NUCLEOTIDE SUBSTITUTIONS IN HEPATITIS B VIRUSES DERIVED FROM CHRONIC HBV PATIENTS
Main Article Content
Keywords
Abstract
Background: Mutations in the S gene (HBsAg), precore (PC) and basic core promoter (BCP) of the hepatitis B virus (HBV) are correlated with a wide spectrum of diseases. This study assessed the frequency of mutations in the S gene, PC and BCP regions in chronic hepatitis B (CHB) patients.
Methods: 104 CHB patients who visited Tehran Hepatitis centers, were included. The viral load of samples was determined based on the TaqMan method. Regions of the S gene, PC and BCP were amplified by the nested PCR. Positive PCR products were sequenced and analyzed.
Results: Successfully sequenced S gene region revealed all the derived strains were genotype D, with the majority (90%) belonging to the ayw2 subtype, and the rest (9%) to the ayw1 subtype. The prevalence of mutations was found to be 51% and 18% in the HBsAg and MHR regions, respectively. 70% of amino acid changes within HBsAg occurred in different immune epitopes, of which 27% and 72% were located in B cell and Th epitopes, respectively. Successfully sequenced PC and BCP regions showed at least one mutation in 84.6% of the patients. The PC and BCP mutations were G1896A (61%), G1899A (23%), A1762T/G1764A (23%) and G1764T/C1766G (26%). None of the strains with A1762T/G1764A mutation carried the G1764T/C1766G mutant.
Conclusions: Our results showed common mutations within HBsAg, occurring in immune epitopes, a high rate of G1896A mutations in the PC region, and a negative correlation between the emergence of A1762T/G1764A mutation and the G1764T/C1766G mutant in the BCP region.
Downloads
Download data is not yet available.
Abstract 861
PDF Downloads 495
HTML Downloads 134
References
Agarwal A, Sen S, Banerjee D, Srivastava R, Praharaj A: Distribution of
hepatitis B virus genotype and cancer predicting precore and basal core
promoter mutations. Medical Journal Armed Forces India 2015,
71(3):225-232.
https://doi.org/10.1016/j.mjafi.2015.04.003
PMid:26288490 PMCid:PMC4534539
2. Wang X-L, Ren J-P, Wang X-Q, Wang X-H, Yang S-F, Xiong Y:
Mutations in pre-core and basic core promoter regions of hepatitis B
virus in chronic hepatitis B patients. World Journal of Gastroenterology
2016, 22(11):3268.
https://doi.org/10.3748/wjg.v22.i11.3268
PMid:27004005 PMCid:PMC4790003
3. Assih M, Ouattara AK, Diarra B, Yonli AT, Compaore TR, ObiriYeboah D, Djigma FW, Karou S, Simpore JJWjoh: Genetic diversity of
hepatitis viruses in West-African countries from 1996 to 2018. 2018,
10(11):807.
https://doi.org/10.4254/wjh.v10.i11.807
PMid:30533182 PMCid:PMC6280160
4. Echevarría JM, Avellón A: Hepatitis B virus genetic diversity. Journal
of medical virology 2006, 78(S1):S36-S42.
https://doi.org/10.1002/jmv.20605
PMid:16622876
5. Pujol FH, Navas M-C, Hainaut P, Chemin I: Worldwide genetic
diversity of HBV genotypes and risk of hepatocellular carcinoma.
Cancer letters 2009, 286(1):80-88.
https://doi.org/10.1016/j.canlet.2009.07.013
PMid:19683385
6. Pourkarim MR, Sharifi Z, Soleimani A, Amini?Bavil?Olyaee S,
Elsadek Fakhr A, Sijmons S, Vercauteren J, Karimi G, Lemey P, Maes
P: Evolutionary analysis of HBV "S" antigen genetic diversity in Iranian
blood donors: a nationwide study. Journal of medical virology 2014,
86(1):144-155.
https://doi.org/10.1002/jmv.23798
PMid:24150816
7. Khedive A, Norouzi M, Ramezani F, Karimzadeh H, Alavian S,
Malekzadeh R, Montazeri G, Nejatizadeh A, Ziaee M, Abedi F:
Hepatitis B virus surface protein mutations clustered mainly in CTL
immune epitopes in chronic carriers: results of an Iranian nationwide
study. Journal of viral hepatitis 2013, 20(7):494-501.
https://doi.org/10.1111/jvh.12045
PMid:23730843
8. Petit M-A, Maillard P, Capel F, Pillot J: Immunochemical structure of
the hepatitis B surface antigen vaccine-II. Analysis of antibody
responses in human sera against the envelope proteins. Molecular
immunology 1986, 23(5):511-523.
https://doi.org/10.1016/0161-5890(86)90114-8
9. Ramezani F, Norouzi M, Sarizade GR, Poortahmasebi V, Kalantar E,
Magnius L, Norder H, Domingo E, Jazayeri SM: Mutation hot spots in
hepatitis B surface antigen in chronic carriers from Khoozestan province,
southern of Iran. Iranian Journal of Allergy, Asthma and Immunology
2013, 12(3):269.
Caligiuri P, Cerruti R, Icardi G, Bruzzone B: Overview of hepatitis B virus mutations and their implications in the management of infection. World Journal of Gastroenterology 2016, 22(1):145.
https://doi.org/10.3748/wjg.v22.i1.145
PMid:26755866 PMCid:PMC4698481
11. Hunt CM, McGill JM, Allen MI, Condreay LD: Clinical relevance of hepatitis B viral mutations. Hepatology 2000, 31(5):1037-1044.
https://doi.org/10.1053/he.2000.6709
PMid:10796877
12. Kramvis A, Kew M: The core promoter of hepatitis B virus. Journal of viral hepatitis 1999, 6(6):415-427.
https://doi.org/10.1046/j.1365-2893.1999.00189.x
PMid:10607259
13. Bozday? AM, Bozkaya H, Türky?lmaz AR, Sarýodlu M, Çetinkaya H, Karayalç?n S, Yurdayd?n C, Uzunalimo?lu ÖJJocv: Nucleotide divergences in the core promoter and precore region of genotype D hepatitis B virus in patients with persistently elevated or normal ALT levels. 2001, 21(1):91-101.
https://doi.org/10.1016/S1386-6532(01)00148-2
14. Jazayeri M, Basuni A, Sran N, Gish R, Cooksley G, Locarnini S, Carman WJJovh: HBV core sequence: definition of genotype?specific variability and correlation with geographical origin. 2004, 11(6):488-501.
https://doi.org/10.1111/j.1365-2893.2004.00534.x
PMid:15500549
15. Mohebbi S, Amini?Bavil?Olyaee S, Zali N, Noorinayer B, Derakhshan F, Chiani M, Nejad MR, Antikchi M, Sabahi F, Zali M: Molecular epidemiology of hepatitis B virus in Iran. Clinical microbiology and infection 2008, 14(9):858-866.
https://doi.org/10.1111/j.1469-0691.2008.02053.x
PMid:18844687
16. Ma Q, Wang Y: Comprehensive analysis of the prevalence of hepatitis B virus escape mutations in the major hydrophilic region of surface antigen. Journal of medical virology 2012, 84(2):198-206.
https://doi.org/10.1002/jmv.23183
PMid:22170538
17. Echevarría JM, Avellón A: Improved detection of natural hepatitis B virus surface antigen (HBsAg) mutants by a new version of the VITROS® HBsAg assay. Journal of medical virology 2008, 80(4):598-602.
https://doi.org/10.1002/jmv.21146
PMid:18297712
18. Diarra B, Yonli AT, Sorgho PA, Compaore TR, Ouattara AK, Zongo WA, Tao I, Traore L, Soubeiga ST, Djigma FWJMjoh et al: Occult hepatitis B virus infection and associated genotypes among HBsAg-negative subjects in Burkina Faso. Mediterr J Hematol Infect Dis. 2018 1;10(1):e2018007. doi: 10.4084/MJHID.2018.007. eCollection 2018.
https://doi.org/10.4084/mjhid.2018.007
PMid:29326804 PMCid:PMC5760064
19. Moradi A, Zhand S, Ghaemi A, Javid N, Tabarraei A: Mutations in the S gene region of hepatitis B virus genotype D in Golestan Province-Iran. Virus Genes 2012, 44(3):382-387.
https://doi.org/10.1007/s11262-012-0715-z
PMid:22274739
20. Norouzi M, Ghorashi SA, Ataei B, Yaran M, Malekzadeh R, Alavian SM, Judaki MA, Ghamari S, Namazi A, Rahimnia R: Hepatitis B virus surface antigen variants clustered within immune epitopes in chronic hepatitis B carriers from Hormozgan Province, south of Iran. Iranian journal of basic medical sciences 2010, 13(4):213-224.
21. Nordin M, Ingman M, Lindqvist B, Kidd?Ljunggren K: Variability in the precore and core promoter region of the hepatitis B virus genome. Journal of medical virology 2014, 86(3):437-445.
https://doi.org/10.1002/jmv.23839
PMid:24249691
22. Constantinescu I, Dinu A-A, Boscaiu V, Niculescu M: Hepatitis B Virus Core Promoter Mutations in Patients With Chronic Hepatitis B and Hepatocellular Carcinoma in Bucharest, Romania. Hepatitis monthly 2014, 14(10).
https://doi.org/10.5812/hepatmon.22072
PMid:25477976 PMCid:PMC4250966
23. Ducancelle A, Pivert A, Bertrais S, Boursier J, Balan V, Veillon P, Guillou?Guillemette H, Thibault V, Castelain S, Roquebert B:
Different precore/core mutations of hepatitis B interact with, limit or favor liver fibrosis severity. Journal of gastroenterology and hepatology 2016.
https://doi.org/10.1111/jgh.13338
PMid:26992056
24. Yoo BC, Park J-W, Kim HJ, Lee DH, Cha YJ, Park SM: Precore and core promoter mutations of hepatitis B virus and hepatitis B e antigen-negative chronic hepatitis B in Korea. Journal of hepatology 2003, 38(1):98-103.
https://doi.org/10.1016/S0168-8278(02)00349-5
25. Ghabeshi S, Sharifi Z, Hosseini SM, Shooshtari MM: Correlation between viral load of HBV in chronic hepatitis B patients and precore and Basal core promoter mutations. Hepatitis monthly 2013, 13(2).
https://doi.org/10.5812/hepatmon.7415
PMid:23599717 PMCid:PMC3628088
26. Moradi A, Zhand S, Ghaemi A, Javid N, Bazouri M, Tabarraei A: Mutations in pre-core and basal-core promoter regions of hepatitis B virus in chronic HBV patients from Golestan, Iran. Iranian journal of basic medical sciences 2014, 17(5):370.
27. Fariba Soleimani, Seyed Ali Mohammmad Arabzadeh, Hamidreza Mollaie, ZahraI ranmanesh, Najmeh Nikpour, Motahar M: Evaluation of the frequency of precore/core mutation in patients with chronic hepatitis B, Kerman, Southeast of Iran. Asian pacific journal of tropical disease 2016, 6(8):603-607.
https://doi.org/10.1016/S2222-1808(16)61093-9
28. Tillmann H, Trautwein C, Walker D, Michitaka K, Kubicka S, Böker K, Manns M: Clinical relevance of mutations in the precore genome of the hepatitis B virus. Gut 1995, 37(4):568-573.
https://doi.org/10.1136/gut.37.4.568
PMid:7489947 PMCid:PMC1382912
29. Chan HL, Leung NW, Hussain M, Wong ML, Lok AS: Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 2000, 31(3):763-768.
https://doi.org/10.1002/hep.510310330
PMid:10706570
30. Fang ZL, Ling R, Wang SS, Nong J, Huang CS, Harrison TJ: HBV core promoter mutations prevail in patients with hepatocellular carcinoma from Guangxi, China. Journal of medical virology 1998, 56(1):18-24.
https://doi.org/10.1002/(SICI)1096-9071(199809)56:1<18::AID-JMV4>3.0.CO;2-Q
31. Poustchi H, Mohamadkhani A, Bowden S, Montazeri G, Ayres A, Revill P, Farrell G, Locarnini S, George J, Malekzadeh R: Clinical significance of precore and core promoter mutations in genotype D hepatitis B?related chronic liver disease. Journal of viral hepatitis 2008, 15(10):753-760.
https://doi.org/10.1111/j.1365-2893.2008.00998.x
PMid:18507754
32. Fujiwara K, Tanaka Y, Orito E, Ohno T, Kato T, Sugihara K, Hasegawa I, Sakurai M, Ito K, Ozasa A: Distribution of HBV genotypes among HBV carriers in Benin: phylogenetic analysis and virological characteristics of HBV genotype E. World journal of gastroenterology: WJG 2005, 11(41):6410-6415.
https://doi.org/10.3748/wjg.v11.i41.6410
PMid:16425408 PMCid:PMC4355778
33. Suppiah J, Zain RM, Bahari N, Nawi SH, Saat Z: G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B. Hepatitis monthly 2015, 15(10).
https://doi.org/10.5812/hepatmon.31490
PMid:26587040 PMCid:PMC4644636
34. Baha W, Ennaji MM, Lazar F, Melloul M, El Fahime E, El Malki A, Bennani A: HBV genotypes prevalence, precore and basal core mutants in Morocco. Infection, Genetics and Evolution 2012, 12(6):1157-1162.
https://doi.org/10.1016/j.meegid.2012.04.026
PMid:22579480
35. Sendi H, Mehrab-Mohseni M, Zali MR, Norder H, Magnius LO: T1764G1766 core promoter double mutants are restricted to Hepatitis B virus strains with an A1757 and are common in genotype D. Journal of general virology 2005, 86(9):2451-2458.
https://doi.org/10.1099/vir.0.81023-0
PMid:16099903
hepatitis B virus genotype and cancer predicting precore and basal core
promoter mutations. Medical Journal Armed Forces India 2015,
71(3):225-232.
https://doi.org/10.1016/j.mjafi.2015.04.003
PMid:26288490 PMCid:PMC4534539
2. Wang X-L, Ren J-P, Wang X-Q, Wang X-H, Yang S-F, Xiong Y:
Mutations in pre-core and basic core promoter regions of hepatitis B
virus in chronic hepatitis B patients. World Journal of Gastroenterology
2016, 22(11):3268.
https://doi.org/10.3748/wjg.v22.i11.3268
PMid:27004005 PMCid:PMC4790003
3. Assih M, Ouattara AK, Diarra B, Yonli AT, Compaore TR, ObiriYeboah D, Djigma FW, Karou S, Simpore JJWjoh: Genetic diversity of
hepatitis viruses in West-African countries from 1996 to 2018. 2018,
10(11):807.
https://doi.org/10.4254/wjh.v10.i11.807
PMid:30533182 PMCid:PMC6280160
4. Echevarría JM, Avellón A: Hepatitis B virus genetic diversity. Journal
of medical virology 2006, 78(S1):S36-S42.
https://doi.org/10.1002/jmv.20605
PMid:16622876
5. Pujol FH, Navas M-C, Hainaut P, Chemin I: Worldwide genetic
diversity of HBV genotypes and risk of hepatocellular carcinoma.
Cancer letters 2009, 286(1):80-88.
https://doi.org/10.1016/j.canlet.2009.07.013
PMid:19683385
6. Pourkarim MR, Sharifi Z, Soleimani A, Amini?Bavil?Olyaee S,
Elsadek Fakhr A, Sijmons S, Vercauteren J, Karimi G, Lemey P, Maes
P: Evolutionary analysis of HBV "S" antigen genetic diversity in Iranian
blood donors: a nationwide study. Journal of medical virology 2014,
86(1):144-155.
https://doi.org/10.1002/jmv.23798
PMid:24150816
7. Khedive A, Norouzi M, Ramezani F, Karimzadeh H, Alavian S,
Malekzadeh R, Montazeri G, Nejatizadeh A, Ziaee M, Abedi F:
Hepatitis B virus surface protein mutations clustered mainly in CTL
immune epitopes in chronic carriers: results of an Iranian nationwide
study. Journal of viral hepatitis 2013, 20(7):494-501.
https://doi.org/10.1111/jvh.12045
PMid:23730843
8. Petit M-A, Maillard P, Capel F, Pillot J: Immunochemical structure of
the hepatitis B surface antigen vaccine-II. Analysis of antibody
responses in human sera against the envelope proteins. Molecular
immunology 1986, 23(5):511-523.
https://doi.org/10.1016/0161-5890(86)90114-8
9. Ramezani F, Norouzi M, Sarizade GR, Poortahmasebi V, Kalantar E,
Magnius L, Norder H, Domingo E, Jazayeri SM: Mutation hot spots in
hepatitis B surface antigen in chronic carriers from Khoozestan province,
southern of Iran. Iranian Journal of Allergy, Asthma and Immunology
2013, 12(3):269.
Caligiuri P, Cerruti R, Icardi G, Bruzzone B: Overview of hepatitis B virus mutations and their implications in the management of infection. World Journal of Gastroenterology 2016, 22(1):145.
https://doi.org/10.3748/wjg.v22.i1.145
PMid:26755866 PMCid:PMC4698481
11. Hunt CM, McGill JM, Allen MI, Condreay LD: Clinical relevance of hepatitis B viral mutations. Hepatology 2000, 31(5):1037-1044.
https://doi.org/10.1053/he.2000.6709
PMid:10796877
12. Kramvis A, Kew M: The core promoter of hepatitis B virus. Journal of viral hepatitis 1999, 6(6):415-427.
https://doi.org/10.1046/j.1365-2893.1999.00189.x
PMid:10607259
13. Bozday? AM, Bozkaya H, Türky?lmaz AR, Sarýodlu M, Çetinkaya H, Karayalç?n S, Yurdayd?n C, Uzunalimo?lu ÖJJocv: Nucleotide divergences in the core promoter and precore region of genotype D hepatitis B virus in patients with persistently elevated or normal ALT levels. 2001, 21(1):91-101.
https://doi.org/10.1016/S1386-6532(01)00148-2
14. Jazayeri M, Basuni A, Sran N, Gish R, Cooksley G, Locarnini S, Carman WJJovh: HBV core sequence: definition of genotype?specific variability and correlation with geographical origin. 2004, 11(6):488-501.
https://doi.org/10.1111/j.1365-2893.2004.00534.x
PMid:15500549
15. Mohebbi S, Amini?Bavil?Olyaee S, Zali N, Noorinayer B, Derakhshan F, Chiani M, Nejad MR, Antikchi M, Sabahi F, Zali M: Molecular epidemiology of hepatitis B virus in Iran. Clinical microbiology and infection 2008, 14(9):858-866.
https://doi.org/10.1111/j.1469-0691.2008.02053.x
PMid:18844687
16. Ma Q, Wang Y: Comprehensive analysis of the prevalence of hepatitis B virus escape mutations in the major hydrophilic region of surface antigen. Journal of medical virology 2012, 84(2):198-206.
https://doi.org/10.1002/jmv.23183
PMid:22170538
17. Echevarría JM, Avellón A: Improved detection of natural hepatitis B virus surface antigen (HBsAg) mutants by a new version of the VITROS® HBsAg assay. Journal of medical virology 2008, 80(4):598-602.
https://doi.org/10.1002/jmv.21146
PMid:18297712
18. Diarra B, Yonli AT, Sorgho PA, Compaore TR, Ouattara AK, Zongo WA, Tao I, Traore L, Soubeiga ST, Djigma FWJMjoh et al: Occult hepatitis B virus infection and associated genotypes among HBsAg-negative subjects in Burkina Faso. Mediterr J Hematol Infect Dis. 2018 1;10(1):e2018007. doi: 10.4084/MJHID.2018.007. eCollection 2018.
https://doi.org/10.4084/mjhid.2018.007
PMid:29326804 PMCid:PMC5760064
19. Moradi A, Zhand S, Ghaemi A, Javid N, Tabarraei A: Mutations in the S gene region of hepatitis B virus genotype D in Golestan Province-Iran. Virus Genes 2012, 44(3):382-387.
https://doi.org/10.1007/s11262-012-0715-z
PMid:22274739
20. Norouzi M, Ghorashi SA, Ataei B, Yaran M, Malekzadeh R, Alavian SM, Judaki MA, Ghamari S, Namazi A, Rahimnia R: Hepatitis B virus surface antigen variants clustered within immune epitopes in chronic hepatitis B carriers from Hormozgan Province, south of Iran. Iranian journal of basic medical sciences 2010, 13(4):213-224.
21. Nordin M, Ingman M, Lindqvist B, Kidd?Ljunggren K: Variability in the precore and core promoter region of the hepatitis B virus genome. Journal of medical virology 2014, 86(3):437-445.
https://doi.org/10.1002/jmv.23839
PMid:24249691
22. Constantinescu I, Dinu A-A, Boscaiu V, Niculescu M: Hepatitis B Virus Core Promoter Mutations in Patients With Chronic Hepatitis B and Hepatocellular Carcinoma in Bucharest, Romania. Hepatitis monthly 2014, 14(10).
https://doi.org/10.5812/hepatmon.22072
PMid:25477976 PMCid:PMC4250966
23. Ducancelle A, Pivert A, Bertrais S, Boursier J, Balan V, Veillon P, Guillou?Guillemette H, Thibault V, Castelain S, Roquebert B:
Different precore/core mutations of hepatitis B interact with, limit or favor liver fibrosis severity. Journal of gastroenterology and hepatology 2016.
https://doi.org/10.1111/jgh.13338
PMid:26992056
24. Yoo BC, Park J-W, Kim HJ, Lee DH, Cha YJ, Park SM: Precore and core promoter mutations of hepatitis B virus and hepatitis B e antigen-negative chronic hepatitis B in Korea. Journal of hepatology 2003, 38(1):98-103.
https://doi.org/10.1016/S0168-8278(02)00349-5
25. Ghabeshi S, Sharifi Z, Hosseini SM, Shooshtari MM: Correlation between viral load of HBV in chronic hepatitis B patients and precore and Basal core promoter mutations. Hepatitis monthly 2013, 13(2).
https://doi.org/10.5812/hepatmon.7415
PMid:23599717 PMCid:PMC3628088
26. Moradi A, Zhand S, Ghaemi A, Javid N, Bazouri M, Tabarraei A: Mutations in pre-core and basal-core promoter regions of hepatitis B virus in chronic HBV patients from Golestan, Iran. Iranian journal of basic medical sciences 2014, 17(5):370.
27. Fariba Soleimani, Seyed Ali Mohammmad Arabzadeh, Hamidreza Mollaie, ZahraI ranmanesh, Najmeh Nikpour, Motahar M: Evaluation of the frequency of precore/core mutation in patients with chronic hepatitis B, Kerman, Southeast of Iran. Asian pacific journal of tropical disease 2016, 6(8):603-607.
https://doi.org/10.1016/S2222-1808(16)61093-9
28. Tillmann H, Trautwein C, Walker D, Michitaka K, Kubicka S, Böker K, Manns M: Clinical relevance of mutations in the precore genome of the hepatitis B virus. Gut 1995, 37(4):568-573.
https://doi.org/10.1136/gut.37.4.568
PMid:7489947 PMCid:PMC1382912
29. Chan HL, Leung NW, Hussain M, Wong ML, Lok AS: Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 2000, 31(3):763-768.
https://doi.org/10.1002/hep.510310330
PMid:10706570
30. Fang ZL, Ling R, Wang SS, Nong J, Huang CS, Harrison TJ: HBV core promoter mutations prevail in patients with hepatocellular carcinoma from Guangxi, China. Journal of medical virology 1998, 56(1):18-24.
https://doi.org/10.1002/(SICI)1096-9071(199809)56:1<18::AID-JMV4>3.0.CO;2-Q
31. Poustchi H, Mohamadkhani A, Bowden S, Montazeri G, Ayres A, Revill P, Farrell G, Locarnini S, George J, Malekzadeh R: Clinical significance of precore and core promoter mutations in genotype D hepatitis B?related chronic liver disease. Journal of viral hepatitis 2008, 15(10):753-760.
https://doi.org/10.1111/j.1365-2893.2008.00998.x
PMid:18507754
32. Fujiwara K, Tanaka Y, Orito E, Ohno T, Kato T, Sugihara K, Hasegawa I, Sakurai M, Ito K, Ozasa A: Distribution of HBV genotypes among HBV carriers in Benin: phylogenetic analysis and virological characteristics of HBV genotype E. World journal of gastroenterology: WJG 2005, 11(41):6410-6415.
https://doi.org/10.3748/wjg.v11.i41.6410
PMid:16425408 PMCid:PMC4355778
33. Suppiah J, Zain RM, Bahari N, Nawi SH, Saat Z: G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B. Hepatitis monthly 2015, 15(10).
https://doi.org/10.5812/hepatmon.31490
PMid:26587040 PMCid:PMC4644636
34. Baha W, Ennaji MM, Lazar F, Melloul M, El Fahime E, El Malki A, Bennani A: HBV genotypes prevalence, precore and basal core mutants in Morocco. Infection, Genetics and Evolution 2012, 12(6):1157-1162.
https://doi.org/10.1016/j.meegid.2012.04.026
PMid:22579480
35. Sendi H, Mehrab-Mohseni M, Zali MR, Norder H, Magnius LO: T1764G1766 core promoter double mutants are restricted to Hepatitis B virus strains with an A1757 and are common in genotype D. Journal of general virology 2005, 86(9):2451-2458.
https://doi.org/10.1099/vir.0.81023-0
PMid:16099903