Antiretroviral Drug Exposure and Response in Obese and Morbidly Obese People With Human Immunodeficiency Virus (HIV): A Study Combining Modelling and Swiss HIV Cohort Data
Authors: Berton Mattia , Bettonte Sara , Stader Felix , Decosterd Laurent , Tarr Philip E , Livio Françoise , Cavassini Matthias , Braun Dominique L , Kusejko Katharina , Hachfeld Anna , Bernasconi Enos , Calmy Alexandra , Schmid Patrick , Battegay Manuel , Marzolini Catia ,   the Swiss HIV Cohort Study, Abela Irene , Aebi-Popp Karoline , Anagnostopoulos Alexia , Battegay Manuel , Bernasconi Enos , Braun Dominique Laurent , Bucher Heiner , Calmy Alexandra , Cavassini Matthias , Ciuffi Angela , Dollenmaier Günter , Egger Matthias , Elzi Luigia , Fehr Jan , Fellay Jacques , Furrer Hansjakob , Fux Christoph , Günthard Huldrych , Hachfeld Anna , Haerry David , Hasse Barbara , Hirsch Hans , Hoffmann Matthias , Hösli Irene , Huber Michael , Jackson-Perry David , Kahlert Christian , Kaiser Laurent , Keiser Olivia , Klimkait Thomas , Kouyos Roger Dimitri , Kovari Helen , Kusejko Katharina , Labhardt Niklaus , Leuzinger Karoline , de Tejada Begona Martinez , Marzolini Catia , Metzner Karin J , Müller Nicolas , Nemeth Johannes , Nicca Dunja , Notter Julia , Paioni Paolo , Pantaleo Giuseppe , Perreau Matthieu , Rauch Andri , Salazar-Vizcaya Luisa , Schmid Patrick , Speck Roberto , Stöckle Marcel , Tarr Philip , Trkola Alexandra , Wandeler Gilles , Weisser Maja , Yerly Sabine 
Published: August 2023

Abstract

Background
Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals.

Methods
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 nonobese individuals.

Results
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 nonobese (BMI: 18.5–25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI &gt;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 nonobese PWH.

Conclusions
The concentrations of ARVs are modestly reduced in obese individuals, with no negative impact on the virological response. Our data provide reassurance that standard doses of ARVs are suitable in obese PWH, including those who gained substantial weight with some of the first-line ARVs.