Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplantation. Sep 10, 2018; 8(5): 156-166
Published online Sep 10, 2018. doi: 10.5500/wjt.v8.i5.156
Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid
Petra E de Ruiter, Yashna Gadjradj, Robert J de Knegt, Herold J Metselaar, Jan NM Ijzermans, Luc JW van der Laan
Petra E de Ruiter, Yashna Gadjradj, Jan NM Ijzermans, Luc JW van der Laan, Department of Surgery, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
Robert J de Knegt, Herold J Metselaar, Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam CN 3015, the Netherlands
Author contributions: de Ruiter PE participated in sample and data collection and analysis and writing of the manuscript; Gadjradj Y participated in sample and data collection and analysis; de Knegt R participated in the design of the study; Metselaar HJ participated in the design of the study; IJzermans JNM participated in the design of the study; van der Laan LJW participated in the design of the study and writing of the manuscript.
Conflict-of-interest statement: All authors have no conflicts of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Luc JW van der Laan, PhD, Associate Professor, Laboratory of Experimental Transplantation and Intestinal Surgery, Department of Surgery, Erasmus MC-University Medical Center, Room Na1006, Wytemaweg 80, Rotterdam CN 3015, the Netherlands. l.vanderlaan@erasmusmc.nl
Telephone: +31-10-7037557 Fax: +31-10-7032793
Received: April 24, 2018
Peer-review started: April 24, 2018
First decision: June 6, 2018
Revised: June 14, 2018
Accepted: June 27, 2018
Article in press: June 27, 2018
Published online: September 10, 2018
Processing time: 136 Days and 16.6 Hours
ARTICLE HIGHLIGHTS
Research background

Liver disease caused by chronic Hepatitis C virus (HCV) infection is a leading indication for liver transplantation. Factors that contribute to the recurrence of HCV after transplantation include viral factors (e.g., HCV RNA levels at the time of transplantation and HCV genotype), host factors (immune response and HCV cryoglobulinemia), and the use of immunosuppressive medication. Current treatment of HCV is based on direct acting antivirals (DAAs), including daclatasvir (DCV) and asunaprevir (ASV). Recently a study reported reduced sustained virological response rates with DCV/ASV therapy after transplantation, indicating potential interference with immunosuppressants.

Research motivation

Although some drug-drug interactions were reported on the pharmacokinetics of DAAs and immunosuppressants, the potential interference of immunosuppressants with the antiviral activity of DAAs post-transplantation is largely unknown.

Research objectives

The aim of our study is to investigate the antiviral action of DCV and ASV in the presence of several different classes of immunosuppressants.

Research methods

The antiviral activity of DCV and ASV combined with immunosuppressants was tested using two in vitro cell culture models for HCV infection. The cells were cultured with different concentrations of DCV or ASV in combination with immunosuppressants from several different classes. The effects on HCV replication were quantified by luciferase assay or quantitative RT-PCR. Effects on the expression of antiviral interferon-stimulated genes were also assessed by quantitative RT-PCR.

Research results

Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid (MPA) showed additive antiviral effects combined with these DAAs. MPA induces interferon-stimulated genes (ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce expression of ISGs nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis.

Research conclusions

Our in vitro study shows that none of the immunosuppressants we tested negatively interfered with the antiviral action of DSV and ASV. The combination of MPA with DSV and ASV resulted in a higher reduction of HCV replication than that could be achieved by treatment with these compounds alone. Although the antiviral action of MPA is evident in cell culture systems, the antiviral effect in patients might be masked by the suppressive effects of MPA on the immune response. Our results can, however, complement the still emerging clinical findings on the effectivity of DAAs in the presence of immunosuppressants.

Research perspectives

Based on this in vitro study, there is no rationale or evidence to withhold or adjust DCV or ASV in combination with immunosuppressants in the post-transplantation management of HCV.