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World J Gastroenterol. Apr 28, 2018; 24(16): 1708-1724
Published online Apr 28, 2018. doi: 10.3748/wjg.v24.i16.1708
Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression
Yu-Min Choi, So-Young Lee, Bum-Joon Kim
Yu-Min Choi, So-Young Lee, Bum-Joon Kim, Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, Seoul National University, College of Medicine, Seoul 110799, South Korea
Author contributions: Kim BJ conceived participated in its design and coordination; Choi YM and Lee SY analyzed and interpreted the data.
Supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute and the Ministry of Health and Welfare, South Korea, No. HI14C0955.
Conflict-of-interest statement: There was no conflict of interest.
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: Bum-Joon Kim, PhD, Professor, Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul 110799, South Korea. kbumjoon@snu.ac.kr
Telephone: +82-2-7408316 Fax: +82-2-7430881
Received: March 27, 2018
Peer-review started: March 27, 2018
First decision: April 3, 2018
Revised: April 10, 2018
Accepted: April 16, 2018
Article in press: April 16, 2018
Published online: April 28, 2018
Processing time: 30 Days and 19.7 Hours
Abstract

The annual number of deaths caused by hepatitis B virus (HBV)-related disease, including cirrhosis and hepatocellular carcinoma (HCC), is estimated as 887000. The reported prevalence of HBV reverse transcriptase (RT) mutation prior to treatment is varied and the impact of preexisting mutations on the treatment of naïve patients remains controversial, and primarily depends on geographic factors, HBV genotypes, HBeAg serostatus, HBV viral loads, disease progression, intergenotypic recombination and co-infection with HIV. Different sensitivity of detection methodology used could also affect their prevalence results. Several genotype-dependent HBV RT positions that can affect the emergence of drug resistance have also been reported. Eight mutations in RT (rtL80I, rtD134N, rtN139K/T/H, rtY141F, rtM204I/V, rtF221Y, rtI224V, and rtM309K) are significantly associated with HCC progression. HBeAg-negative status, low viral load, and genotype C infection are significantly related to a higher frequency and prevalence of preexisting RT mutations. Preexisting mutations are most frequently found in the A-B interdomain of RT which overlaps with the HBsAg “a” determinant region, mutations of which can lead to simultaneous viral immune escape. In conclusion, the presence of baseline RT mutations can affect drug treatment outcomes and disease progression in HBV-infected populations via modulation of viral fitness and host-immune responses.

Keywords: Polymerase; Hepatocellular carcinoma; Reverse transcriptase; Preexisting mutations; Hepatitis B virus

Core tip: The prevalence of preexisting reverse transcriptase (RT) mutations in treatment-naïve patients largely depends on geographic factors, HBV genotypes, HBeAg serostatus, hepatitis B virus (HBV) viral loads, disease progression, intergenotypic recombination, co-infection with HIV and the method used for detecting the mutation. Genotype-dependent polymorphic amino acid substitutions in RT may affect the emergence of drug resistance, and genotype C exhibits relatively elevated spontaneous RT mutation rates. HBeAg-negative status and low viral loads are significantly associated with a higher frequency and prevalence of HBV preexisting RT mutations. Preexisting mutations are most frequently found in the A-B interdomain of RT, mutations of which can lead to simultaneous viral immune escape.