1887

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Volume 96, Issue 3

Nucleotide analogue-resistant mutations in hepatitis B viral genomes found in hepatitis B patients Free

Abstract

Chronic hepatitis B (CHB) is treated with nucleos(t)ide analogues (NAs). The reverse transcriptase (RT) region in the hepatitis B virus (HBV) genome mutates to resist NA treatment, yet the RT mutations have not been well characterized. Furthermore, the HBV genotype might influence RT sequence evolution, NA resistance (NAr) mutation patterns and drug resistance development. We examined 42 NAr mutation sites in 169 untreated and 131 NA-treated CHB patient samples. Patients were identified with HBV-B and HBV-C genotype infections, with a higher prevalence and mutation frequency of HBV-C than HBV-B. Seventeen reported NAr mutation sites and 13 novel mutations were detected. NAr-related mutation prevalence was significantly higher in NA-treated versus untreated patients. Primary antiviral-resistant mutants only existed in NA-treated patients. Sequencing data revealed seven HBV-C-specific mutations and three HBV-B-specific mutations. In conclusion, NA treatment and HBV genotype might constitute the selection basis and promote NA-resistant HBV strain evolution under antiviral therapy.

  • Received:
  • Accepted:
  • Published Online:
© 2015 The Authors
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2015-03-01
2024-04-25
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References

  1. Baldick C. J., Tenney D. J., Mazzucco C. E., Eggers B. J., Rose R. E., Pokornowski K. A., Yu C. F., Colonno R. J. 2008; Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance. Hepatology 47:1473–1482 [View Article][PubMed]
     [Google Scholar]
  2. Bartholomeusz A., Tehan B. G., Chalmers D. K. 2004; Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations. Antivir Ther 9:149–160[PubMed]
     [Google Scholar]
  3. Chen G. C., Yu T., Huang K. H., Chen Q. K. 2012; Antiviral therapy of decompensated hepatitis B virus-related cirrhosis. Chin Med J (Engl) 125:373–377[PubMed]
     [Google Scholar]
  4. Damerow H., Yuen L., Wiegand J., Walker C., Bock C. T., Locarnini S., Tillmann H. L. 2010; Mutation pattern of lamivudine resistance in relation to hepatitis B genotypes: hepatitis B genotypes differ in their lamivudine resistance associated mutation pattern. J Med Virol 82:1850–1858 [View Article][PubMed]
     [Google Scholar]
  5. Franco E., Bagnato B., Marino M. G., Meleleo C., Serino L., Zaratti L. 2012; Hepatitis B: epidemiology and prevention in developing countries. World J Hepatol 4:74–80 [View Article][PubMed]
     [Google Scholar]
  6. Fung J., Lai C. L., Seto W. K., Yuen M. F. 2011; Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. J Antimicrob Chemother 66:2715–2725 [View Article][PubMed]
     [Google Scholar]
  7. Ghany M. G., Doo E. C. 2009; Antiviral resistance and hepatitis B therapy. Hepatology 49:SupplS174–S184 [View Article][PubMed]
     [Google Scholar]
  8. Han Y., Huang L. H., Liu C. M., Yang S., Li J., Lin Z. M., Kong X. F., Yu M., Zhang D. H.other authors 2009; Characterization of hepatitis B virus reverse transcriptase sequences in Chinese treatment naive patients. J Gastroenterol Hepatol 24:1417–1423 [View Article][PubMed]
     [Google Scholar]
  9. Kao J. H., Chen P. J., Lai M. Y., Chen D. S. 2000; Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 118:554–559 [View Article][PubMed]
     [Google Scholar]
  10. Keeffe E. B., Dieterich D. T., Pawlotsky J. M., Benhamou Y. 2008; Chronic hepatitis B: preventing, detecting, and managing viral resistance. Clin Gastroenterol Hepatol 6:268–274 [View Article][PubMed]
     [Google Scholar]
  11. Khudyakov Y. 2010; Coevolution and HBV drug resistance. Antivir Ther 15:505–515 [View Article][PubMed]
     [Google Scholar]
  12. Kobashi H., Fujioka S., Kawaguchi M., Kumada H., Yokosuka O., Hayashi N., Suzuki K., Okanoue T., Sata M.other authors 2009; Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naive chronic hepatitis B. Hepatol Int 3:403–410 [View Article][PubMed]
     [Google Scholar]
  13. Lee Y. S., Chung Y. H., Kim J. A., Jin Y. J., Park W. H., Kim S. E., Lee D., Shim J. H., Kim K. M.other authors 2012; rtL180M mutation of hepatitis B virus is closely associated with frequent virological resistance to adefovir dipivoxil therapy. J Gastroenterol Hepatol 27:300–305 [View Article][PubMed]
     [Google Scholar]
  14. Leung N. W., Lai C. L., Chang T. T., Guan R., Lee C. M., Ng K. Y., Lim S. G., Wu P. C., Dent J. C.other authors 2001; Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 33:1527–1532 [View Article][PubMed]
     [Google Scholar]
  15. Li X. G., Liu B. M., Xu J., Liu X. E., Ding H., Li T. 2012; Discrepancy of potential antiviral resistance mutation profiles within the HBV reverse transcriptase between nucleos(t)ide analogue-untreated and -treated patients with chronic hepatitis B in a hospital in China. J Med Virol 84:207–216 [View Article][PubMed]
     [Google Scholar]
  16. Liaw Y. F., Sung J. J., Chow W. C., Farrell G., Lee C. Z., Yuen H., Tanwandee T., Tao Q. M., Shue K.other authors 2004; Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 351:1521–1531 [View Article][PubMed]
     [Google Scholar]
  17. Liu B. M., Li T., Xu J., Li X. G., Dong J. P., Yan P., Yang J. X., Yan L., Gao Z. Y.other authors 2010; Characterization of potential antiviral resistance mutations in hepatitis B virus reverse transcriptase sequences in treatment-naïve Chinese patients. Antiviral Res 85:512–519 [View Article][PubMed]
     [Google Scholar]
  18. Liu Y., Wang C., Zhong Y., Li X., Dai J., Ren X., Xu Z., Li L., Yao Z.other authors 2011; Genotypic resistance profile of hepatitis B virus (HBV) in a large cohort of nucleos(t)ide analogue-experienced Chinese patients with chronic HBV infection. J Viral Hepat 18:e29–e39 [View Article][PubMed]
     [Google Scholar]
  19. Locarnini S. 2008; Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure. Hepatol Int 2:147–151 [View Article][PubMed]
     [Google Scholar]
  20. Locarnini S., Mason W. S. 2006; Cellular and virological mechanisms of HBV drug resistance. J Hepatol 44:422–431 [View Article][PubMed]
     [Google Scholar]
  21. Locarnini S., Hatzakis A., Heathcote J., Keeffe E. B., Liang T. J., Mutimer D., Pawlotsky J. M., Zoulim F. 2004; Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther 9:679–693[PubMed]
     [Google Scholar]
  22. Lok A. S., Zoulim F., Locarnini S., Bartholomeusz A., Ghany M. G., Pawlotsky J. M., Liaw Y. F., Mizokami M., Kuiken C.Hepatitis B Virus Drug Resistance Working Group 2007a; Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 46:254–265 [View Article][PubMed]
     [Google Scholar]
  23. Lok A. S., Everhart J. E., Chung R. T., Padmanabhan L., Greenson J. K., Shiffman M. L., Everson G. T., Lindsay K. L., Bonkovsky H. L.other authors 2007b; Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial. Clin Gastroenterol Hepatol 5:245–254 [View Article][PubMed]
     [Google Scholar]
  24. Maeshiro T., Arakaki S., Watanabe T., Aoyama H., Shiroma J., Yamashiro T., Hirata T., Hokama A., Kinjo F.other authors 2007; Different natural courses of chronic hepatitis B with genotypes B and C after the fourth decade of life. World J Gastroenterol 13:4560–4565[PubMed]
     [Google Scholar]
  25. Mirandola S., Campagnolo D., Bortoletto G., Franceschini L., Marcolongo M., Alberti A. 2011; Large-scale survey of naturally occurring HBV polymerase mutations associated with anti-HBV drug resistance in untreated patients with chronic hepatitis B. J Viral Hepat 18:e212–e216 [View Article][PubMed]
     [Google Scholar]
  26. Mirandola S., Sebastiani G., Rossi C., Velo E., Erne E. M., Vario A., Tempesta D., Romualdi C., Campagnolo D., Alberti A. 2012; Genotype-specific mutations in the polymerase gene of hepatitis B virus potentially associated with resistance to oral antiviral therapy. Antiviral Res 96:422–429 [View Article][PubMed]
     [Google Scholar]
  27. Nakayoshi T., Maeshiro T., Nakayoshi T., Nakasone H., Sakugawa H., Kinjo F., Orito E., Mizokami M. 2003; Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands: a prospective study. J Med Virol 70:350–354 [View Article][PubMed]
     [Google Scholar]
  28. Pan X. P., Li L. J., Du W. B., Li M. W., Cao H. C., Sheng J. F. 2007; Differences of YMDD mutational patterns, precore/core promoter mutations, serum HBV DNA levels in lamivudine-resistant hepatitis B genotypes B and C. J Viral Hepat 14:767–774 [View Article][PubMed]
     [Google Scholar]
  29. Pan X., Zhang K., Yang X., Liang J., Sun H., Li X., Zou Y., Xu Q., An G.other authors 2013; Relapse rate and associated-factor of recurrence after stopping NUCs therapy with different prolonged consolidation therapy in HBeAg positive CHB patients. PLoS One 8:e68568 [View Article][PubMed]
     [Google Scholar]
  30. Pastor R., Habersetzer F., Fafi-Kremer S., Doffoel M., Baumert T. F., Gut J. P., Stoll-Keller F., Schvoerer E. 2009; Hepatitis B virus mutations potentially conferring adefovir/tenofovir resistance in treatment-naive patients. World J Gastroenterol 15:753–755 [View Article][PubMed]
     [Google Scholar]
  31. Rapti I., Dimou E., Mitsoula P., Hadziyannis S. J. 2007; Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 45:307–313 [View Article][PubMed]
     [Google Scholar]
  32. Seifer M., Patty A., Serra I., Li B., Standring D. N. 2009; Telbivudine, a nucleoside analog inhibitor of HBV polymerase, has a different in vitro cross-resistance profile than the nucleotide analog inhibitors adefovir and tenofovir. Antiviral Res 81:147–155 [View Article][PubMed]
     [Google Scholar]
  33. Shaw T., Bartholomeusz A., Locarnini S. 2006; HBV drug resistance: mechanisms, detection and interpretation. J Hepatol 44:593–606 [View Article][PubMed]
     [Google Scholar]
  34. Svicher V., Gori C., Trignetti M., Visca M., Micheli V., Bernassola M., Salpini R., Gubertini G., Longo R.other authors 2009; The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes. J Hepatol 50:461–470 [View Article][PubMed]
     [Google Scholar]
  35. Warner N., Locarnini S., Kuiper M., Bartholomeusz A., Ayres A., Yuen L., Shaw T. 2007; The L80I substitution in the reverse transcriptase domain of the hepatitis B virus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro. Antimicrob Agents Chemother 51:2285–2292 [View Article][PubMed]
     [Google Scholar]
  36. Yang J. X., Liu B. M., Li X. G., Yan C. H., Xu J., Sun X. W., Wang Y. H., Jiao X. J., Yan L.other authors 2010; Profile of HBV antiviral resistance mutations with distinct evolutionary pathways against nucleoside/nucleotide analogue treatment among Chinese chronic hepatitis B patients. Antivir Ther 15:1171–1178 [View Article][PubMed]
     [Google Scholar]
  37. Zhang A. M., Wang H. F., Wang H. B., Su H. B., Xin S. J., Hu J. H., You S. L. 2011; Distribution and clinical significance of HBV genotypes in patients with HBV infection in 30 regions of China. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 25:126–128 (in Chinese) [PubMed]
     [Google Scholar]
  38. Zhao S., Tang L., Fan X., Chen L., Zhou R., Dai X. 2010; Comparison of the efficacy of lamivudine and telbivudine in the treatment of chronic hepatitis B: a systematic review. Virol J 7:211 [View Article][PubMed]
     [Google Scholar]
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Nucleotide analogue-resistant mutations in hepatitis B viral genomes found in hepatitis B patients
J. Gen. Virol. 96, 663 (2015); https://doi.org/10.1099/jgv.0.000010
/content/journal/jgv/10.1099/jgv.0.000010
/content/journal/jgv/10.1099/jgv.0.000010
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