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©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies
Hyoung Su Kim, Hyung Joon Yim, Myoung Kuk Jang, Ji Won Park, Sang Jun Suh, Yeon Seok Seo, Ji Hoon Kim, Bo Hyun Kim, Sang Jong Park, Sae Hwan Lee, Sang Gyune Kim, Young Seok Kim, Jung Il Lee, Jin-Woo Lee, In Hee Kim, Tae Yeob Kim, Jin-Wook Kim, Sook-Hyang Jeong, Young Kul Jung, Hana Park, Seong Gyu Hwang; on behalf of Antiviral Resistance Study Group
Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea
Hyung Joon Yim, Sang Jun Suh, Young Kul Jung, Department of Internal Medicine, Korea University Ansan Hospital, Ansan 425-707, South Korea
Yeon Seok Seo, Ji Hoon Kim, Department of Internal Medicine, Korea University Medical College, Seoul 136-705, South Korea
Bo Hyun Kim, Sang Jong Park, Department of Internal Medicine, Bundang Jesaeng Hospital, Seongnam 463-774, South Korea
Sae Hwan Lee, Department of Internal Medicine, Soon Chun Hyang University College of Medicine, Cheonan 330-721, South Korea
Sang Gyune Kim, Young Seok Kim, Department of Internal Medicine, Soon Chun Hyang University College of Medicine, Bucheon 330-721, South Korea
Jung Il Lee, Jin-Woo Lee, Department of Internal Medicine, Inha University School of Medicine, Incheon 400-711, South Korea
In Hee Kim, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju 561-712, South Korea
Tae Yeob Kim, Department of Internal Medicine, Hanyang University College of Medicine, Guri 471-701, South Korea
Jin-Wook Kim, Sook-Hyang Jeong, Department of Internal Medicine, Seoul National University College of Medicine, Seongnam 463-707, South Korea
Young Kul Jung, Department of Internal Medicine, Gachon University School of Medicine, Incheon 405-760, South Korea
Hana Park, Seong Gyu Hwang, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 463-712, South Korea
Author contributions: Kim HS, Yim HJ and Hwang SG designed the research; Kim HS, Yim HJ, Jang MK, Park JW, Suh SJ, Seo YS, Kim JH, Kim BH, Park SJ, Lee SH, Kim SG, Kim YS, Lee JI, Lee JW, Kim IH, Kim TY, Kim JW, Jeong SH, Jung YK, Park H and Hwang SG performed research; Yim HJ collected data; Kim HS analyzed the data and wrote the paper; and Yim HJ and Hwang SG share corresponding authorship.
Supported by Research Funds from the Korean Association for the Study of the Liver (in part).
Institutional review board statement: The study was reviewed and approved by the local ethics committee (Korea University Ansan Hospital, approval No. AS11102-001).
Informed consent statement: All participants provided written informed consent prior to study enrollment.
Conflict-of-interest statement: The authors have no conflicts of interest to declare with respect to this manuscript.
Data sharing statement: Participants gave informed consent for data sharing. Technical appendix, statistical code, and dataset are available from one of the corresponding author at gudwns21@medimail.co.kr. No additional data are available.
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: Hyung Joon Yim, MD, PhD, Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-Gu, Ansan-Si, Gyeonggi-Do 425-707, South Korea. gudwns21@medimail.co.kr
Telephone: +82-31-4126565 Fax: +82-31-4125582
Received: February 2, 2015
Peer-review started: February 5, 2015
First decision: March 26, 2015
Revised: May 13, 2015
Accepted: July 18, 2015
Article in press: July 18, 2015
Published online: October 14, 2015
AIM: To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients.
METHODS: Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by real-time PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a log-rank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively.
RESULTS: Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.
CONCLUSION: If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.
Core tip: Studies regarding optimal treatment strategies for entecavir-resistant chronic hepatitis B are sparse. Tenofovir may be the best option, but it is still not available in many countries. Where tenofovir is not available, adefovir plus entecavir can be considered an alternative treatment option in patients with favorable predictive factors. These factors included lower baseline hepatitis B virus (HBV) DNA levels (< 5.2 log10 IU/mL) and reduction of HBV DNA < 3.3 log10 IU/mL after 3 mo of treatment in our study. The present study will guide the treatment of entecavir-resistant chronic hepatitis B.
