Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2010)

Potential short-term mortality risk in patients undergoing entecavir treatment for spontaneous exacerbation of chronic hepatitis B: Fact or bias? Spontaneous acute reactivation and clinical exacerbation of chronic hepatitis B virus (HBV) infection (CHB) are well recognized complications in HBsAg carriers in both the Western and Eastern hemispheres. Spontaneous reactivation was reported in 22% of a cohort of 45 Italian HBsAg+/HBeAg+ patients, who seroconverted to anti-HBe+, followed for up to 15 years [[1]Fattovich G. Brollo L. Alberti A. Realdi G. Pontisso P. Giustina G. et al.Spontaneous reactivation of hepatitis B virus infection in patients with chronic type B hepatitis.Liver. 1990; 10: 141-146PubMed Google Scholar]. Spontaneous reactivation was also reported in a cohort of 386 Chinese patients followed for 1–5 years [[2]Lok A.S. Lai C.L. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology.J Hepatol. 1990; 10: 29-34Abstract Full Text PDF PubMed Scopus (203) Google Scholar]. In this study, the cumulative probability for HBV reactivation was as high as 15% in patients with pre-reactivation ALT levels<200 iu/L and increased up to 47% in those with ALTs>200 iu/L. Such HBV reactivation can be asymptomatic but may frequently lead to hepatic decompensation associated with significant morbidity and mortality when not treated on time. Until recently, lamivudine (and sometimes adefovir) was the most commonly used anti-viral agent available for such patients worldwide and especially in Asia. Current EASL and AASLD guidelines recommend that chronic HBV patients with active liver disease and appropriate viral replication should be treated with the most potent available anti-viral agent such as entecavir or tenofovir [3EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol 2009;50:227–242.Google Scholar, 4Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2455) Google Scholar]. Indeed, both agents have been shown to be highly potent and safe in the suppression of viral load, reversal of hepato-cellular injury, and control of fibrosis in patients with compensated CHB. However, both guidelines emphasize that data are still lacking regarding the safety of these agents in patients with decompensated liver disease. Concern regarding the safety of entecavir in patients with severe CHB has been raised for the first time in 2006 following the report of lactic acidosis and worsening of the MELD score in 5/16 patients with cirrhosis and CHB [[5]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 (232) Google Scholar]. In this context it is important to distinguish between spontaneous reactivation with exacerbation of CHB, which is most likely immune-mediated as compared to hepatic decompensation following continuous progression of chronic liver disease toward liver failure. A recent retrospective study from China provides some evidence for an acceptable short-term safety profile of entecavir in the treatment of CHB patients with severe hepatitis B treated up to 1 year [[6]Chen J. Han J.H. Liu C. Yu R.H. Li F.Z. Li Q.F. et al.Short-term entecavir therapy of chronic severe hepatitis B.Hepatobiliary Pancreat Dis Int. 2009; 8: 261-266PubMed Google Scholar]. One noteworthy observation recorded in this study was that short-term survival of entecavir treated patients was not different as compared to non-treated patients, despite the potent suppression of HBV viral load by entecavir. Except for these two reports, information regarding the safety of entecavir treatment in patients with decompensated or severe CHB liver disease is not yet available. In the present issue of the Journal, Wong and co-workers report their retrospective analysis on the safety and efficacy in 36 CHB patients who developed acute spontaneous exacerbation of hepatitis B, treated with entecavir. The historical control group consisted of 117 patients treated by lamivudine. By week 48, mortality in the entecavir treated group reached 19% as compared to only 4% in lamivudine recipients (p= 0.010). Furthermore, despite a lower prevalence of cirrhosis among entecavir recipients and the faster and more efficient suppression of viral load, this group had higher liver related mortality, associated with prolonged bilirubinemia, hepatic encephalopathy, and ascites. These results require attention, especially in view of the widespread use of entecavir worldwide and the so far excellent safety record of this potent anti-viral agent, obtained mainly in CHB patients with relatively compensated liver disease. As stated in the current guidelines, a main goal of anti-viral treatment in CHB is rapid and maximal viral suppression, previously shown to be associated with improvement in hepato-cellular injury as well as prevention of cirrhosis and its complications. The data presented in the present new study suggest that this rule may not apply across the board to all patients with CHB and one has to distinguish between patients with spontaneous acute exacerbation of HBV, in whom entecavir treatment maybe associated with increased short-term mortality, and those with progressively active disease, who have repeatedly been shown to benefit from such treatment, irrespective of their HBeAg status. The study of Wong et al. provides new evidence that entecavir treatment in patients with spontaneous acute reactivation of CHB may be associated with increased mortality. Unfortunately, lactate levels were not recorded systematically in this cohort of patients. Thus, it is still not known if the reported increased rate in early and liver related mortality in entecavir recipients correlates with lactic acidosis. Although the cause of this phenomenon remains at present unknown, the authors provide a hypothesis that the rapid and effective suppression of viral replication induced by entecavir may lead to an accelerated intense immune response, associated with HBeAg seroconversion which in turn augments hepato-cellular injury. Based on their observations, the investigators suggest that lamivudine should remain the initial anti-viral agent of choice for patients with acute spontaneous exacerbation of CHB. The study of Wong et al. has, however, a number of limitations including the retrospective, non-randomized design and the differences in age, ALT levels and gender between both study groups. Consequently, in view of this author, it is premature to endorse the investigators recommendation to prefer lamivudine over entecavir in such patients until their results are confirmed in a prospective randomized controlled clinical trial. Yet, this report deserves close attention until a future clinical trial confirms or rejects this safety signal observed retrospectively in entecavir treated patients with spontaneous acute exacerbation of CHB. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.