Opinion Review
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2021; 27(8): 666-676
Published online Feb 28, 2021. doi: 10.3748/wjg.v27.i8.666
New therapeutic options for persistent low-level viremia in patients with chronic hepatitis B virus infection: Increase of entecavir dosage
Guo-Qing Yin, Jun Li, Bei Zhong, Yong-Fong Yang, Mao-Rong Wang
Guo-Qing Yin, Department of Infectious Diseases, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu Province, China
Jun Li, Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Bei Zhong, The Sixth Affiliated Hospital, Guangzhou Medical University/Qingyuan People’s Hospital, Qingyuan 511518, Guangdong Province, China
Yong-Fong Yang, Department of Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
Mao-Rong Wang, Department of Infectious Diseases and Liver Disease Center, The Affiliated Nanjing Jinling Hospital, Nanjing University, Nanjing 210002, Jiangsu Province, China
Author contributions: Yin GQ and Zhong B proposed the views to the infectious disease academic community; all the authors participated in the conception, plan, writing, question-and-answer, and modification of the manuscript; all authors contributed equally to this work.
Conflict-of-interest statement: The authors declare no conflict of interests.
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 NonCommercial (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: Guo-Qing Yin, MD, PhD, Chief Doctor, Chief Physician, Department of Infectious Diseases, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, No. 87 Dingjiaqiao, Nanjing 210009, Jiangsu Province, China. yingq62@sina.com
Received: October 21, 2020
Peer-review started: October 21, 2020
First decision: December 3, 2020
Revised: December 25, 2020
Accepted: January 21, 2021
Article in press: January 21, 2021
Published online: February 28, 2021
Abstract

Chronic hepatitis B virus (HBV) infection (CHB) is a public health concern worldwide. Current therapies utilizing nucleos(t)ide analogs (NA) have not resulted in a complete cure for CHB. Furthermore, patients on long-term NA treatment often develop low-level viremia (LLV). Persistent LLV, in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of NA therapy. Here, we review the literature on LLV, NA treatment, and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent. For LLV patients, three therapeutic options are available, switching to another antiviral monotherapy, interferon-α switching therapy, and continuing monotherapy. In real-world clinical practice, entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV, which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies. The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety, and has great potential in inhibiting HBV replication, in all of the NAs. In the particular section of the drug approval package published by the United States Food and Drug Administration, entecavir doses 2.5-20 mg/d do not increase adverse events, and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy. The literature survey led us to two suggestions: (1) Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA >2 × 106 IU/mL is feasible and would provide better prognosis; and (2) Further research is needed to assess the long-term toxic effects of higher entecavir doses (2.5 and 5.0 mg/d), which may prove beneficial in treating patients with prior NA treatment, partial virological response, or LLV state.

Keywords: Chronic hepatitis B virus infection, Low-level viremia, Therapeutic options, Entecavir, Dose, Efficacy

Core Tip: Persistent low-level viremia (LLV), in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of nucleos(t)ide analog (NA) therapy. Since 2006, the authors focused on NA-refractory and participated in treating LLV patients. We presented the interferon-α switching therapy to treat LLV patient with failure of combined nucleoside plus nucleotide therapy. The current study scoured the literature to shed light on the possibility of improving the antiviral effect of entecavir by increasing the dose. Here, we recommend that clinical trials involving entecavir should trial doses over more 1.0 mg/d for treating NA-refractory patients.