Z Gastroenterol 2013; 51 - V_5_03
DOI: 10.1055/s-0032-1332114

Treatment of acute hepatitis B with lamivudine vs. placebo: A prospective randomized multicenter trial

J Wiegand 1, H Wedemeyer 2, A Franke 3, U Stölzel 4, S Zeuzem 5, G Teuber 6, M Wächtler 7, U Römmele 8, B Ruf 9, U Spengler 10, C Trautwein 11, J Thiery 12, MP Manns 2, O Brosteanu 3, HL Tillmann 13
  • 1Universitätsklinikum Leipzig, Klinik für Gastroenterologie und Rheumatologie, Leipzig, Germany
  • 2Medizinische Hochschule Hannover, Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
  • 3Universität Leipzig, Zentrum für Klinische Studien, Leipzig, Germany
  • 4Klinikum Chemnitz gGmbH, Klinik für Innere Medizin II, Chemnitz, Germany
  • 5Johann Wolfgang Goethe Universität, Medizinische Klinik I, Frankfurt, Germany
  • 6Ambulantes Krebszentrum Schaubstrasse, Frankfurt, Germany
  • 7Krankenhaus München-Schwabing, Abteilung für Infektions- und Tropenmedizin, München, Germany
  • 8Klinikum Kirchheim-Nürtingen, Medizinische Klinik I, Kirchheim-Nürtingen, Germany
  • 9Städtisches Klinikum St. Georg, Klinik für Infektiologie, Tropenmedizin und Nephrologie, Leipzig, Germany
  • 10Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I, Bonn, Germany
  • 11Universitätsklinikum Aachen, Medizinische Klinik III, Aachen, Germany
  • 12Universitätsklinikum Leipzig, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Medizin, Leipzig, Germany
  • 13Duke Clinical Research Institute, Duke University Medical Center, Durham, USA

Aims: Acute hepatitis B virus infection can lead to fulminant liver failure with the consequence of liver transplantation or death. Several case series have attributed lamivudine with improved survival, prohibiting a placebo-controlled trial in fulminant hepatitis B. Even non-fulminant but severe acute hepatitis B (aHB) can lead to significant morbidity and impaired quality of life for a long period of time. We evaluated lamivudine in patients with severe acute hepatitis B in a placebo controlled trial.

Methods: 40 Patients with severe aHB (>18 years, ALT >10x ULN, bilirubin >85µmol/l, prothrombin time >50%) were randomized and treated with lamivudine 100mg/d or placebo within eight days after diagnosis. Other liver diseases or ongoing drug abuse were excluded. The primary endpoint was time to bilirubin <34µmol/l. Secondary endpoints were time to clear HBsAg and HBV-DNA, occurrence of anti-HBs, normalization of ALT, and rate of adverse events.

Kaplan-Meier curves illustrated time courses. Mann-Whitney-U-Tests (2-sided, α=0,05) were used. Arm differences were estimated by Hodges-Lehmann estimators with 95% confidence limits.

Results: After screening 5 exclusions occurred due to violated I/E criteria, withdrawn consent, or worsening of disease prior to treatment.

18 cases were randomized to lamivudine, 17 to placebo (86% male, median age 39 years). Mode of infection was unknown or sexual in 49% and 43% of cases, respectively. Hospitalisation was necessary in 94% of patients.

Median bilirubin and ALT levels were 146 vs. 182µmol/l and 1320 vs. 1860U/l in the lamivudine and placebo arm, respectively.

No individual progressed to hepatic failure, all patients achieved the primary endpoint. Observed median time endpoints [in days] were: Bilirubin <34µmol/l (25 vs. 32), ALT normalization (35 vs. 48) and HBsAg clearance (48 vs. 67) referring to earlier recovery under lamivudine, in contrast to loss of HBV-DNA (62 vs. 54) and occurrence of anti-HBs titers (119 vs. 109).

After 12 months follow-up all individuals with data available (n=22) were HBsAg-negative.

One patient per treatment arm had a prothrombin time <70% at baseline which normalized earlier under lamivudine therapy (8 vs. 19 days). No safety concerns were observed.

Recruitment was prematurely stopped because only 40 of 140 planned patients from 24 of 79 centers could be screened within 25 months. Due to early termination and smaller than expected patient numbers, we observed trends but no statistically significant differences between treatment arms.

Conclusion: Lamivudine seems to ameliorate severe aHBV infection, shorten disease duration and does not increase the risk of chronicity.