Browse > Article
http://dx.doi.org/10.7314/APJCP.2013.14.9.5489

Prevelance of Common YMDD Motif Mutations in Long Term Treated Chronic HBV Infections in a Turkish Population  

Alagozlu, Hakan (Department of Gastroenterology, Faculty of Medicine, Cumhuriyet University)
Ozdemir, Ozturk (Department of Medical Genetics, Faculty of Medicine, Canakkale Onsekiz Mart University)
Koksal, Binnur (Department of Medical Genetics, Faculty of Medicine, Cumhuriyet University)
Yilmaz, Abdulkerim (Department of Gastroenterology, Faculty of Medicine, Cumhuriyet University)
Coskun, Mahmut (Department of Medical Biology, Faculty of Medicine, Canakkale Onsekiz Mart University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.14, no.9, 2013 , pp. 5489-5494 More about this Journal
Abstract
In the current study we aimed to show the common YMDD motif mutations in viral polymerase gene in chronic hepatitis B patients during lamivudine and adefovir therapy. Forty-one serum samples obtained from chronic hepatitis B patients (24 male, 17 female; age range: 34-68 years) were included in the study. HBV-DNA was extracted from the peripheral blood of the patients using an extraction kit (Invisorb, Instant Spin DNA/RNA Virus Mini Kit, Germany). A line probe assay and direct sequencing analyses (INNO-LIPA HBV DR v2; INNOGENETICS N.V, Ghent, Belgium) were applied to determine target mutations of the viral polymerase gene in positive HBV-DNA samples. A total of 41 mutations located in 21 different codons were detected in the current results. In 17 (41.5%) patients various point mutations were detected leading to lamivudin, adefovir and/or combined drug resistance. Wild polymerase gene profiles were detected in 24 (58.5%) HBV positive patients of the current cohort. Eight of the 17 samples (19.5%) having rtM204V/I/A missense transition and/or transversion point mutations and resistance to lamivudin. Six of the the mutated samples (14.6%) having rtL180M missense transversion mutation and resistance to combined adefovir and lamivudin. Three of the mutated samples (7.5%) having rtG215H by the double base substituation and resistance to adefovir. Three of the mutated samples (7.5%) having codon rtL181W due to the missense transversion point mutations and showed resistance to combined adefovir and lamivudin. Unreported novel point mutations were detected in the different codons of polymerase gene region in the current HBV positive cohort fromTurkish population. The current results provide evidence that rtL180M and rtM204V/I/A mutations of HBV-DNA may be associated with a poor antiviral response and HBV chronicity during conventional therapy in Turkish patients.
Keywords
YMDD; HBV; polymerase gene mutation; long term treatment; HCC risk;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Agca H, Sayiner AA, Sengonul A et al., (2011). A real-time PCR assay for the quantification of hepatitis B virus DNA and concurrent detection of YMDD motif mutations. Mikrobiyol Bul, 45, 664-76.
2 Allen MI, Deslauriers M, Andrews CW, et al (1998). Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology, 27, 1670-7.   DOI   ScienceOn
3 Angus P, Vaughan R, Xiong S, et al (2003). Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology, 125, 292-7.   DOI   ScienceOn
4 Aspinall EJ, Hawkins G, Fraser A, et al (2011). Hepatitis B prevention, diagnosis, treatment and care: a review. Occup Med (Lond), 61, 531-40.   DOI   ScienceOn
5 Balzarini J, Wedgwood O, Kruining J, et al (1996). Anti-HIV and anti-HBV activity and resistance profile of 3TC and its arylphosphoramidate derivative CF 1109. Biochem Biophys Res Commun, 2, 363-9.
6 Bartholomeusz A, Locarnini SA (2006). Antiviral drug resistance: clinical consequences consequences and molecular aspects. Semin Liver Dis, 26, 162-70.   DOI   ScienceOn
7 Baumert TF, Rogers SA, Hasegawa K, Liang TJ (1996). Two core promotor mutations identified in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication. J Clin Invest, 98, 2268-76.   DOI   ScienceOn
8 Carman WF, Trautwein C, van Deursen FJ, et al (1996). Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology, 24, 489.   DOI
9 Chen Y, Wang L, Xu H, et al (2013). Exome capture sequencing reveals new insights into hepatitis B virus-induced hepatocellular carcinoma at the early stage of tumorigenesis. Oncol Rep, 30, 1906-12.   DOI
10 Gaillard RK, Barnard J, Lopez V, et al (2002). Kinetic analysis of wild-type and YMDD mutant hepatitis B virus polymerases and effects of deoxyribonucleotide concentrations on polymerase activity. Antimicrob Agents Chemother, 46, 1005-13.   DOI
11 Chen YM, Wu SH, Qiu CN, et al (2013). Hepatitis B virus subgenotype C2- and B2-associated mutation patterns may be responsible for liver cirrhosis and hepatocellular carcinoma, respectively. Braz J Med Biol Res, 46, 614-22.   DOI
12 Fontana RJ, Keeffe EB, Carey W, et al (2002). Effect of lamivudine treatment on survival of 309 North American patients awaiting liver transplantation for chronic hepatitis B. Liver Transpl, 8, 433-9.   DOI   ScienceOn
13 Geramizadeh B, Nikeghbalian S, Kazemi K, et al (2013). Hepatocellular carcinoma in explanted livers of patients with genotype d HBV cirrhosis: report of the first experience from Iran. Arch Iran Med, 16, 348-50.
14 Fung SK, Chae HB, Fontana RJ, et al (2006). Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol, 44, 283-90   DOI   ScienceOn
15 Ganem D, Prince AM (2004). Hepatitis B virus infection− natural history and clinical consequences. N Engl J Med, 350, 1118-29.   DOI   ScienceOn
16 Gao C, Fang L, Zhao HC, et al (2013). Potential role of diabetes mellitus in the progression of cirrhosis to hepatocellular carcinoma: a cross-sectional case-control study from Chinese patients with HBV infection. Hepatobiliary Pancreat Dis Int, 12, 385-93.   DOI   ScienceOn
17 Guerrieri F, Belloni L, Pediconi N, Levrero M (2013). Molecular mechanisms of HBV-associated hepatocarcinogenesis. Semin Liver Dis, 33, 147-56.   DOI   ScienceOn
18 Gwak GY, Lee CY, Lee DH, et al (2011). Clinical impact of the development of YMDD mutants in hepatitis B virusassociated glomerulonephritis. Hepatogastroenterology, 58, 1291-5.   DOI   ScienceOn
19 Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al (2006). Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis b for up to 5 years. Gastroenterology, 131, 1743-51.   DOI   ScienceOn
20 Johnson MS, McClure MA, Feng DF, et al (1986). Computer analysis of retroviral pol genes: assignment of enzymatic functions to specific sequences and homologies with nonviral enzymes. Proc Natl Acad Sci USA, 83, 7648-52.   DOI   ScienceOn
21 Lavarone M, Colombo M (2013). HBV infection and hepatocellular carcinoma. Clin Liver Dis, 17, 375-97.   DOI   ScienceOn
22 Kim HJ, Park JH, Park DI, et al (2012). The influence of YMDD mutation patterns on clinical outcomes in patients with adefovir add-on lamivudine combination treatment. Liver Int, 32, 303-10.   DOI   ScienceOn
23 Kohlstaedt LA, Wang J, Friedman JM, et al (1992). Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science, 256, 1783-90.   DOI   ScienceOn
24 Lai CL, Chien RN, Leung NW, et al (1998). A one year trial of lamivudine for chronic hepatitis B. Asia hepatitis lamivudine study group. N Engl J Med, 339, 61-8.   DOI   ScienceOn
25 Lee CZ, Lee HS, Huang GT, et al (2006). Detection of YMDD mutation using mutant-specific primers in chronic hepatitis B patients before and after lamivudine treatment. World J Gastroenterol, 12, 5301-5.   DOI
26 Lee SH, Kim HS, Byun IS, et al (2012). Pre-existing YMDD mutants in treatment-naïve patients with chronic hepatitis B are not selected during lamivudine therapy. J Med Virol, 84, 217-22.   DOI   ScienceOn
27 Lee YS, Suh DJ, Lim YS, et al (2006). Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology, 43, 1385-91.   DOI   ScienceOn
28 Li D, Cheng H, Gong W, et al (2013). Detection of primary YMDD mutations in HBV-related hepatocellular carcinoma using hybridization-fluorescence polarization. J Virol Methods, 187, 259-63.   DOI   ScienceOn
29 Lin CL, Kao JH (2008). Hepatitis B viral factors and clinical outcomes of chronic hepatitis B. J Biomed Sci, 15, 137-45.   DOI
30 Liu K, Hou W, Zumbika E, Ni Q (2005). Clinical features of chronic hepatitis B patients with YMDD mutation after lamivudine therapy. J Zhejiang Univ Science B, 6, 1182-8.   DOI   ScienceOn
31 Markowitz JS, Martin P, Conrad AJ, et al (1998). Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatolog, 28, 585-9.   DOI   ScienceOn
32 Matsuda M, Suzuki F, Suzuki Y, et al (2004). YMDD mutants in patients with chronic hepatitis B before treatment are not selected by lamivudine. J Med Virol, 74, 361-6.   DOI   ScienceOn
33 Mello FC, Lago BV, Lewis-Ximenez LL, et al (2012). Detection of mixed populations of wild-type and YMDD hepatitis B variants by pyrosequencing in acutely and chronically infected patients. BMC Microbiol, 12, 96.   DOI
34 Ogata N, Fujii K, Takigawa S, et al (1999). Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in Japanese patients with chronic hepatitis B. J Med Virol, 59, 270-6.   DOI
35 Poch O, Sauvaget I, Delarue M, Tordo N (1989). Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J, 8, 3867-74.
36 Sarma MP, Asim M, Medhi S, et al (2012). Viral genotypes and associated risk factors of hepatocellular carcinoma in India. Cancer Biol Med, 9, 172-81.
37 Sato S, Suzuki K, Akahane Y, et al (1995). Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med, 122, 241-8.   DOI   ScienceOn
38 Schildgen O, Sirma H, Funk A, et al (2006). Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med, 354, 1807-12.   DOI   ScienceOn
39 Singh S, Singh PP, Roberts LR, Sanchez W (2013). Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol, [Epub ahead of print].
40 Schildgen V, Ziegler S, Tillmann RL, Schildgen O (2010). Novel mutation in YMDD motif and direct neighbourhood in a child with chronic HBV-infection and clinical lamivudine and adefovir resistance - a scholarly case. Virol J, 7, 167.   DOI   ScienceOn
41 Tan YW, Ge GH, Zhao W, et al (2012). YMDD motif mutations in chronic hepatitis B antiviral treatment naïve patients: a multi-center study. Braz J Infect Dis, 16, 250-5.   DOI   ScienceOn
42 Vassiliadis T, Nikolaidis N, Giouleme O, et al (2005). Adefovir dipivoxil added to ongoing lamivudine therapy in patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B. Aliment Pharmacol Ther, 21, 531-7.   DOI   ScienceOn
43 Villamil FG (2002). Hepatitis B progress in the last 15 years. Liver Transpl, 8, 59-66.   DOI   ScienceOn
44 Wang LL, Yu XJ, Dong QJ, et al (2012). HBV genotypes distribution and YMDD spontaneous mutation in Qingdao population. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi, 26, 250-2.
45 Wu F, Wu MJ, Zhuge XL et al (2012). Correlation of the occurrence of YMDD mutations with HBV genotypes, HBV-DNA levels, and HBeAg status in Chinese patients with chronic hepatitis B during lamivudine treatment. Hepatobiliary Pancreat Dis Int, 11, 172-6.   DOI   ScienceOn
46 Yang JH, Zhang H, Chen XB, et al (2013). Relationship between hepatocellular carcinoma and hepatitis B virus genotype with spontaneous YMDD mutations. World J Gastroenterol, 19, 3861-5.   DOI   ScienceOn
47 Zhao J, Guo Y, Yan Z, et al (2012). The natural YMDD mutations of hepatitis B virus in Western China. Scand J Infect Dis, 44, 44-7.   DOI   ScienceOn