Yamada N, Igarashi H, Murayama A, Suzuki M, Yasuda K, Saito M, Isogawa M, Kato T. Deep sequencing analysis of hepatitis B virus in patients with incomplete response to tenofovir alafenamide fumarate treatment. World J Hepatol 2025; 17(5): 104519 [DOI: 10.4254/wjh.v17.i5.104519]
Corresponding Author of This Article
Takanobu Kato, MD, PhD, Department of Virology II, National Institute of Infectious Diseases, Toyama, 1-23-1, Tokyo 162-8640, Japan. takato@niid.go.jp
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
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/
Norie Yamada, Michihiro Suzuki, Kiyomi Yasuda, Department of Internal Medicine, Center for Liver Diseases, Seizankai Kiyokawa Hospital, Tokyo 166-0004, Japan
Norie Yamada, Hitomi Igarashi, Asako Murayama, Masumichi Saito, Masanori Isogawa, Takanobu Kato, Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Masumichi Saito, Center for Emergency Preparedness and Response, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Author contributions: Yamada N and Kato T conceived of this study; Yamada N, Suzuki M and Yasuda K were the patient’s attending physicians; Yamada N, Igarashi H, Murayama A, Saito M and Kato T carried out the experiments; Yamada N and Kato T discussed and interpreted the results; Yamada N and Kato T wrote the manuscript; Isogawa M supervised the experiments and project; all authors have read and approved the final manuscript.
Supported by the Japan Agency for Medical Research and Development (AMED), No. JP22fk0310503.
Institutional review board statement: This study was approved by the Ethics Committees of our institutions (approval numbers: 0167 and 1081 from Seizankai Kiyokawa Hospital and the National Institute of Infectious Diseases, respectively).
Informed consent statement: Written informed consent was obtained from each patient.
Conflict-of-interest statement: None of the authors have anything to disclose.
Data sharing statement: The dataset will be provided by the corresponding author (takato@niid.go.jp) upon request.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Takanobu Kato, MD, PhD, Department of Virology II, National Institute of Infectious Diseases, Toyama, 1-23-1, Tokyo 162-8640, Japan. takato@niid.go.jp
Received: December 24, 2024 Revised: March 14, 2025 Accepted: May 10, 2025 Published online: May 27, 2025 Processing time: 154 Days and 23 Hours
Abstract
BACKGROUND
Tenofovir alafenamide fumarate (TAF) is one of the first-line treatments used to treat chronic hepatitis B patients; TAF has strong antiviral activity and a high barrier to resistance. Although virological breakthroughs in patients during TAF treatment are rare, patients with incomplete responses to TAF are occasionally observed.
AIM
To investigate responsible mutations in the reverse transcriptase region of hepatitis B virus (HBV) for TAF-incomplete responses.
METHODS
Thirteen chronic hepatitis B patients who received TAF monotherapy were included. A TAF-incomplete responder was defined as one who was continuously positive for HBV DNA over 2 years after TAF treatment initiation. The emergences of mutations in TAF-incomplete responders were evaluated before, one year after, and two years after treatment by deep sequencing of HBV DNA and RNA.
RESULTS
Two patients were continuously positive for HBV DNA over two years. The rtL269I mutation, one of the CYEI mutations linked to tenofovir resistance, was detected in both patients by direct sequencing. The deep sequencing analysis revealed that a combination of rtT118A and rtL220I mutations and the rtL269I mutation were predominantly detected in HBV DNA even when these mutations were barely detected in HBV RNA. This suggests a superior replication capability of the HBV variants with these mutations under TAF treatment.
CONCLUSION
The deep sequencing analysis of HBV DNA and RNA and comparing the detection rates of mutations were useful for estimating responsible mutations for TAF-incomplete responses. Such analysis is needed to evaluate the association between mutations that emerge during TAF treatment and incomplete responses to TAF.
Core Tip: Tenofovir alafenamide fumarate (TAF) is a potent treatment for chronic hepatitis B with low resistance rates. In this study, two TAF-incomplete responders were investigated. In these patients, mutations of rtL269I and combinations of rtT118A/rtL220I were detected in hepatitis B virus (HBV) DNA predominantly as associated with incomplete response to TAF treatment. The deep sequencing of infected HBV DNA and RNA effectively identified responsible mutations, emphasizing its utility in understanding the association between emerged mutations and incomplete responses to TAF and guiding treatment strategies for incomplete responders.
