Multiple drug-resistant HBV mutation may contribute to poor response of adefovir + entecavir in entecavir-resistant patients

  • Jinman Shao The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Yan Liu The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Li-Ming Liu Beijing Xiaotangshan Hospital, Beijing, China
  • Rongjuan Chen The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Li Zhao The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Yi Zhou The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Le Li The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Xiaodong Li The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Jin Li MedicaI Department, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
  • Dongping Xu The Institute of Infectious Diseases, Fifth Medical Center of PLA General Hospital (Beijing 302 Hospital), Beijing, China
Keywords: Hepatitis B virus, Entecavir-resistant, Multidrug-resistant, Mutation, Rescue therapy

Abstract

Introduction: Adefovir plus entecavir (ADV+ETV) rescue therapy in ETV-resistant patients with chronic hepatitis B virus (HBV) infection is suboptimal in some patients. This study aims to elucidate the evolutionary characteristics of drug-resistant HBV mutants and their association with clinical responses in such patients.

Methodology: Thirty-seven ETV-resistant patients were enrolled, among whom twelve had an inadequate virological response to ADV+ETV rescue therapy. The clonal sequence (³ 20 clones/sample) of HBV reverse transcriptase gene was performed to identify the resistance mutations. Phenotypic analysis was performed to evaluate the replication capacity and drug susceptibility of the mutants.

Results: ETV-resistant mutants were continuously detected in 10 of the 12 patients, and multidrug-resistant (MDR) mutants, including a novel strain (rtL180M+A181V+T184A+S202G+M204V), were detected in two patients. Seven of the 12 patients who subsequently received tenofovir (TDF)-based therapy for 38 (23−60) months all achieved undetectable HBV DNA after treatment, and ETV-resistant mutants converted to wild-type in the four patients’ samples. In contrast, the other five patients who did not achieve an adequate virological response had remaining of ETV-resistant mutants. The novel MDR strain exhibited multiple resistances to LAM, ADV, and ETV, and 11.2-fold lower susceptibility to TDF.

Conclusions: This study is the first to demonstrate that MDR HBV mutations may contribute to the poor efficacy of ADV+ETV combination therapy in ETV-resistant patients. Moreover, a novel MDR HBV strain was identified. Our results indicate that a TDF-based rescue therapy would be effective for the treatment of the refractory cases.

Published
2021-01-31
How to Cite
1.
Shao J, Liu Y, Liu L-M, Chen R, Zhao L, Zhou Y, Li L, Li X, Li J, Xu D (2021) Multiple drug-resistant HBV mutation may contribute to poor response of adefovir + entecavir in entecavir-resistant patients. J Infect Dev Ctries 15:131-140. doi: 10.3855/jidc.12643
Section
Original Articles