Detection and analysis of resistance mutations of hepatitis B virus.

OBJECTIVE To investigate the relationships of resistance mutations of hepatitis B virus (HBV) with replication and genotypes of HBV and to understand the common resistance mutations and mutation pattern. METHODS The mutation patterns related to resistance to nucleoside drugs were analyzed, and the relationships of resistance mutations with HBV genotypes, Ct value, HBeAg, alanine aminotransferase (ALT), age and gender were evaluated. RESULTS Genotype B was found in 52 patients (73.2%) and genotype C in 19 patients (26.8%). In addition, 32 patients (45.07%) had resistance mutations at different loci, of which single base mutation accounted for 56.25% (18/32) and multi-base mutation for 43.75% (14/32). Of single base mutation, L180M, M204I, M204V and V173L had higher prevalence, and the incidence of L180M was closely related to the genotype of HBV. L180M, M204I and M204V were associated with the resistance to lamivudine and telbivudine; L180M, M204I, M204V and V173L were associated with the resistance to entecavir; A181T, N236T and N/H238T were related to the resistance to adefovir. Of multi-base mutations, L180M combined M204V had a high prevalence and were frequently found in patients with resistance to lamivudine and telbivudine. There was cross-resistance between lamivudine and telbivudine, between lamivudine and entecavir, and between entecavir and telbivudine. The Ct value of HBV DNA, HBeAg, ALT, age and gender were comparable among patients with different resistance mutations and HBV genotypes. CONCLUSION Detection of mutations of multiloci resistance genes is helpful for timely identification of HBV resistance and the clinical anti-virus therapy.

[1]  K. Koike,et al.  Resistance mutations of hepatitis B virus in entecavir‐refractory patients , 2017, Hepatology communications.

[2]  V. Wong,et al.  The rtA181S mutation of hepatitis B virus primarily confers resistance to adefovir dipivoxil , 2015, Journal of viral hepatitis.

[3]  Xinxin Zhang,et al.  Investigation into Drug-Resistant Mutations of HBV from 845 Nucleoside/Nucleotide Analogue-Naive Chinese Patients with Chronic HBV Infection , 2015, Antiviral therapy.

[4]  T. Santantonio,et al.  Chronic hepatitis B: Advances in treatment. , 2014, World journal of hepatology.

[5]  M. Yuen,et al.  Extrahepatic effects of nucleoside and nucleotide analogues in chronic hepatitis B treatment , 2014, Journal of gastroenterology and hepatology.

[6]  Z. Saat,et al.  Drug-Resistance Associated Mutations in Polymerase (P) Gene of Hepatitis B Virus Isolated From Malaysian HBV Carriers , 2014, Hepatitis monthly.

[7]  Soon Sun Kim,et al.  Multidrug‐resistant hepatitis B virus resulting from sequential monotherapy with lamivudine, adefovir, and entecavir: Clonal evolution during lamivudine plus adefovir therapy , 2013, Journal of medical virology.

[8]  H. Lee,et al.  rtL180M mutation of hepatitis B virus is closely associated with frequent virological resistance to adefovir dipivoxil therapy , 2012, Journal of gastroenterology and hepatology.

[9]  Pei-Jer Chen,et al.  High-Resolution Melting and Real-Time Pcr for Quantification and Detection of Drug-Resistant HBV Mutants in a Single Amplicon , 2012, Antiviral therapy.

[10]  C. Yeh,et al.  Identification of hepatitis B virus rtS117F substitution as a compensatory mutation for rtM204I during lamivudine therapy. , 2012, The Journal of antimicrobial chemotherapy.

[11]  P. Hu,et al.  Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis , 2011, Virology Journal.

[12]  Y. Kondo,et al.  Four‐year study of lamivudine and adefovir combination therapy in lamivudine‐resistant hepatitis B patients: influence of hepatitis B virus genotype and resistance mutation pattern , 2011, Journal of viral hepatitis.

[13]  Jia Jidon.  [The guideline of prevention and treatment for chronic hepatitis B (2010 version)]. , 2011, Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology.

[14]  H. Zhuang,et al.  Profile of HBV antiviral resistance mutations with distinct evolutionary pathways against nucleoside/ nucleotide analogue treatment among Chinese chronic hepatitis B patients , 2010, Antiviral therapy.

[15]  F. Zoulim,et al.  Hepatitis B virus resistance to nucleos(t)ide analogues. , 2009, Gastroenterology.

[16]  F. Zoulim,et al.  Hepatitis B virus in tenofovir-naive Chinese patients with chronic hepatitis B contains no mutation of rtA194T conferring a reduced tenofovir susceptibility. , 2009, Chinese medical journal.

[17]  F. Lu,et al.  Management of hepatitis B in China. , 2009, Chinese medical journal.

[18]  Yoshiyuki Suzuki,et al.  Low risk of adefovir resistance in lamivudine-resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: two-year follow-up. , 2008, Journal of hepatology.

[19]  S. Locarnini.  Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure , 2008, Hepatology international.

[20]  Boping Zhou,et al.  Hepatitis B virus (HBV) genotypes/subgenotypes in China: mutations in core promoter and precore/core and their clinical implications. , 2007, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[21]  S. Locarnini,et al.  Cellular and virological mechanisms of HBV drug resistance. , 2006, Journal of hepatology.

[22]  J. Gollan,et al.  Emerging therapeutics for chronic hepatitis B. , 2006, Annual review of medicine.

[23]  S. Ma,et al.  Geographic distribution, virologic and clinical characteristics of hepatitis B virus genotypes in China , 2005, Journal of viral hepatitis.

[24]  Huiling Yang,et al.  Cross-Resistance Testing of Next-Generation Nucleoside and Nucleotide Analogues against Lamivudine-Resistant HBV , 2005, Antiviral therapy.

[25]  J. Villeneuve,et al.  Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir , 2005, Hepatology.

[26]  M. Wulfsohn,et al.  Activity of adefovir dipivoxil against all patterns of lamivudine‐resistant hepatitis B viruses in patients , 2005, Journal of viral hepatitis.

[27]  W. Hou,et al.  Character of HBV (hepatitis B virus) polymerase gene rtM204V/I and rtL180M mutation in patients with lamivudine resistance. , 2005, Journal of Zhejiang University. Science. B.

[28]  F. Zoulim.  Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection. , 2004, Antiviral research.

[29]  P. Angus,et al.  Clinical Emergence of Entecavir-Resistant Hepatitis B Virus Requires Additional Substitutions in Virus Already Resistant to Lamivudine , 2004, Antimicrobial Agents and Chemotherapy.

[30]  E. Keeffe,et al.  Management of Antiviral Resistance in Patients with Chronic Hepatitis B , 2004, Antiviral therapy.

[31]  C. Katlama,et al.  In Vitro Susceptibility of Lamivudine-Resistant Hepatitis B Virus to Adefovir and Tenofovir , 2003, Antiviral therapy.

[32]  J. L. Sims.  Management of hepatitis. , 1969, Wisconsin medical journal.