Antiretroviral drug exposure and response in obese and morbidly obese people with HIV: a study combining modelling and Swiss HIV Cohort data. Clinical Infectious Disease.
Berton et al. aimed to perform virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with therapeutic drug monitoring (TDM) data and the corresponding viral load data obtained from people with HIV (PWH) enrolled in the Swiss HIV Cohort Study (SHCS) to determine the exposure and response to antiretrovirals (ARVs) in obese and non-obese PWH and provide dosing guidance.
Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5 and 60 kg/m2. Therapeutic drug-monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. Subsequently, the model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and non-obese individuals.
The PBPK model predicted an average reduction in ARV exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared with non-obese (BMI: 18.5–25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load than non-obese PWH.
In conclusion, this study shows that obesity lowers the exposure of ARVs; nevertheless, the minimal concentrations of all evaluated ARVs were maintained above the target threshold, except for etravirine and rilpivirine in morbidly obese individuals in whom TDM is advised. When considering the data of the SHCS, the proportion of individuals with viral loads above 50 copies/mL was not higher in obese compared with non-obese PWH. Thus, a dose adjustment of ARVs is a priori not required in obese PWH. This data provide reassurance that substantial weight gain observed in some individuals on treatment with integrase inhibitors and/or the switch from tenofovir disoproxil fumarate to tenofovir alafenamide is unlikely to result in suboptimal drug exposure and response.