Abstract
Purpose
Data on genotypes, basal core promoter (BCP) and precore mutants of hepatitis B virus and their association with different HBV related liver disease have been studied inadequately and are controversial. Thus, the aim of this study was to determine the incidence of BCP and precore HBV mutants and their relationship with HBV genotype and different stages of HBV related liver disease in North Indian patients.
Methods
A total 273 patients with different stages of HBV related liver diseases were enrolled. Nested polymerase chain reaction (PCR) was used to amplify the BCP/PC regions. RFLP and direct sequencing were performed to validate the mutations identified in these regions. HBV genotyping was accomplished by multiplex PCR.
Results
Genotype D was the predominant genotype found in each of the various HBV related liver diseases. The BCP mutation was found significantly more often in inactive carriers and compensated cirrhosis as compared to the other groups. The BCP mutation was present in 29.1% of patients with genotype D versus 17.1% with genotype A (P = 0.001). The precore mutation was also more frequently observed with genotype D compared with genotype A (36.9 vs. 4.8%, P = 0.0007).
Conclusion
Genotype D is predominant in North Indian patients. The BCP and precore mutations occur in one-third of HBV positive patients in association with the genotype D. We did not find any correlation with severity of liver disease with genotypes and mutations.
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References
Lee WM. Hepatitis B virus infection. N Engl J Med. 1997;337:1733–1745.
John TJ, Abraham P. Hepatitis B in India: A review of disease epidemiology. Indian Pediatr. 2001;38:1318–1322.
Thyagrajan SP, Jayaram S, Mohanvalli B. Prevalence of HBV in the general population of India. In: Sarin SK, Singhal AK, eds. Hepatitis B in India. New Delhi: CBS Publishers; 1996:9.
Locarnini S, Mcmillan J, Bartholomeusz A. The hepatitis B virus and common mutants. Semin Liver Dis. 2003;23:5–20.
Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Hepatology. 2000;31:1037–1044.
Petrosillo N, Ippolito G, Solforosi L, Varaldo PE, Clementi M, Manzin A. Molecular epidemiology of an outbreak of fulminant hepatitis B. J Clin Microbiol. 2000;38:2975–2981.
Okamoto H, Tsuda F, Sakugawa H, et al. Typing hepatitis B virus by homology in nucleotide sequence: Comparison of surface antigen subtypes. J Gen Virol. 1988;69:2575–2583.
Thakur V, Guptan RC, Kazim SN, Malhotra V, Sarin SK. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. J Gastroenterol Hepatol. 2002;17:165–170.
Kumar A, Kumar SI, Pandey R, Naik S, Aggarwal R. Hepatitis B virus genotype A is more often associated with severe liver disease in northern India than is genotype D. Indian J Gastroenterol. 2005;24:19–22.
Gandhe SS, Chadha MS, Arankalle VA. Hepatitis B virus genotypes and serotypes in western India: Lack of clinical significance. J Med Virol. 2003;69:324–330.
Sugauchi F, Orito E, Kato H, et al. Genotype, serotype, and phylogenetic characterization of the complete genome sequence of hepatitis B virus isolates from Malawian chronic carriers of the virus. J Med Virol. 2003;69:33–40.
Chan HL, Wong ML, Hui AY, Hung LC, Chan FK, Sung JJ. Hepatitis B virus genotype C takes a more aggressive disease course than hepatitis B virus genotype B in hepatitis B e antigen-positive patients. J Clin Microbiol. 2003;41:1277–1279.
Sakugawa H, Nakasone H, Nakayoshi T, et al. Preponderance of hepatitis B virus genotype B contributes to a better prognosis of chronic HBV infection in Okinawa, Japan. J Med Virol. 2002;67:484–489.
Sherlock S, Dooley J. Virus hepatitis. In: Diseases of the Liver and Biliary System. Blackwell Science;1997:265–302.
Trey C, Lipworth L, Chalmers TC, et al. Fulminant hepatic failure. Presumably contribution of halothane. N Eng J Med. 1968;279:798–801.
Fujiwara K, Yokosuka O, Ehata T, et al. The two different states of hepatitis B virus DNA in asymptomatic carriers: HBe-antigen-positive versus anti-HBe-positive asymptomatic carriers. Dig Dis Sci. 1998;43:368–376.
Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000—summary of a workshop. Gastroenterology. 2001;120:1828–1853.
Gentilini P, Laffi G, La Villa G, et al. Long course and prognostic factors of virus-induced cirrhosis of the liver. Am J Gastroenterol. 1997;92:66–72.
Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona–2000 EASL conference. European Association for the Study of Liver. J Hepatol. 2001;35:421–430.
Naito H, Hayashi S, Abe K. Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers. J Clin Microbiol. 2001;39:362–364.
Takahashi K, Aoyama K, Ohno N, et al. The precore/core promoter mutant (T1762A1764) of hepatitis B virus: Clinical significance and an easy method for detection. J Gen Virol. 1995;76:3159–3164.
Vivekanandan P, Abraham P, Sridharan G, et al. Distribution of hepatitis B virus genotypes in blood donors and chronically infected patients in a tertiary care hospital in southern India. Clin Infect Dis. 2004;38:81–86.
Arankalle VA, Murhekar KM, Gandhe SS, et al. Hepatitis B virus: Predominance of genotype D in primitive tribes of the Andaman and Nicobar Islands, India (1989–1999). J Gen Virol. 2003;84:1915–1920.
Chattopadhyay S, Das BC, Hussain Z, Kar P. Hepatitis B virus genotypes in acute and fulminant hepatitis patients from North India using two different molecular genotyping approaches. Hepatol Res. 2006;35:79–82.
Guptan RC, Thakur V, Sarin SK, Banerjee K, Khandekar P. Frequency and clinical profile of precore and surface hepatitis B mutants in Asian-Indian patients with chronic liver disease. Am J Gastroenterol. 1996;91:1312–1317.
Song BC, Cui XJ, Kim UH, Cho YK. Sequential accumulation of the basal core promoter and the precore mutations in the progression if hepatitis B virus related chronic liver disease. Intervirology. 2006;49:266–273.
Okamoto H, Tsuda F, Akahane Y, et al. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol. 1994;68:8102–8110.
Okamoto H, Yotsumoto S, Akahane Y, et al. Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol. 1990;64:1298–1303.
Chu CJ, Keeffe EB, Han SH, et al. U.S. HBV epidemiology study group. Prevalence of HBV precore/core promoter variants in the United States. Hepatology. 2003;38:619–628.
Datta S, Biswas A, Chandra PK, et al. Molecular epidemiology and clinical significance of hepatitis B virus genotypes, core promoter and precore mutations in eastern India. Intervirology. 2008;51:275–284.
Chauhan R, Kazim SN, Bhattacharjee J, Sakhuja P, Sarin SK. Basal core promoter, precore region mutations of HBV and their association with e antigen, genotype, and severity of liver disease in patients with chronic hepatitis B in India. J Med Virol. 2006;78:1047–1054.
Li JS, Tong SP, Wen YM, Vitvitski L, Zhang Q, Trepo C. Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region. J Virol. 1993;67:5402–5410.
Honda A, Yokosuka O, Ehata T, Tagawa M, Imazeki F, Saisho H. Detection of mutations in the enhancer 2/core promoter region of hepatitis B virus in patients with chronic hepatitis B virus infection: Comparison with mutations in precore and core regions in relation to clinical status. J Med Virol. 1999;57:337–344.
Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci USA. 1994;91:4077–4081.
Junker-Niepmann M, Bartenschlager R, Schaller H. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J. 1990;9:3389–3396.
Kramvis A, Kew MC. Structure and function of the encapsidation signal of hepadnaviridae. J Viral Hepat. 1998;5:357–367.
Tsugeno H, Yamada G, Kinoshita M, Shimomura H, Iwasaki Y, Tsuji T. Quantitative analysis of wild-type and precore mutant hepatitis B virus in carriers. Hepatol Res. 2002;23:48–54.
Sterneck M, Gunther S, Santantonio T, et al. Hepatitis B virus genomes of patients with fulminant hepatitis do not share a specific mutation. Hepatology. 1996;24:300–306.
Chan HL, Hussain M, Lok AS. Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology. 1999;29:976–984.
Kidd-Ljunggren K, Miyakawa Y, Kidd AH. Genetic variability in hepatitis B viruses. J Gen Virol. 2002;83:1267–1280.
Laskus T, Rakela J, Persing DH. The stem-loop structure of the cis-encapsidation signal is highly conserved in naturally occurring hepatitis B virus variants. Virology. 1994;200:809–812.
Niitsuma H, Ishii M, Saito Y, et al. Prevalence of precore-defective mutant of hepatitis B virus in HBV carriers. J Med Virol. 1995;46:397–402.
Cabrerizo M, Bartolome J, Ruiz-Moreno M, Otero M, Lopez-Alcorocho JM, Carreno V. Distribution of the predominant hepatitis B virus precore variants in hepatitis B e antigen-positive children and their effect on treatment response. Pediatr Res. 1996;39:980–984.
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Sharma, S., Sharma, B., Singla, B. et al. Clinical Significance of Genotypes and Precore/Basal Core Promoter Mutations in HBV Related Chronic Liver Disease Patients in North India. Dig Dis Sci 55, 794–802 (2010). https://doi.org/10.1007/s10620-009-1083-y
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DOI: https://doi.org/10.1007/s10620-009-1083-y