This finding is consistent with prior studies in which participants were immediately switched from a three-drug regimen containing an enzyme inducer to a three-drug regimen containing DTG or RPV.…”

“…RPV C0 and Cavg were also at or above 70 ng mL À1 (the lowest C0 value of 68.91 ng mL À1 occurred at week 4 in the earlyswitch group of the NNRTI subset), which was recently proposed by others as the clinical target from an observational cohort of treatmentnaive and treatment-experienced people with HIV-1. 14 The categorical analysis exploring the effect of age (≥50 and <50 years) on PK did not reveal any clinically meaningful differences in the DTG or RPV C0avg between the two age groups (Table 1).…”

Evaluation of drug-drug interaction between rilpivirine and rifapentine using PBPK modelling

“…Current target trough concentration (C trough ) for rilpivirine is 0.05 mg/L (Néant et al, 2020), which is suggested as four times the concentration required for 90% inhibition (IC 90 0.012 mg/L) (Margolis et al, 2015). However, a recent study with rilpivirine based regimen have highlighted that the current C trough target might need to be reassessed (Néant et al, 2019) and an optimal target C trough of 0.07 mg/L is required to achieve virologic response, especially in pre-treated patients (Néant et al, 2020). This is further complicated considering that 11% of a population in Aouri et al study did not reach a C trough of 0.05 mg/L (Aouri et al, 2017).…”

“…Current target trough concentration (C trough ) for rilpivirine is 0.05 mg/L ( Néant et al, 2020 ), which is suggested as four times the concentration required for 90% inhibition (IC 90 0.012 mg/L) ( Margolis et al, 2015 ). However, a recent study with rilpivirine based regimen have highlighted that the current C trough target might need to be reassessed ( Néant et al, 2019 ) and an optimal target C trough of 0.07 mg/L is required to achieve virologic response, especially in pre-treated patients ( Néant et al, 2020 ). This is further complicated considering that 11% of a population in Aouri et al study did not reach a C trough of 0.05 mg/L ( Aouri et al, 2017 ).…”