The pros and cons of lamivudine vs. entecavir in decompensated or severe acute exacerbation of chronic hepatitis B
Authors: Daniel Shouval
Journal: Journal of Hepatology (2014)

Entecavir vs. lamivudine in chronic hepatitis B patients with severe acute exacerbation and hepatic decompensationJournal of HepatologyVol. 60Issue 6PreviewWe compared the mortality and treatment response between lamivudine (LAM) and entecavir (ETV) in chronic hepatitis B (CHB) patients with severe acute exacerbation and hepatic decompensation. Full-Text PDF In patients with chronic hepatitis B (CHB) and cirrhosis, the 5-year probability for hepatic decompensation if untreated is around 15–20% with a 5 year survival ranging between 14% and 35% [[1]Liaw Y.F. Chu C.M. Hepatitis B virus infection.Lancet. 2009; 373: 582-592Abstract Full Text Full Text PDF PubMed Scopus (1040) Google Scholar]. The development of oral nucleotide and nucleoside analogues (NUCs) for treatment of chronic hepatitis B (CHB) has revolutionized the prognosis of this large population of patients worldwide. For more than a decade, such agents are now routinely used for treatment of decompensated CHB. Indeed, early studies conducted in Taiwan, provided already evidence that lamivudine (LAM) prevents fatality in decompensated CHB, reducing mortality from 25% (in historical controls) to only 4.2%, provided treatment is started early enough before bilirubin levels rise above 20 mg/dl [[2]Chien R.N. Lin C.H. Liaw Y.F. The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B.J Hepatol. 2003; 38: 322-327Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar]. The introduction of more potent NUCs with a better resistance profile than LAM and an excellent safety record such as Entecavir (ETV), Tenofovir, and Telbivudine lead to further improvement in the care of patients with imminent hepatic decompensation [3Liaw Y.F. Sheen I.S. Lee C.M. Akarca U.S. Papatheodoridis G.V. 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: 62-72Crossref PubMed Scopus (274) Google Scholar, 4Roche B. Samuel D. Treatment of patients with HBV-related decompensated cirrhosis and liver transplanted patients.Clin Liver Dis. 2013; 17: 451-473Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. Yet, with the cumulative clinical experience using such NUCs, it became clear that use of anti-viral agents may be associated with a number of hepatic and extra hepatic undesirable adverse effects [[5]Fung J. Seto W.K. Lai C.L. Yuen M.F. Extrahepatic effects of nucleoside and nucleotide analogues in chronic hepatitis B treatment.J Gastroenterol Hepatol. 2014; 29: 428-434Crossref PubMed Scopus (75) Google Scholar]. In 2006, Lange and co-workers reported the development of lactic acidosis believed to be the consequence of mitochondrial toxicity, observed in 5 out of 16 patients with cirrhosis and advanced liver disease and a MELD score >20 treated with ETV [[6]Lange C.M. Bojunga J. Hofmann W.P. Wunder K. Mihm U. Zeuzem S. et al.Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function.Hepatology. 2009; 50: 2001-2006Crossref PubMed Scopus (226) Google Scholar]. The authors consequently advised caution in administration of ETV in patients with impaired liver functions. Furthermore, in 2011, investigators from Hong-Kong reported a mortality rate of 19% in ETV treated patients with acute exacerbation of HBV by week 48 as compared to only 4% in LAM treated historical controls [[7]Wong V.W. Wong G.L. Yiu K.K. Chim A.M. Chu S.H. Chan H.Y. et al.Entecavir treatment in patients with severe acute exacerbation of chronic hepatitis B.J Hepatol. 2011; 54: 236-242Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. This report added further concern regarding the safety of ETV in patients with acute exacerbation of CHB or decompensated CLD. To the best knowledge of this reviewer, prospectively controlled trials testing specifically lactic acidosis during hepatic decompensation in NUCs recipients are not available. Thus, the accurate risk of lactic acidosis in ETV recipients with acute exacerbation or decompensated CHB remains controversial and most probably low as also reflected in a letter from Italy, where 1 out of 6 patients with a high MELD score treated with ETV developed lactic acidosis albeit in association with septicemia [[8]Marzano A. Marengo A. Marietti M. Rizzetto M. Lactic acidosis during Entecavir treatment in decompensated hepatitis B virus-related cirrhosis.Dig Liver Dis. 2011; 43: 1027-1028Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. The short and long-term risk/benefit ratio in using NUCs in patients with acute exacerbation/and or decompensated CHB is clearly in favor of a benefit [9Chen T. He Y. Liu X. Yan Z. Wang K. Liu H. et al.Nucleoside analogues improve the short-term and long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure.Clin Exp Med. 2012; 12: 159-164Crossref PubMed Scopus (45) Google Scholar, 10Cui Y.L. Yan F. Wang Y.B. Song X.Q. Liu L. Lei X.Z. et al.Nucleoside analogue can improve the long-term prognosis of patients with hepatitis B virus infection-associated acute on chronic liver failure.Dig Dis Sci. 2010; 55: 2373-2380Crossref PubMed Scopus (73) Google Scholar]. Yet, although ETV has repeatedly been shown to suppress HBV load more efficiently and with a much better resistance profile as compared to LAM, the cost of ETV is significantly higher. Moreover, AASLD (2009) and EASL (2012) guidelines do not recommend a specific NUC for treatment of decompensated CLD or acute exacerbation, although there is a consensus regarding the importance of treatment with a potent anti-viral agent. Consequently, LAM is still widely used in many countries and especially in low resource regions. Recently, Xiao-Guang Ye et al. from China conducted a meta-analysis of 12 randomized controlled Chinese and one English clinical trials comparing treatment of LAM (N = 450) with ETV (N = 423) in decompensated HBV cirrhosis [[11]Ye X.G. Su Q.M. Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: meta-analysis.World J Gastroenterol. 2013; 19: 6665-6678Crossref PubMed Scopus (32) Google Scholar]. One of the major conclusions of this analysis was that despite the much better suppression of viral load in ETV recipients, the mortality rate in LAM and ETV recipients with decompensated cirrhosis was similar ranging between 7.89% and 6.37% respectively. In this meta-analysis the safety record for both anti-viral agents was similar. Thus, although no data are provided on incidence of lactic acidosis, and despite the fact that mortality rates were similar using either agent, the authors practically "vindicate" and endorse the long-term use of ETV which has a better resistance profile and is more effective in suppression of viral load in decompensated cirrhosis. In the present issue of the journal Chen and co-workers from Taiwan add their own experience in treating CHB patients with severe acute exacerbation and hepatic decompensation with LAM or ETV [[12]Chen C.H. Lin C.L. Hu T.H. Hung C.H. Tseng P.L. Wang J.H. et al.Entecavir vs. lamivudine in chronic hepatitis B patients with severe acute exacerbation and hepatic decompensation.J Hepatol. 2014; 60: 1127-1134Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. In this retrospective, non-randomized study, 215 and 107 patients were treated with ETV or LAM respectively. The main result of this study using univariate analysis at week 24 of treatment suggest that LAM recipients had a higher rate of over-all and liver related short-term (24 weeks) mortality (despite a higher HBeAg loss) as compared to ETV. As expected, at week 24 of treatment, suppression of viral load was more effective in ETV as compared to LAM recipients. However, after adjusting for baseline factors, i.e., MELD score, ascites, and hepatic encephalopathy, overall and liver related mortality were similar for both groups as also reported in the recent meta-analysis from China [[11]Ye X.G. Su Q.M. Effects of entecavir and lamivudine for hepatitis B decompensated cirrhosis: meta-analysis.World J Gastroenterol. 2013; 19: 6665-6678Crossref PubMed Scopus (32) Google Scholar]. The choice between ETV and LAM was not an independent factor for overall and liver related mortality in patients with decompensated CHB. A cut-off of a MELD score >24 was predictive for treatment ineffectiveness and week 24 mortality suggesting referral for liver transplantation. As also acknowledged by the authors, the study has two major limitations, namely the retrospective and the non-randomized design. Consequently it appears that LAM recipients had more advanced liver injury at baseline as compared to the ETV group. Therefore, the strength of the conclusions and the implications on routine clinical practice which can be drawn from the results are limited. Regardless of this reservation, LAM can still be used in countries where more advanced (and more costly) NUCs are unavailable. Yet, available clinical evidence suggests that clinicians treating CHB patients with acute HBV exacerbation or decompensated liver disease should use the most potent NUC available to them. The study results provide further indirect evidence regarding the safety of ETV in such patients. Yet, as already suggested before, these patients require close follow-up and dose adjustment of ETV when indicated. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.