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To the Editor:

We read with great interest Garg et al.'s article1 published in HEPATOLOGY. The authors conducted a randomized study to compare the efficacy of tenofovir disoproxil fumarate (TDF) therapy and placebo therapy in patients suffering from a severe spontaneous reactivation of chronic hepatitis B (CHB) presenting as acute-on-chronic liver failure. They reported a high overall mortality rate of 63.0% (17/27), with rates of 43% and 85% in the TDF and placebo arms, respectively. TDF significantly reduced the mortality rate and hepatitis B virus DNA levels and improved the Child-Turcotte-Pugh and Model for End-Stage Liver Disease (MELD) scores in these patients at 3 months.

It is noteworthy that some patients with cirrhosis were enrolled. First, we consider 3 months of observation to be too short for determining the survival of these patients. We reexamined 96 patients with liver decompensation treated with lamivudine in our previous study in Taiwan.2 Eight patients (8.3%), two patients (2.1%), and three patients (3.1%) died within 1, 1 to 3, and 3 to 6 months of lamivudine treatment, respectively. In other words, 23.1% of the patients (3/13) who did not survive for 6 months died after 3 months of antiviral treatment. Villeneuve et al.3 reported that 25% of their patients (1/4) without hepatocellular carcinoma died from hepatic failure within 3 to 6 months of the initiation of lamivudine treatment. Fontana et al.4 reported that patients with decompensated cirrhosis were still dying even after the first 6 months. Hence, the mortality rate is possibly underestimated in Garg et al.'s study.1 The mean baseline MELD scores (27 and 25 in the TDF and placebo arms, respectively) reflect the fact that the patients enrolled in their study had more severe liver disease. In HEPATOLOGY, Liaw et al.5 reported lower mortality rates for patients with CHB and decompensated liver disease who were treated with TDF (4.4% or 2/45) or entecavir (9.1% or 2/22) by 48 weeks. The lower mortality rate is likely related to the milder severity of the patients' liver disease (the median baseline MELD scores were 11 and 10.5 for the TDF and entecavir arms, respectively). Hence, the earlier initiation of nucleot(s)ide analogue therapy seems critical for these patients.

Another issue is the design of this study of patients with cirrhosis and CHB-related acute-on-chronic liver failure: a placebo arm was included. With a lack of facilities for liver transplantation, Garg et al.1 observed a high mortality rate, and most deaths (82%) occurred because of progressive liver failure that led to the development of multiorgan failure.1 With a mortality rate of 4% to 30% 6 to 12 months after lamivudine, telbivudine, and entecavir therapy3-8 and with significant improvements in the long-term survival of patients with hepatic failure,4 it does not seem appropriate to include a placebo arm in studies enrolling patients with cirrhosis and critical liver failure. In the era of nucleot(s)ide analogue therapy with more potent anti–hepatitis B virus effects, we look forward to the results of more large-scale studies seeking to clarify whether the efficacy can be improved, particularly in patients with cirrhosis, CHB, and acute exacerbation, who have a poorer prognosis.

References

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  • 1
    Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. HEPATOLOGY 2011; 53: 774-780.
  • 2
    Dai CY, Chuang WL, Hou NJ, Lee LP, Hsieh MY, Lin ZY, et al. Early mortality in Taiwanese lamivudine-treated patients with chronic hepatitis B-related decompensation: evaluation of the Model for End-Stage Liver Disease and index scoring systems as prognostic predictors. Clin Ther 2006; 28: 2081-2092.
  • 3
    Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. HEPATOLOGY 2000; 31: 207-210.
  • 4
    Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology 2002; 123: 719-727.
  • 5
    Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. HEPATOLOGY 2011; 53: 62-72.
  • 6
    Chien RN, Lin CH, Liaw YF. The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B. J Hepatol 2003; 38: 322-327.
  • 7
    Gane EJ, Chan HL, Choudhuri G, Suh DJ, Chutaputti A, Safadi R, et al. Treatment of decompensated HBV-cirrhosis: results from 2-year randomized trial with telbivudine or lamivudine. J Hepatol 2010; 52: S4.
  • 8
    Wong VW, Wong GL, Yiu KK, Chim AM, Chu SH, Chan HY, et al. Entecavir treatment in patients with severe acute exacerbation of chronic hepatitis B. J Hepatol 2011; 54: 236-242.

Chia-Yen Dai M.D., Ph.D.* † ‡, Ming-Lun Yeh M.D.*, Chung-Feng Huang M.D., M.S.* † §, Jee-Fu Huang M.D.* ‡ ¶, Ming-Lung Yu M.D., Ph.D.* ‡ §, Wan-Long Chuang M.D., Ph.D.* ‡, * Departments of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, † Departments of Occupational Medicine (Hepatobiliary Division), Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ‡ Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, § Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, ¶ Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.