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OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ

Year 2021, Volume: 84 Issue: 3, 402 - 410, 31.07.2021

Bülent Çakal Alp Atasoy Bilger Çavuş Aslı Örmeci Mehveş Poda Mesut Bulakçı Mine Güllüoğlu Mehmet Güven Günver Filiz Akyüz

Abstract

Amaç: Okült Hepatit B Virus (HBV) enfeksiyonu (Occult HBV infection; OBI) mevcut serolojik testler ile HBV yüzey antijeni (Surface antigen; HBsAg) negatif tespit edilen bireylerin karaciğerinde HBV genomunun uzun süreli persistan varlığı ile karakterizedir. Bu çalışmada OBI tanılı hastalardan elde edilen HBV’lerin genotip, subgenotip ve subtip profillerinin karakteristiğinin irdelenmesi amaçlanmıştır. Gereç ve Yöntem: Çalışmaya HBsAg negatif farklı klinik endikasyonlar nedeniyle karaciğer parankim biyopsisi gerçekleştirilen hastaların karaciğer biyopsi örneklerinde Nested PCR yöntemiyle HBV DNA varlığı tanımlanan 32 OBI tanılı hasta ile 17 kronik hepatit B hastası dahil edildi. HBV S gen MHR bölgesini hedefleyen DNA fragmanları nested PCR kullanılarak amplifiye edildi. HBV’nin genotip, subgenotip ve subtip/serotiplerinin belirlemek için Sanger sekans metodu kullanıldı. Bulgular: Bu çalışmada OBI ve kronik hepatit B hastalarından izole edilen HBV’lerin tümününün genotipi D, subgenotipler sırasıyla HBV/D1 (%75,5), HBV/D2 (%6,1) ve HBV/D3 (%18,4) serotipler sırasıyla ayw2 (%73,5) ve ayw3 (%26,5) olarak belirlenmiştir. OBI’li hastaların %28,1’nin subgenotipi HBV/D3 olarak belirlenmesine karşın kronik hepatit B hastalarının hiç birinde HBV/D3 subgenotipi saptanmamıştır. Sonuç: Subgenotip HBV/D3’ün viral biyogenezin dinamiği üzerindeki potansiyel etkileri HBsAg negatifliği ve düşük replikasyon yetkinliği ile karakterize OBI ile ilişkili olabilir.

Keywords

OBI Genetik varyasyon Genotip Subgenotip HBsAg Subtipleri Hepatit B virüsü

Supporting Institution

İstanbul Üniversitesi Bilimsel Araştırma Projeleri

Project Number

THZ-2018- 26422

Thanks

İstanbul Tıp Fakültesi Gastroenterohepatoloji Bilim Dalında görevli Sayın Hemşire Nilay Arabacı ve Sayın Hemşire Derya Kaya ile İstanbul Tıp Fakültesi Radyoloji Anabilim Dalı Girişimsel Radyoloji Birimi’nde görevli Sayın Hemşire Arzu Örentel’e projenin gerçekleştirilmesi aşamasındaki bilimsel duyarlılıkları, katkıları ve emeklerinden dolayı şükranlarımı sunarım.

References

  • Revill PA, Chisari FV, Block JM, Dandri M, Gehring AJ, Guo H, et al. Lancet Gastroenterol. Hepatol 2019;4:545-58.
  • 2. Raimondo G, Locarnini S, Pollicino T, Levrero M, Zoulim F, Lok AS, and the Taormina Workshop on Occult HBV Infection Faculty Members. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J Hepatol 2019;71(2):397-408. [CrossRef]
  • 3. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008;49:652-7. [CrossRef]
  • 4. Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002;2:479-86. [CrossRef]
  • 5. Chemin I, Trepo C. Clinical impact of occult HBV infections. J Clin Virol 2005;34:15-21. [CrossRef]
  • 6. Pondé RAA. Molecular mechanisms underlying HBsAg negativity in occult HBV infection. Eur J Clin Microbiol Infect Dis 2015;34:1709-31. [CrossRef]
  • 7. Pollicino T, Raimondo G. Occult Hepatitis B Infection. Journal of Hepatology 2014;61:688-9. [CrossRef]
  • 8. Raimondo G, Caccamo G, Filomia R, Pollicino T. Occult HBV infection. Semin Immunopathol 2013;35:39-52. [CrossRef]
  • 9. Lugoboni F, Quaglio G, Civitelli P, Mezzelani P. Bloodborne viral hepatitis infections among drug users: the role of vaccination. Int J Environ Res Public Health 2009;6(1):400-13. [CrossRef]
  • 10. Chen BF, Chen PJ, Jow GM, Sablon E, Liu CJ, Chen DS, et al. High prevalence of mixed genotype infections in hepatitis B virus infected intravenous drug users. J Med Virol 2004;74(4):536-42. [CrossRef]
  • 11. Locarnini S, Zoulim F. Molecular genetics of HBV infection Antivir Ther 2010;3:3-14. [CrossRef]
  • 12. Seddigh-Tonekaboni S, Waters JA, Jeffers S, Gehrke R, Ofenloch B, Horsch A, et al. Effect of variation in the common “a” determinant on the antigenicity of hepatitis B surface antigen. J Med Virol 2000;60:113-21. [CrossRef]
  • 13. Waters J, Kennedy M, Voet P, Hauser P, Petre J, Carman W, et al. Loss of the common ‘a’ determinant of hepatitis B surface antigen by a vaccine-induced escape mutant. J Clin Invest 1992;90:2543-47. [CrossRef]
  • 14. Osiowy C. Detection of HBsAg mutants. J Med Virol 2006;78:48-51. [CrossRef]
  • 15. Huang CH, Yuan Q, Chen PJ, Zhang YL, Chen CR, Zheng QB, et al. Influence of mutations in hepatitis B virus surface protein on viral antigenicity and phenotype in occult HBV strains from blood donors. Journal of Hepatology 2012;57:720-9. [CrossRef]
  • 16. McMahon, BJ. The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B Hepatol Int 2009;3:334-42. [CrossRef]
  • 17. Purdy MA, Talekar G, Swenson P, Araujo A, Fields H. A New Algorithm for Deduction of Hepatitis B Surface Antigen Subtype Determinants from the Amino Acid Sequence. Intervirology 2007;50:45-51. [CrossRef]
  • 18. Norder H, Couroucé AM, Coursaget P, Echevarria JM, Lee SD, Mushahwar IK, et al. Genetic diversity of hepatitis B virus strains derived worldwide: Genotypes, subgenotypes, and HBsAg subtypes. Intervirology 2004;47:289‑309. [CrossRef]
  • 19. Kramvis A. Genotypes and Genetic Variability of Hepatitis B Virus. Intervirology 2014;57(3-4):141-50. [CrossRef]
  • 20. Zhang ZH, Wu CC, Chen XW, Li X, Li J, Lu MJ. Genetic variation of hepatitis B virus and its significance for pathogenesis. World J Gastroenterol 2016;22(1):126-44. [CrossRef]
  • 21. Revill PA, Tu T, Netter HJ, Yuen LKW, Locarnini SA, Littlejohn M. The evolution and clinical impact of hepatitis B virus genome diversity. Nature Reviews Gastroenterology & Hepatology 2020. [CrossRef]
  • 22. Blumberg BS, Alter HJ, Visnich S. A new antigen in leukemia sera. JAMA 1965;191:541. [CrossRef]
  • 23. Bancroft WH, Mundon FK, Russell PK. Detection of additional antigenic determinants of hepatitis B antigen. J Immunol 1972;109: 842-8.
  • 24. Weinberger KM, Bauer T, Bohm S, Jilg W. High genetic variability of the group-specific a-determinant of hepatitis B virus surface antigen (HBsAg) and the corresponding fragment of the viral polymerase in chronic virus carriers lacking detectable HBsAg in serum. J Gen Virol 2000;81:1165-74. [CrossRef]
  • 25. Raney AK, Johnson JL, Palmer CNA, McLachlan A. Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter. J Virol 1997;71:1058-71. [CrossRef]
  • 26. Pollicino T, Cacciola I, Saffioti F, Raimondo G. Hepatitis B virus PreS/S gene variants: Pathobiology and clinical implications. Journal of Hepatology 2014;61:408-17. [CrossRef]
  • 27. Sheldon J, Rode`s B, Zoulim F, Bartholomeusz A, Soriano V. Mutations affecting the replication capacity of the hepatitis B virus. Journal of Viral Hepatitis 2006;13:427-34. [CrossRef]
  • 28. Mirabelli C, Surdo M, Hemert F-V, Lian Z, Salpini R, Cento V. Specific mutations in the C-terminus domain of HBV surface antigen significantly correlate with low level of serum HBVDNA in patients with chronic HBV infection. Journal of Infection 2015;70:288e298. [CrossRef]
  • 29. Huang X, Qin Y, Li W, Shi Q, Xue Y, Li J, et al. Molecular analysis of the hepatitis B virus presurface and surface gene in patients from eastern China with occult hepatitis B. J Med Virol 2013;85:979-86. [CrossRef]
  • 30. Chandra PK, Biswas A, Datta S, Banerjee A, Panigrahi R, Chakrabarti S. et al. Subgenotypes of hepatitis B virus genotype D (D1, D2, D3 and D5) in India: differential pattern of mutations, liver injury and occult HBV infection. J Viral Hepat 2009;16:749-56. [CrossRef]
  • 31. Datta S, Dasgupta D, Ghosh A, Ghosh S, Manna A, Datta S. Oncogenic potential of hepatitis B virus subgenotype D1 surpasses D3: significance in the development of hepatocellular carcinoma. Carcinogenesis 2018;39:283-92. [CrossRef]
  • 32. Khatun M, Mondal RK, Pal S, Baidya A, Bishnu D, Banerjee P, et al. Distinctiveness in virological features and pathogenic potentials of subgenotypes D1, D2, D3 and D5 of Hepatitis B virus. Sci Rep 2018;23;8(1):8055. [CrossRef]
  • 33. Alestig E, Söderström A, Norkrans G, Lindh M. Genetic Diversity of Genotype D3 in Acute Hepatitis B. J Med Virol 2013;85(7):1148-54. [CrossRef]
  • 34. Biswas A, Panigrahi R, Chandra PK, Banerjee A, Datta S, Pal M. Characterization of the Occult Hepatitis B Virus Variants Circulating among the Blood Donors from Eastern India. ScientificWorld Journal 2014;4:212704.
  • 35. Scheiblauer H, El-Nageh M, Diaz S, Nick S, Zeichhardt H, Grunert HP, et al. Performance evaluation of 70 hepatitis B virus (HBV) surface antigen (HBsAg) assays from around the world by a geographically diverse panel with an array of HBV genotypes and HBsAg subtypes Vox Sanguinis 2010;98:403-14. [CrossRef]

ANALYSIS OF GENOTYPE, SUBGENOTYPE AND SEROTYPE OF OCCULT HEPATITIS B VIRUS

Year 2021, Volume: 84 Issue: 3, 402 - 410, 31.07.2021

Bülent Çakal Alp Atasoy Bilger Çavuş Aslı Örmeci Mehveş Poda Mesut Bulakçı Mine Güllüoğlu Mehmet Güven Günver Filiz Akyüz

Abstract

Objective: Occult hepatitis B infection (OBI) can be characterized by the long-term persistence of HBV DNA in the liver of individuals who test negative for the hepatitis B surface antigen (HBsAg) using the currently available assays. This study aimed to evaluate genotype, subgenotype and subtype profiles of HBVs obtained from patients with OBI. Material and Method: The study included 32 patients with OBI who were diagnosed with HBV DNA by Nested PCR method in liver biopsy samples of patients who underwent liver parenchymal biopsy due to HBsAg negative different clinic indications and 17 chronic hepatitis B patients. The MHR region of the HBV S gene was amplified using nested PCR. Sanger sequencing method was used to determine the genotype, subgenotypes and subtype/serotype of HBV. Results: In this study it was determined that the genotypes of all HBVs isolated from OBI and chronic hepatitis B patients were HBV/D, subgenotypes were respectively HBV/ D1 (75.5%), HBV/ D2 (6.1%) and HBV/D3 (18.4%), serotypes were respectively ayw2 (73.5%) and ayw3 (26.5%). Although the subgenotype of 28.1% of patients with OBI was determined as HBV/D3, none of the chronic hepatitis B patients had the HBV/D3 subgenotype. Conclusion: The potential effects of subgenotype HBV/D3 on the dynamics of viral biogenesis may be associated with OBI, characterized by low replication competence and HBsAg negativity.

Keywords

OBI Genetic diversity Genotypes Subgenotypes HBsAg Subtypes Hepatitis B virus

Project Number

THZ-2018- 26422

References

  • Revill PA, Chisari FV, Block JM, Dandri M, Gehring AJ, Guo H, et al. Lancet Gastroenterol. Hepatol 2019;4:545-58.
  • 2. Raimondo G, Locarnini S, Pollicino T, Levrero M, Zoulim F, Lok AS, and the Taormina Workshop on Occult HBV Infection Faculty Members. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J Hepatol 2019;71(2):397-408. [CrossRef]
  • 3. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008;49:652-7. [CrossRef]
  • 4. Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002;2:479-86. [CrossRef]
  • 5. Chemin I, Trepo C. Clinical impact of occult HBV infections. J Clin Virol 2005;34:15-21. [CrossRef]
  • 6. Pondé RAA. Molecular mechanisms underlying HBsAg negativity in occult HBV infection. Eur J Clin Microbiol Infect Dis 2015;34:1709-31. [CrossRef]
  • 7. Pollicino T, Raimondo G. Occult Hepatitis B Infection. Journal of Hepatology 2014;61:688-9. [CrossRef]
  • 8. Raimondo G, Caccamo G, Filomia R, Pollicino T. Occult HBV infection. Semin Immunopathol 2013;35:39-52. [CrossRef]
  • 9. Lugoboni F, Quaglio G, Civitelli P, Mezzelani P. Bloodborne viral hepatitis infections among drug users: the role of vaccination. Int J Environ Res Public Health 2009;6(1):400-13. [CrossRef]
  • 10. Chen BF, Chen PJ, Jow GM, Sablon E, Liu CJ, Chen DS, et al. High prevalence of mixed genotype infections in hepatitis B virus infected intravenous drug users. J Med Virol 2004;74(4):536-42. [CrossRef]
  • 11. Locarnini S, Zoulim F. Molecular genetics of HBV infection Antivir Ther 2010;3:3-14. [CrossRef]
  • 12. Seddigh-Tonekaboni S, Waters JA, Jeffers S, Gehrke R, Ofenloch B, Horsch A, et al. Effect of variation in the common “a” determinant on the antigenicity of hepatitis B surface antigen. J Med Virol 2000;60:113-21. [CrossRef]
  • 13. Waters J, Kennedy M, Voet P, Hauser P, Petre J, Carman W, et al. Loss of the common ‘a’ determinant of hepatitis B surface antigen by a vaccine-induced escape mutant. J Clin Invest 1992;90:2543-47. [CrossRef]
  • 14. Osiowy C. Detection of HBsAg mutants. J Med Virol 2006;78:48-51. [CrossRef]
  • 15. Huang CH, Yuan Q, Chen PJ, Zhang YL, Chen CR, Zheng QB, et al. Influence of mutations in hepatitis B virus surface protein on viral antigenicity and phenotype in occult HBV strains from blood donors. Journal of Hepatology 2012;57:720-9. [CrossRef]
  • 16. McMahon, BJ. The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B Hepatol Int 2009;3:334-42. [CrossRef]
  • 17. Purdy MA, Talekar G, Swenson P, Araujo A, Fields H. A New Algorithm for Deduction of Hepatitis B Surface Antigen Subtype Determinants from the Amino Acid Sequence. Intervirology 2007;50:45-51. [CrossRef]
  • 18. Norder H, Couroucé AM, Coursaget P, Echevarria JM, Lee SD, Mushahwar IK, et al. Genetic diversity of hepatitis B virus strains derived worldwide: Genotypes, subgenotypes, and HBsAg subtypes. Intervirology 2004;47:289‑309. [CrossRef]
  • 19. Kramvis A. Genotypes and Genetic Variability of Hepatitis B Virus. Intervirology 2014;57(3-4):141-50. [CrossRef]
  • 20. Zhang ZH, Wu CC, Chen XW, Li X, Li J, Lu MJ. Genetic variation of hepatitis B virus and its significance for pathogenesis. World J Gastroenterol 2016;22(1):126-44. [CrossRef]
  • 21. Revill PA, Tu T, Netter HJ, Yuen LKW, Locarnini SA, Littlejohn M. The evolution and clinical impact of hepatitis B virus genome diversity. Nature Reviews Gastroenterology & Hepatology 2020. [CrossRef]
  • 22. Blumberg BS, Alter HJ, Visnich S. A new antigen in leukemia sera. JAMA 1965;191:541. [CrossRef]
  • 23. Bancroft WH, Mundon FK, Russell PK. Detection of additional antigenic determinants of hepatitis B antigen. J Immunol 1972;109: 842-8.
  • 24. Weinberger KM, Bauer T, Bohm S, Jilg W. High genetic variability of the group-specific a-determinant of hepatitis B virus surface antigen (HBsAg) and the corresponding fragment of the viral polymerase in chronic virus carriers lacking detectable HBsAg in serum. J Gen Virol 2000;81:1165-74. [CrossRef]
  • 25. Raney AK, Johnson JL, Palmer CNA, McLachlan A. Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter. J Virol 1997;71:1058-71. [CrossRef]
  • 26. Pollicino T, Cacciola I, Saffioti F, Raimondo G. Hepatitis B virus PreS/S gene variants: Pathobiology and clinical implications. Journal of Hepatology 2014;61:408-17. [CrossRef]
  • 27. Sheldon J, Rode`s B, Zoulim F, Bartholomeusz A, Soriano V. Mutations affecting the replication capacity of the hepatitis B virus. Journal of Viral Hepatitis 2006;13:427-34. [CrossRef]
  • 28. Mirabelli C, Surdo M, Hemert F-V, Lian Z, Salpini R, Cento V. Specific mutations in the C-terminus domain of HBV surface antigen significantly correlate with low level of serum HBVDNA in patients with chronic HBV infection. Journal of Infection 2015;70:288e298. [CrossRef]
  • 29. Huang X, Qin Y, Li W, Shi Q, Xue Y, Li J, et al. Molecular analysis of the hepatitis B virus presurface and surface gene in patients from eastern China with occult hepatitis B. J Med Virol 2013;85:979-86. [CrossRef]
  • 30. Chandra PK, Biswas A, Datta S, Banerjee A, Panigrahi R, Chakrabarti S. et al. Subgenotypes of hepatitis B virus genotype D (D1, D2, D3 and D5) in India: differential pattern of mutations, liver injury and occult HBV infection. J Viral Hepat 2009;16:749-56. [CrossRef]
  • 31. Datta S, Dasgupta D, Ghosh A, Ghosh S, Manna A, Datta S. Oncogenic potential of hepatitis B virus subgenotype D1 surpasses D3: significance in the development of hepatocellular carcinoma. Carcinogenesis 2018;39:283-92. [CrossRef]
  • 32. Khatun M, Mondal RK, Pal S, Baidya A, Bishnu D, Banerjee P, et al. Distinctiveness in virological features and pathogenic potentials of subgenotypes D1, D2, D3 and D5 of Hepatitis B virus. Sci Rep 2018;23;8(1):8055. [CrossRef]
  • 33. Alestig E, Söderström A, Norkrans G, Lindh M. Genetic Diversity of Genotype D3 in Acute Hepatitis B. J Med Virol 2013;85(7):1148-54. [CrossRef]
  • 34. Biswas A, Panigrahi R, Chandra PK, Banerjee A, Datta S, Pal M. Characterization of the Occult Hepatitis B Virus Variants Circulating among the Blood Donors from Eastern India. ScientificWorld Journal 2014;4:212704.
  • 35. Scheiblauer H, El-Nageh M, Diaz S, Nick S, Zeichhardt H, Grunert HP, et al. Performance evaluation of 70 hepatitis B virus (HBV) surface antigen (HBsAg) assays from around the world by a geographically diverse panel with an array of HBV genotypes and HBsAg subtypes Vox Sanguinis 2010;98:403-14. [CrossRef]
There are 35 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section RESEARCH
Authors

Bülent Çakal 0000-0002-1254-844X

Alp Atasoy This is me 0000-0003-1791-897X

Bilger Çavuş This is me 0000-0003-2203-4255

Aslı Örmeci This is me 0000-0001-6297-8045

Mehveş Poda 0000-0002-1957-6072

Mesut Bulakçı 0000-0003-0993-6465

Mine Güllüoğlu This is me 0000-0002-3967-0779

Mehmet Güven Günver 0000-0002-4628-8391

Filiz Akyüz 0000-0001-7498-141X

Project Number THZ-2018- 26422
Publication Date July 31, 2021
Submission Date August 4, 2020
Published in Issue Year 2021 Volume: 84 Issue: 3

Cite

APA Çakal, B., Atasoy, A., Çavuş, B., Örmeci, A., et al. (2021). OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ. Journal of Istanbul Faculty of Medicine, 84(3), 402-410.
AMA Çakal B, Atasoy A, Çavuş B, Örmeci A, Poda M, Bulakçı M, Güllüoğlu M, Günver MG, Akyüz F. OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ. İst Tıp Fak Derg. July 2021;84(3):402-410.
Chicago Çakal, Bülent, Alp Atasoy, Bilger Çavuş, Aslı Örmeci, Mehveş Poda, Mesut Bulakçı, Mine Güllüoğlu, Mehmet Güven Günver, and Filiz Akyüz. “OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ”. Journal of Istanbul Faculty of Medicine 84, no. 3 (July 2021): 402-10.
EndNote Çakal B, Atasoy A, Çavuş B, Örmeci A, Poda M, Bulakçı M, Güllüoğlu M, Günver MG, Akyüz F (July 1, 2021) OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ. Journal of Istanbul Faculty of Medicine 84 3 402–410.
IEEE B. Çakal, “OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ”, İst Tıp Fak Derg, vol. 84, no. 3, pp. 402–410, 2021.
ISNAD Çakal, Bülent et al. “OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ”. Journal of Istanbul Faculty of Medicine 84/3 (July 2021), 402-410.
JAMA Çakal B, Atasoy A, Çavuş B, Örmeci A, Poda M, Bulakçı M, Güllüoğlu M, Günver MG, Akyüz F. OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ. İst Tıp Fak Derg. 2021;84:402–410.
MLA Çakal, Bülent et al. “OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ”. Journal of Istanbul Faculty of Medicine, vol. 84, no. 3, 2021, pp. 402-10.
Vancouver Çakal B, Atasoy A, Çavuş B, Örmeci A, Poda M, Bulakçı M, Güllüoğlu M, Günver MG, Akyüz F. OKÜLT HEPATİT B VİRÜSÜNÜN GENOTİP, SUBGENOTİP VE SUBTİP ANALİZİ. İst Tıp Fak Derg. 2021;84(3):402-10.
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