Diagnostischer Wert der quantitativen HBsAg-Bestimmung bei der Hepatitis B-Infektion

Zusammenfassung

Die Einführung von systematischen Hepatitis B-Impfungen hat zwar zu einem starken Rückgang der Neuerkrankungen geführt, aber es gibt immer noch eine sehr hohe Anzahl von chronisch Infizierten, die an den Spätfolgen der Infektion leiden. Durch die quantitative Bestimmung der HBsAg-Konzentration (qHBsAg) hat sich unser Verständnis der chronischen Hepatitis B (CHB) verbessert. In den verschiedenen Infektionsphasen werden stark unterschiedliche HBsAg-Konzentrationen gemessen. Durch die quantitative HBsAg-Bestimmung erhält man nicht nur zusätzliche Informationen zur Infektionsaktivität, sie eröffnet auch neben der Bestimmung der Viruslast zusätzliche, unabhängige Informationen zur Verlaufsbeobachtung. Als unabhängiger prognostischer Marker weist sie auf ein erhöhtes Risiko für die Entwicklung einer Zirrhose oder ein hepatozelluläres Karzinom (HCC) hin. qHBsAg wird eingesetzt zum Therapiemonitoring bei der PEG-Interferon-Therapie. Bei der Therapie mit Nukleos(t)id-Analoga (NUC) korreliert der HBsAg-Abfall zwar nicht mit dem rascheren Absinken der HBV-DNA. Trotzdem kann man bei rapidem HBsAg-Abfall die Patienten identifizieren, die letztlich HBsAg eliminieren werden. Unter der NUC-Therapie wird daher eine 6 – 12-monatige Kontrolle der HBsAg-Spiegel empfohlen. Aufgrund dieses zusätzlichen Informationsgewinns wird durch die qHBsAg-Bestimmung neben der Messung der Viruslast das Management von Patienten mit chronischer Hepatitis B-Infektion deutlich verbessert.

Abstract

Introduction of systematic hepatitis B vaccination has lead to a strong decrease of new infections, but there are still a high numbers of chronically infected persons suffering on long-term complications. Using quantitative assays for the determination of HbsAg (qHBsAg) has improved our understanding of chronic hepatitis B (CHB). The concentrations of HBsAg are strongly varying through the different stages of infection. The quantitative determination of HBsAg does not only yield in additional information to the infection activity, but also provides data for an improved follow up independent from the virus load. As to the prediction of disease progression, low-viremic carriers with high HbsAg levels have been shown to be at higher risk of HBeAg negative hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Although, quantitative HBsAg determination has been widely used in CHB patients receiving pegylated interferon therapy, the HbsAg decline is slow compared to HBV-DNA levels during nucleos(t)ide analogue (NUC) therapy. However a rapid HbsAg decline during NUC therapy may identify patients who will finally clear HbsAg. A 6- to 12-monthly assessment of HbsAg level could be considered during NUC therapy. Taking these lines of evidence together, qHBsAg can complement HBV-DNA levels to optimize the management of CHB patients.

Schlüsselwörter

Hepatitis B - Virushepatitis - Leber

Key words

hepatitis B - virus hepatitis - liver

• Literatur

• 1 Robert Koch Institut. Impfepidemiologisches Jahrbuch meldepflichtiger Erkrankungen für 2014. 2015: 99-104
• 2 Radun D, Hamouda O. Epidemiologie der Hepatitis B und C in Deutschland. Med Welt 2004; 55: 206-210
• 3 Tseng TC, Kao JH. Clinical utility of quantitative HBsAg in natural history and nucleos(t)ide analogue treatment of chronic hepatitis B: new trick of old dog. J Gastroenterol 2013; 48: 13-21
• 4 Chen CJ, Yang HJ, Su J et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65-73
• 5 Kobayashi M, Koike K. Complete nucleotide sequence of hepatitis B virus DNA of subtype adr and its conserved gene organization. Gene 1984; 30: 227-232
• 6 Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. JAMA 1965; 191: 541-546
• 7 Okochi K, Murakami S. Observations on Australia antigen in Japanese. Vox Sang 1968; 15: 374-385
• 8 Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet 1970; 1: 695-698
• 9 Kaplan PM, Greenman RL, Gerin JL et al. DNA polymerase associated with human hepatitis B antigen. J Virol 1973; 12: 995-1005
• 10 Robinson WS, Clayton DA, Greenman RL. DNA of a human hepatitis B virus candidate. J Virol 1974; 14: 384-391
• 11 Galibert F, Mandart E, Fitoussi F et al. Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature 1979; 281: 646-650
• 12 Kramvis A, Kew M, François G. Hepatitis B virus genotypes. Vaccine 2005; 23: 2409-2423
• 13 Hernández S, Venegas M, Brahm J et al. Full-genome sequence of a hepatitis B virus genotype f1b clone from a chronically infected chilean patient. Genome Announc 2014; 2: e01075-e1114
• 14 Yano Y, Azuma T, Hayashi Y. Variations and mutations in the hepatitis B virus genome and their associations with clinical characteristics. World J Hepatol 2015; 7: 583-592
• 15 Mahtab MA, Rahman S, Khan M et al. Hepatitis B virus genotypes: an overview. Hepatobiliary Pancreat Dis Int 2008; 7: 457-464
• 16 Kim BK, Revill PA, Ahn SH. HBV genotypes: relevance to natural history, pathogenesis and treatment of chronic hepatitis B. Antivir Ther 2011; 16: 1169-1186
• 17 Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009; 373: 582-592
• 18 Cerino A, Bremer CM, Glebe D et al. A human monoclonal antibody against hepatitis B surface antigen with potent neutralizing activity. Plos one 2015; 10: e0125704
• 19 Martinot-Peignoux M, Lapalus M, Asselah T et al. HBsAg quantification: useful for monitoring natural history and treatment outcome. Liver Int 2014; 34 (Suppl. 01) 97-107
• 20 Liaw YF, Lau GK, Kao JH et al. Hepatitis B e antigen seroconversion: a critical event in chronic hepatitis B virus infection. Dig Dis Sci 2010; 55: 2727-2734
• 21 Chen YC, Chu CM, Liaw YF. Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B. Hepatology 2010; 51: 435-444
• 22 Tseng TC, Liu CJ, Chen CL et al. Serum hepatitis B virus-DNA levels correlate with long- term adverse outcomes in spontaneous hepatitis B e antigen seroconverters. J Infect Dis 2012; 205: 54-63
• 23 Tai D, Lin SM, Sheen IS et al. Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine amino tranferase levels over time. Hepatology 2009; 49: 1859-1867
• 24 McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009; 49: 545-555
• 25 Chu CM, Liaw YF. Hepatitis B surface antigen seroclearance during chronic HBV infection. Antivir Ther 2010; 15: 133-143
• 26 Tsutsumi Y, Yamamoto Y, Shimono J et al. Hepatitis B reactivation with rituximab-containing regimen. World J Hepatitis 2013; 5: 612-620
• 27 Glebe D, Bremer CM. The molecular virology of hepatitis B virus. Semin Liver Dis 2013; 33: 103-112
• 28 Verheyen J, Neumann-Fraune M, Berg T et al. The detection of HBsAg mutants expressed in vitro using two different quantitative HBsAg assays. J Clin Virol 2012; 54: 279-281
• 29 Gerlich WH, Bremer CM, Saniewski M et al. Occult hepatitis B virus infection: detection and significance. Dig Dis 2010; 28: 116-125
• 30 Chan HL, Wong VW, Wong WL et al. A longitudinal study on the natural history of serum hepatitis B surface antigen changes in chronic hepatitis B. Hepatology 2010; 52: 1232-1241
• 31 Nguyen T, Thompson AJ, Bouwden S et al. Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. J Hepatol 2010; 52: 508-513
• 32 Joroszewicz J, Calle Serrano B, Wursthorn K et al. Hepatitis B surface antigen (HBsAg) levels in natural history of hepatitis B virus (HBV) infection: a European perspective. J Hepatol 2010; 52: 514-522
• 33 Chen YC, Sheen IS, Chu CM et al. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002; 123: 1084-1089
• 34 Cornberg M, Protzer U, Petersen J et al. Prophylaxis, Diagnosis and Therapy of Hepatitis B Virus Infection – The German Guideline. Z Gastroenterol 2011; 49: 871-930
• 35 Tseng TC, Liu CJ, Su TH et al. Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. Gastroenterology 2011; 141: 517-525
• 36 Seto WK, Wong DK, Fung J et al. A large case control study on the predictability of hepatitis B surface antigen (HBsAg) levels three years before HBsAg seroclearance. Hepatology 2012; 56: 812-819
• 37 Brunetto MR, Oliveri F, Colombatto P et al. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 2010; 139: 483-490
• 38 Tseng TC, Liu CJ, Yang HC et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology 2013; 57: 441-450
• 39 Chu CM, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long term follow up. Hepatology 2007; 45: 1187-1192
• 40 Liu J, Yang HJ, Lee MH et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community based follow-up study. Gastroenterology 2010; 139: 474-482
• 41 Tseng TC, Liu CJ, Yang HC et al. Determinations of spontaneous surface antigen loss in hepatitis B e antigen negative patients with a low viral load. Hepatology 2012; 55: 68-76
• 42 Iloeje UH, Yang HJ, Su J et al. Predicting cirrhosis risk based on the level of circulating hepatitis B virus load. Gastroenterology 2006; 130: 678-686
• 43 Chen JD, Yang HJ, Iloeje UH et al. Carriers of inactive hepatitis B virus are still at risk for pepatocellular carcinoma and liver-related death. Gastroenterology 2010; 138: 1747-1754
• 44 Lin CL, Koa JH. Recent advances in the treatment of chronic hepatitis B. Expert Opin Pharmacother 2011; 12: 2025-2040
• 45 Piratvisuth T, Marcellin P, Popescu M et al. Hepatitis B surface antigen association with sustained response to peginterferon alfa-2a in hepatitis B e antigen positive patients. Hepatol Int 2012; 6: 556-562
• 46 Chen EQ, Tang H. Optimization therapy for the treatment of chronic hepatitis B. World J Hepatol 2014; 20: 5730-5736
• 47 Rijckhorst V, Hansen BE, Ferenci P et al. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg negative patients treated with peginterferon alfa-2a. J Hepatol 2012; 56: 1006-1011
• 48 Heathcote EJ, Marcellin P, Buti M et al. Three year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011; 140: 132-143
• 49 Yang J, Chen J, Ye P et al. HBsAg a an important predictor of HBeAg seroconversion following antiviral treatment for HBeAg-positive chronic hepatitis B patients. J Translational Med 2014; 12: 183-192
• 50 Wursthorn K, Jung M, Riva A et al. Kinetics of hepatitis B surface antigen decline during 3 years telbivudine treatment in Hepatitis B e antigen-positive patients. Hepatology 2010; 52: 1611-1620
• 51 Gish RG, Chang TT, Lai CL et al. Loss of HBsAg during treatment with entecavir or lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B. J Viral Hepat 2010; 17: 16-22
• 52 Tseng TC, Liu CJ, Yang HC et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012; 142: 1140-1149