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
Author:
Berton Mattia12, Bettonte Sara12, Stader Felix3, Decosterd Laurent4, Tarr Philip E5, Livio Françoise4, Cavassini Matthias6, Braun Dominique L7, Kusejko Katharina7, Hachfeld Anna8, Bernasconi Enos9, Calmy Alexandra10, Schmid Patrick11, Battegay Manuel12, Marzolini Catia12412ORCID, 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,
Affiliation:
1. Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel , Basel , Switzerland 2. Faculty of Medicine, University of Basel , Basel , Switzerland 3. Certara UK Limited , Sheffield , United Kingdom 4. Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, University Hospital Lausanne and University of Lausanne , Lausanne , Switzerland 5. Kantonsspital Baselland, University of Basel , Bruderholz , Switzerland 6. Service of Infectious Diseases, Lausanne University Hospital, University of Lausanne , Lausanne , Switzerland 7. Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich , Zurich , Switzerland 8. Department of Infectious Diseases, University Hospital Bern, University of Bern , Bern , Switzerland 9. Division of Infectious Diseases, Ente Ospedaliero Cantonale Lugano, University of Geneva and University of Southern Switzerland , Lugano , Switzerland 10. Division of Infectious Diseases, University Hospital Geneva, University of Geneva , Geneva , Switzerland 11. Department of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St Gallen , St Gallen , Switzerland 12. Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool , United Kingdom
Abstract
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 >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.
Funder
Swiss National Foundation
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Microbiology (medical)
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