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Z Gastroenterol 2016; 54(12): 1306-1311
DOI: 10.1055/s-0042-120418
Originalarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Treatment of fulminant acute Hepatitis B with nucles(t)id analogues is safe and does not lead to secondary chronification of Hepatitis B

Therapie der akuten fulminanten Hepatitis B mit Nucleos(t)id-Analogen ist sicher und führt nicht zur Chronifizierung der Hepatitis B
C. Jochum
1   Gastroenterology and Hepatology, University Hospital Essen, Germany
,
F. Maischack
1   Gastroenterology and Hepatology, University Hospital Essen, Germany
,
O. E. Anastasiou
1   Gastroenterology and Hepatology, University Hospital Essen, Germany
,
J. Verheyen
2   Institute for Virology, University Hospital Essen, Germany
,
J. Timm
3   Institut für Virologie, Universitatsklinikum Dusseldorf, Germany
,
L. Bechmann
1   Gastroenterology and Hepatology, University Hospital Essen, Germany
,
G. Gerken
1   Gastroenterology and Hepatology, University Hospital Essen, Germany
,
A. Canbay
1   Gastroenterology and Hepatology, University Hospital Essen, Germany
› Institutsangaben
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Publikationsverlauf

06. August 2016

04. November 2016

Publikationsdatum:
09. Dezember 2016 (online)

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Abstract

Background: Acute hepatitis B virus (HBV) infection is still a major cause of acute liver failure (ALF), necessitating a high rate of emergency liver transplantation (LTx). Acute infection is followed by high viral replication rates leading to hepatocyte death and, ultimately, ALF. The objective of treating HBV-induced ALF thus is to eliminate, or significantly suppress, HBV replication and therefore reduce cell death and support regeneration.

Objective: In this retrospective study, we want to evaluate the timing, the safety, and the long-term virological outcome of this approach.

Methods/results: In this study, we included 32 patients (16 female and 16 males; median age 39.5 years) with ALF due to hepatitis B, who were transferred to the university hospital Essen, Germany between January 2009 and December 2013. Before treatment, transaminases were highly elevated, bilirubin was increased, and elevated international normalized ratio (INR) revealed impaired liver function. HBV-DNA and HBsAg were positive. All 32 patients received oral antiviral treatment (3 lamivudine, 21 entecavir, and 8 tenofovir) between 1 day and 4 months after diagnosis of acute hepatitis B. One patient died, 2 were transplanted, one died shortly after LTx the other patient survived after LTx. These 3 patients received treatment in a state of advanced liver failure, and 1 patient 4 months after initial diagnosis of hepatitis B. Twenty-nine patients survived without LTx. Five patients were discharged without further follow-up. All 24 remaining patients became HBV-DNA negative in median of 100 days. Twenty-two patients were followed further, and all patients lost their HBsAg in median of 108 days. Sixteen of the 22 patients experienced a seroconversion to anti-HBs in median of 137 days. Four patients who were followed for 1 more year after HBsAg did not develop anti-HBs. None of the patients developed chronic hepatitis B.

Conclusion: Immediate treatment of HBV-induced ALF with nucleos(t)id-analogues (NUCs) appears save and prevents LTx and death, and there is no indication for increased chronicity.

Zusammenfassung

Hintergrund: Akute Hepatitis-B-Virus (HBV) Infektion stellt immer noch eine bedeutende Ursache für das akute Leberversagen (ALV) dar und ist verbunden mit einer hohen Rate an High-Urgency Lebertransplantationen. Die akute Infektion führt über Virusreplikation und Zelltod schließlich zum ALV. Die Grundlage für die Behandlung der akuten fulminanten Hepatitis B ist daher durch Unterdrückung der Virusreplikation den Zelltod zu stoppen und die Regeneration der Leber zu unterstützen.

Studienziel: Ziel dieser retrospektiven Analyse war die Evaluation des optimalen Zeitpunktes, der Sicherheit und des Langzeit virologischen Ergebnisses dieser Therapie.

Methoden/Ergebnisse: In dieser Studie wurden 32 Patienten [16 Frauen und 16 Männer, medianes Alter 39,5 Jahre] mit ALV durch akute fulminante Hepatitis B retrospektiv untersucht, die in das Universitätsklinikum Essen zwischen Januar 2009 und Dezember 2013 stationär behandelt wurden. Vor Therapiebeginn waren die Transaminasen und Bilirubin stark erhöht; und ein erhöhter INR zeigte eine eingeschränkte Lebersyntheseleistung. HBV DNA und HBsAg waren positiv. Alle 32 Patienten erhielten orale antivirale Therapie (3 Lamivudin, 21 Entecavir und 8 Tenofovir) zwischen 1 Tag und 4 Monaten nach Diagnosestellung einer akuten Hepatitis B. Ein Patient starb, zwei erhielten eine Lebertransplantation von denen ein Patient kurz nach Transplantation starb. Bei diesen drei Patienten wurde die Therapie erst in einem Stadium fortgeschrittenen ALV begonnen, bei einem Patienten 4 Monate nach Diagnosestellung einer akuten Hepatitis B. 29 Überlebten ohne Transplantation. 5 Patienten wurden entlassen ohne weitere Kontrolluntersuchungen. Alle 24 übrigen Patienten wurden HBV-DNA negativ im median von 100 Tagen. 22 Patienten wurden weiter beobachtet und alle Patienten verloren das HBsAg im Median von 108 Tagen. 16 der 22 Patienten zeigten eine Serokonversion zu anti-HBs in einem Median von 137 Tagen. Vier Patienten, die für mehr als ein Jahr nach HBsAg-Verlust nachbeobachtet wurden entwickelten kein anti-HBs. Kein Patient entwickelte eine chronische Hepatitis B.

Zusammenfassung: Sofortige Therapie des ALV bei akuter fulminanter Hepatitis B mit Nucleos(t)id-Analogen erscheint sicher und kann Lebertransplantation und Tod verhindern und begünstigt nicht die Entwicklung einer chronischen Hepatitis B.

Schlüsselwörter

Hepatitis B - Akutes Leberversagen - Virushepatitis

Key words

Hepatitis B - acute liver failure - virus hepatitis
 

  • References

  • 1 O'Grady JG. Acute liver failure. Postgrad Med J 2005; 81: 148-154
    CrossrefPubMedGoogle Scholar
  • 2 Chen X, Fu C, Liu J et al. Recent epidemiological and clinical features of acute hepatitis B in a single center of China. Int J Clin Exp Med 2015; 8: 16652-16657
    PubMedGoogle Scholar
  • 3 Koskinas J, Deutsch M, Kountouras D et al. Aetiology and outcome of acute hepatic failure in Greece: experience of two academic hospital centres. Liver Int 2008; 28: 821-827
    CrossrefPubMedGoogle Scholar
  • 4 Escorsell A, Mas A, de la Mata M. Acute liver failure in Spain: analysis of 267 cases. Liver Transpl 2007; 13: 1389-1395
    CrossrefPubMedGoogle Scholar
  • 5 Tillmann HL, Hadem J, Leifeld L et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006; 13: 256-263
    CrossrefPubMedGoogle Scholar
  • 6 Teo EK, Ostapowicz G, Hussain M et al. Hepatitis B infection in patients with acute liver failure in the United States. Hepatology 2001; 33: 972-976
    CrossrefPubMedGoogle Scholar
  • 7 Samuel D, Muller R, Alexander G et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993; 329: 1842-1847
    CrossrefPubMedGoogle Scholar
  • 8 Verhaz A. Experience with lamivudine treatment for severe acute hepatitis B. Srp Arh Celok Lek 2014; 142: 703-707
    CrossrefPubMedGoogle Scholar
  • 9 Dao DY, Seremba E, Ajmera V et al. Use of nucleoside (tide) analogues in patients with hepatitis B-related acute liver failure. Dig Dis Sci 2012; 57: 1349-1357
    CrossrefPubMedGoogle Scholar
  • 10 Girke J, Wedemeyer H, Wiegand J et al. Acute hepatitis B: is antiviral therapy indicated? Two case reports. Dtsch Med Wochenschr 2008; 133: 1178-1182
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 11 Wiegand J, Wedemeyer H, Franke A et al. Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double-blinded multicentre trial. J Viral Hepat 2014; 21: 744-750
    CrossrefPubMedGoogle Scholar
  • 12 Tillmann HL, Patel K. Therapy of acute and fulminant hepatitis B. Intervirology 2014; 57: 181-188
    CrossrefPubMedGoogle Scholar
  • 13 Oketani M, Uto H, Ido A et al. Management of hepatitis B virus-related acute liver failure. Clin J Gastroenterol 2014; 7: 19-26
    CrossrefPubMedGoogle Scholar
  • 14 Palumbo E. Entecavir for chronic hepatitis B: a review. Ther Drug Monit 2008; 30: 1-4
    CrossrefPubMedGoogle Scholar
  • 15 Jochum C, Gieseler RK, Gawlista I et al. Hepatitis B-associated acute liver failure: immediate treatment with entecavir inhibits hepatitis B virus replication and potentially its sequelae. Digestion 2009; 80: 235-240
    CrossrefPubMedGoogle Scholar
  • 16 Yu JW, Sun LJ, Yan BZ et al. Lamivudine treatment is associated with improved survival in fulminant hepatitis B. Liver Int 2011; 31: 499-506
    CrossrefPubMedGoogle Scholar
  • 17 Delic D, Nesic Z, Prostran M et al. Treatment of subacute hepatitis B with lamivudine: a pilot study in Serbia. Vojnosanit Pregl 2009; 66: 199-202
    CrossrefPubMedGoogle Scholar
  • 18 Canbay A, Tacke F, Hadem J et al. Acute liver failure: a life-threatening disease. Dtsch Arztebl Int 2011; 108: 714-720
    PubMedGoogle Scholar
  • 19 Bower WA, Johns M, Margolis HS et al. Population-based surveillance for acute liver failure. Am J Gastroenterol 2007; 102: 2459-2463
    CrossrefPubMedGoogle Scholar
  • 20 Bechmann LP, Marquitan G, Jochum C et al. Apoptosis versus necrosis rate as a predictor in acute liver failure following acetaminophen intoxication compared with acute-on-chronic liver failure. Liver Int 2008; 28: 713-716
    PubMedGoogle Scholar
  • 21 Takikawa Y, Suzuki K. Clinical epidemiology of fulminant hepatitis in Japan. Hepatol Res 2008; 38 (Suppl. 01) S14-S18
    CrossrefPubMedGoogle Scholar
  • 22 Oketani M, Ido A, Nakayama N et al. Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: summary of the annual nationwide survey between 2004 and 2009. Hepatol Res 2013; 43: 97-105
    CrossrefPubMedGoogle Scholar
  • 23 Bernal W, Cross TJ, Auzinger G et al. Outcome after wait-listing for emergency liver transplantation in acute liver failure: a single centre experience. J Hepatol 2009; 50: 306-313
    CrossrefPubMedGoogle Scholar
  • 24 Volkmann X, Anstaett M, Hadem J et al. Caspase activation is associated with spontaneous recovery from acute liver failure. Hepatology 2008; 47: 1624-1633
    CrossrefPubMedGoogle Scholar
  • 25 Bechmann LP, Jochum C, Kocabayoglu P et al. Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepatol 2010; 53: 639-647
    CrossrefPubMedGoogle Scholar
  • 26 Wang CY, Zhao P, Liu WW et al. Acute liver failure caused by severe acute hepatitis B: a case series from a multi-center investigation. Ann Clin Microbiol Antimicrob 2014; 13: 23
    CrossrefPubMedGoogle Scholar
  • 27 Ferraz ML, Yoradjian A, Barbieri A et al. Epidemiology of acute hepatitis B in a university hospital in Sao Paulo, Brazil: retrospective study of two five-year periods. Sao Paulo Med J 1998; 116: 1695-1699
    CrossrefPubMedGoogle Scholar
  • 28 Gerken G, Paterlini P, Kremsdorf D et al. Clinical significance of the polymerase chain reaction (PCR) assay in chronic HBV carriers. Arch Virol Suppl 1992; 4: 97-101
    PubMedGoogle Scholar
  • 29 Gerken G, Paterlini P, Manns M et al. Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to pre-S- and S-encoded viral surface antigens. Hepatology 1991; 13: 158-166
    CrossrefPubMedGoogle Scholar
  • 30 McMahon BJ, Bender TR, Berquist KR et al. Delayed development of antibody to hepatitis B surface antigen after symptomatic infection with hepatitis B virus. J Clin Microbiol 1981; 14: 130-134
    PubMedGoogle Scholar