Trough concentrations of cabotegravir and rilpivirine and their association with detectable viral load in people with HIV on long-acting treatment

Abstract

Background: Cabotegravir (CAB) and rilpivirine (RPV) constitute the first complete non-oral ART regimen for HIV-1 treatment. Due to virologic failure (VF) with resistance in clinical trials, concerns persist regarding broader use in clinical practice. In particular, the role of trough drug concentrations in relation to viremia and VF remains unclear. This study explored the association between CAB and RPV trough concentrations in a retrospective, single-center study.

Methods: We retrospectively analyzed data from the HIV research and clinical care center MVZ München am Goetheplatz, Germany. Inclusion criteria were CAB and RPV long-acting therapy every 8 weeks without additional ART and availability of drug concentrations within 7 days before the next administration. A modified Wilcoxon test assessed differences in concentrations between samples with HIV-1 RNA < 20 vs. ≥20 copies/mL. Odds ratios (ORs) were estimated using generalized estimation equation (GEE) models, and ROC analysis identified potential alternative drug concentration thresholds.

Findings: A total of 737 samples from 185 individuals were included. Median CAB concentrations were 1,480 µg/L (IQR: 1,097-1,955) vs. 1,180 µg/L (879-1,570) for samples with HIV-1 RNA levels < 20 copies/mL vs. ≥ 20 copies/mL, respectively (p = 0.001); for RPV, 77 µg/L (53-107) vs. 63 µg/L (47-87) (p = 0.001). Using ROC-derived thresholds, low concentrations of CAB (< 1,240 µg/L) or RPV (< 76 µg/L) were found in 11.5% and 25.4% of samples, respectively, and associated with ORs of 2.4 (1.5-4.0) and 2.3 (1.4-3.8) for HIV-1 RNA ≥ 20 copies/mL.

Interpretation: Lower CAB and RPV concentrations were associated with viremia, particularly using the ROC-derived thresholds. Among individuals with VF and available drug concentration data, 87.5% had at least one drug below these thresholds. Further research on therapeutic drug monitoring is warranted.

Fig. 1

Receiver operating characteristics (ROC) for the sensitivity and 1-specificity throughout the range of possible ‘optimized’ thresholds for Cabotegravir (top) and Rilpivirine (bottom) on the left. The results of the maximized sum of sensitivity and specificity can be found on top of the figure. For both drugs, the right graphs depict the sums for sensitivity and specificity for a range of drug concentrations

Fig. 2

Scatter plot of measurement pairs for cabotegravir (CAB) and rilpivirine (RPV) concentrations for all samples with HIV-1 RNA ≥ 20 copies/mL (top) and ≥ 50 copies/mL (bottom). Red dashed lines indicate the data-derived thresholds for CAB and RPV, tables in the upper right corner of the plots indicate the number of samples per quadrant in relation to the number of samples with HIV-1 RNA ≥ 20 copies/mL (n = 87) or HIV-1 RNA ≥ 50 copies/mL (n = 18), respectively. Colors indicate the result of HIV-1 RNA quantification, also indicated by the numbers next to each measurement

Fig. 3

Box- and jitter-plots of the concentrations of Cabotegravir and Rilpivirine by status of virologic suppression. Numbers below the plots indicate the median together with the interquartile ranges for the respective drug