Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: a multicenter prospective observational study in Switzerland. The Lancet Regional Health – Europe
Thoueille et al. analyzed the drug levels of participants from the Swiss HIV Cohort Study (SHCS) who received long-acting cabotegravir (CAB) and rilpivirine (RPV) after the approval in March 2022 in Switzerland.
Drug concentrations were measured by multiplex high-performance liquid chromatography coupled with tandem mass spectrometry. The authors assessed the relationship between the observed drug trough levels with the following previously proposed thresholds: the protein-adjusted concentrations required for 90% inhibition of viral replication (PAIC90), the clinical threshold set at four times the PAIC90 (4xPAIC90), and the 25th percentile of the trough levels observed in the registrational ATLAS-2M trial (Q1trough). In addition, the influence of sex, body mass index (BMI), and albumin on the observed variability of drug concentrations was evaluated using multivariable mixed-effect models.
Between March 2022 and March 2023, 186 people with HIV (PWH) were included: 82% were male, 57% were white, the median age was 45 years (range 20-79), and 172 (92%) received an oral lead-in. In total, 725 samples were obtained, of which 569 were collected during the injection phase. For RPV, 273 measurements (48%) were below 4xPAIC90, 108 (18%) were below Q1trough, and 3 (<1%) were below PAIC90. For CAB, 201 drug levels (37%) were below Q1trough, 83 (15%) were below 4xPAIC90, and 8 (1%) were below PAIC90. CAB levels were 35% lower (95% CI -47 to -20) in males compared to females, whereas there was no variation according to BMI or albumin. Neither sex, BMI, nor albumin did impact RPV concentrations. Three individuals (1.6%) experienced virologic failure (defined as an HIV viral load >200 copie/mL), of whom two had suboptimal drug levels. Three additional individuals had CAB/RPV discontinued due to persistently low drug levels.
In summary, whereas RPV levels were similar to previous results from randomized trials, CAB levels were substantially lower in the present real-world analysis compared with previous analyses. Sex differences appear to explain some of the observed interindividual variability, which may be due to differences in the distribution of fat and muscle mass. Nevertheless, the proportion of individuals experiencing virologic failure was similar to what was observed in registrational trials, which is reassuring for implementing long-acting CAB/RPV in clinical care. Further studies are ongoing to improve the characterization of the pharmacokinetic profile of these new drugs.