Retrospective Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jun 27, 2019; 11(6): 553-561
Published online Jun 27, 2019. doi: 10.4254/wjh.v11.i6.553
Risk factors for ribavirin treatment failure in Asian organ transplant recipients with chronic hepatitis E infection
En Xian Sarah Low, Edhel Tripon, Kieron Lim, Poh Seng Tan, How Cheng Low, Yock Young Dan, Yin Mei Lee, Mark Muthiah, Wai Mun Loo, Calvin Jianyi Koh, Wah Wah Phyo, JunXiong Pang, Seng Gee Lim, Guan-Huei Lee
En Xian Sarah Low, Department of Medicine, Ng Teng Fong General Hospital, National University Health System, Singapore 609606, Singapore
Edhel Tripon, Centre for Liver Disease Management and Transplant of Medical City, Manila 1605, Philippines
Kieron Lim, Mount Elizabeth Medical Centre, Singapore 228510, Singapore
Poh Seng Tan, How Cheng Low, Yock Young Dan, Yin Mei Lee, Mark Muthiah, Wai Mun Loo, Calvin Jianyi Koh, Seng Gee Lim, Guan-Huei Lee, Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
Wah Wah Phyo, Department of Medicine, National University of Singapore, Singapore 119077, Singapore
JunXiong Pang, Centre for Infectious Disease Epidemiology and Research, National University of Singapore, Singapore 117549, Singapore
Seng Gee Lim, Guan-Huei Lee, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
Author contributions: Low EXS compiled the data and wrote the main section of the manuscript; Tripon E collected the patient data and carried out the initial analysis; Lim K, Tan PS, Low HC, Dan YY, Koh CJ and Lee YM were involved in subject recruitment and data collection; Muthiah M, Loo WM, and Phyo WW carried out the statistical analysis and preparation of the tables and figures; Lim SG assisted in the study design and edited the manuscript; Pang JX assisted in the biostatistics statement and edited the manuscript; Lee GH designed the study and wrote the final version of the manuscript.
Institutional review board statement: The study is approved by the NHG Domain Specific Review Board.
Informed consent statement: All involved subjects provided consent for study participation.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article that 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/
Corresponding author: Guan-Huei Lee, MBBS, MRCP, PhD, Attending Doctor, Division of Gastroenterology and Hepatology, National University Health System, 1E Kent Ridge Road, Singapore 119228, Singapore. guan_huei_lee@nuhs.edu.sg
Telephone: +65-67795555
Received: February 12, 2019
Peer-review started: February 13, 2019
First decision: April 11, 2019
Revised: June 11, 2019
Accepted: June 17, 2019
Article in press: June 17, 2019
Published online: June 27, 2019
Processing time: 136 Days and 22.7 Hours
ARTICLE HIGHLIGHTS
Research background

There has been an increase in the amount of literature and our understanding of Hepatitis E virus (HEV) infection since the landmark paper by Kamar et al in 2014. This study describes the outcome of HEV treatment in a transplant center in Singapore, where immunosuppressed Asian hosts appear to have lower sustained virologic response (SVR) rates after a 12-wk course of ribavirin than reported earlier.

Research motivation

Singapore is a unique industrialized country where, although ethnic Chinese make up 76% of the population, it is a thriving hub with many international visitors. Seven genotypes of HEV have been described so far, and studies have reported a rate of chronicity of 50%-60%. Ribavirin is considered an effective treatment option for chronic HEV in post-transplant patients, where success rates > 75% have been reported in France and Germany alongside a reduction in immunosuppression dose. Since most clinical studies come from Europe and the United States, there is a pressing need to characterize and investigate the state of chronic HEV infection in Asian populations.

Research objectives

Our report describes the first 10 consecutive cases of hepatitis E diagnosed in post-transplant patients in an organ transplant center in Singapore.

Research methods

This is a retrospective case series that studied all newly diagnosed HEV infections in post-transplant patients from May 2012 to September 2015. Subjects who had transaminitis that were caused by persistent HEV replication were treated with ribavirin, and the results were collected and tabulated. Data from the first 10 HEV RNA-positive patients who had received a solid organ transplant (5 kidney transplant recipients, 4 liver-transplant recipients, and 1 bone marrow transplant recipient) were analysed.

Research results

One of the patients was from United Arab Emirates, and the other nine were Singapore residents. The median starting dose of ribavirin was 600 mg per day. The dosages were subsequently adjusted based on the estimated GFR. In more than half of patients (5 out of 9), dose reductions of ribavirin were necessary due to clinically significant anemia. The overall failure rate of achieving sustained viral clearance for a 12-wk course of ribavirin was 66.67% (delayed virologic response plus viral recurrence after completing treatment) – far higher than that reported in Western populations. All four patients with viremia recurrence were kidney transplant recipients, which was found to be the only statistically significant predictive factor. The most common side effect of ribavirin was anemia.

Research conclusions

This study proposes that kidney transplant recipients, particularly those with poorer renal function, are more susceptible to the adverse effects of ribavirin. Asian patients with lower body weight may be even more likely to suffer from the side effects. This Asian single-centre case series shows that the SVR rate of HEV infection treated with a 12-wk course of ribavirin may be lower than reported earlier. Kidney transplant recipients are at higher risk of relapse, possibly due to higher immunosuppression requirements and reduced tolerance for higher ribavirin dosages.

Research perspectives

More effective therapy for chronic HEV infection may be needed, including more accurate markers to predict ribavirin response. A large, prospective, controlled study comparing kidney transplants and other groups of chronic HEV patients will be useful to confirm the results of this study and minimise bias.