Identification of novel HBV resistant to tenofovir (TDF) and elucidation of the resistance mechanisms

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16996
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kumamoto University
• Principal Investigator: Hayashi Sanae 熊本大学, 大学院生命科学研究部(医), 特任助教 (10597587)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: B型肝炎ウイルス / 核酸アナログ / テノホビル / 変異 / 耐性 / genotype / 肝臓学

Outline of Final Research Achievements

HBV from thirty-four patients with chronic hepatitis B with multiple drug failure at nationwide multicenter survey were sequenced. Among 23 patients with LAM+ETV failure, 3 patients with LAM or ETV+ADV failure, and 8 patients with ETV+TDF failure, we identified novel mutation in RT region of HBV in 20 of 25 patients with the well-documented drug resistance mutations. A plasmid carrying a replication-competent 1.24-fold HBV genome, isolated from sera of patient who developed VBT during TDF/ETV combination therapy and with the novel RT mutation and ETV-resistant mutations, was tested for TDF susceptibility in vitro. The novel RT mutation plus ETV-resistance mutations reduced susceptibility to TDF compared with the wild-type genotype Ce HBV clone, ADV-resistant 1 strain, and ETV-resistant 2 strains, while the novel RT mutation was equally susceptible to TDF treatment compared with wild-type clone.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

現在推奨される核酸アナログ(NAs)はいずれも強力にHBV複製を抑制するが、HBV根絶には至らないため、B型慢性肝炎の治療適応例の多くは多剤NAs治療を継続している。我々は、ETV/TDFに対して抵抗性を示すB型慢性肝炎症例より新規コンビネーションHBV株を同定し、TDF感受性の低下に寄与することを明らかにした。これまでにETV・TDFに対する交叉耐性変異の報告はないとされるが、推奨NAsであるETVおよびTDF/TAFに対する耐性変異を保有する慢性肝炎症例も散見されることから、今後もNAs治療により薬剤耐性変異株が出現する可能性は疑う余地がない。