1796
CORRESPONDENCE
however, that on multivariate analysis of lack of secondary prophylaxis, BCLC classification and liver failure as measured by ChildPugh score were independent predictors of death. We agree with the concerns that Drs. Chen and Hou express regarding the grouping of BCLC C/D patients. This was done due to the similarities in the survival curves of these patients (see Supporting fig. 1 of the article). Taking into account the subjective nature of some aspects of this classification, such as the performance status, it is possible that the difference between BCLC C and D patients is not so clear-cut. We would like to underline that not all patients received the standard secondary prophylaxis in our study. In Spain, standard secondary prophylaxis is done with a combination of beta-blockers and endoscopic band ligation.2 Many patients received only betablockers as secondary prophylaxis, and only a minority of patients received endoscopic treatment as the sole prophylactic measure. The reason for this is not clear, but it could be due to the fact that endoscopic band ligation is perceived as a more aggressive option than beta-blocker therapy. Unfortunately, our study cannot answer the question of whether the administration of beta-blockers without endoscopic band ligation offers a better risk-benefit balance than standard secondary prophylaxis. However, we disagree with the comment made by Drs. Chen and Hou regarding the possible association between beta-blocker use and poor survival in3 patients with more advanced liver failure. The study they refer to is also a retrospective study with major baseline differences between groups, including the presence or absence of varices, which has a wellknown impact on survival. In conclusion, we agree that the decision for secondary prophylaxis in patients with BCLC C/D should be made carefully, but our data suggest that secondary prophylaxis does offer a survival benefit in these patients. Physicians taking care of patients with advanced hepatocellular carcinoma should individualize therapies according to common sense and patient need. CRISTINA RIPOLL, M.D.1 JOAN GENESCA`, M.D.2 JAIME BOSCH, M.D.3 1 Servicio de Aparato Digestivo Hospital Universitario Gregorio Mara~ non
HEPATOLOGY, November 2014
IiSGM, CiberEHD Universidad Complutense Madrid, Spain 2 Servicio Medicina Interna-Hepatologıa Hospital Universitari Vall d’Hebron Universidad Aut onoma de Barcelona CiberEHD Barcelona, Spain 3 Hepatic Hemodynamic Laboratory, Liver Unit Hospital Clınic IDIBAPS, CiberEHD University of Barcelona Barcelona, Spain
References 1. Ripoll C, Genesca J, Araujo IK, Graupera I, Augustin S, Tejedor M, et al. Rebleeding prophylaxis improves outcomes in patients with hepatocellular carcinoma. A multicenter case-control study. HEPATOLOGY 2013;58:2079-2088. 2. Bosch J, Abraldes JG, Albillos A, Aracil C, Banares R, Berzigotti A, et al. [Portal hypertension: recommendations for evaluation and treatment: consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Center for Liver and Digestive Diseases(CIBERehd)]. Gastroenterol Hepatol 2012;35:421-450. 3. Serste T, Francoz C, Durand F, Rautou PE, Melot C, Valla D, et al. Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol 2011;55:794-799. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27119 Potential conflict of interest: Dr. Bosch consults for Gilead, Chiasma, and Norgine.
Finite Entecavir Therapy Is a Feasible Alternative to Indefinite Therapy To the Editor: We highly appreciate the editorial comments of Dr. Reijnders and Janssen1 on our study concerning off-therapy durability of response to entecavir therapy published in the December issue of HEPATOLOGY.2 They raised several points requiring clarification or further discussion. First, 193 patients were excluded because their off-therapy duration was 2 3 105 IU/mL as the predictor of the off-therapy relapse, the sensitivity was 79% and the specificity was 42.3%. Although the rates are not high enough, it was the only factor for clinical relapse in logistic analysis (P 5 0.012), and was able to carefully discriminate the cumulative incidence of clinical relapse (53 versus 29%, P 5 0.036), as shown in fig. 2 of the article.2 Fourth, they seem to suggest that clinical relapse occurred in approximately one-third of the patients, while longer consolidation duration is still too high. However, two-thirds of the patients had sustained remission and free of medication is in fact a
very promising finding to practicing physicians. The finding also indicates that the glass is not half empty! Fifth, indeed the spontaneous remission rate (21%) and hepatitis B virus surface antigen (HBsAg) clearance rate (4.2%) of our patients with clinical relapse was lower than 55% and 39%, respectively, in the patients of Hadziyannis et al.3 Besides much longer maintained remission in that study, different genotype and duration of HBV infection (perinatal versus horizontal) may also play some role in these differences. However, it remains to be studied using head-to-head comparisons. We have to emphasize that cirrhosis patients did not have a higher relapse rate and only one who failed to follow the monitoring schedule developed decompensation. This speaks against the notion that all cirrhosis patients require indefinite therapy if proper monitoring is provided. In conclusion, discontinuing entecavir therapy in HBeAgnegative patients by the stopping rule of Asian-Pacific guidelines4 is a feasible alternative to indefinite therapy, even in cirrhosis patients if proper off-therapy monitoring is provided. WEN-JUEI JENG, M.D.1-3 Liver Research Unit, Chang Gung Memorial Hospital Taipei, Taiwan
1
HEPATOLOGY, Vol. 60, No. 5, 2014
2
Division of Hepatology, Department of Hepatology and Gastroenterology, Linkou Medical Center Chang Gung Memorial Hospital, Taipei, Taiwan 3 College of Medicine, Chang Gung University Taipei, Taiwan
References 1. Reijnders JGP, Janssen HLA. Relapse of chronic hepatitis B after discontinuation of nucleos(t)ide analogues: Is the glass half full or half empty? HEPATOLOGY 2013;58:1885-1887. 2. Jeng W-J, Sheen IS, Chen Y-C, Hsu C-W, Chien R-N, Chu C-M, et al. Offtherapy durability of response to entecavir therapy in hepatitis B e antigennegative chronic hepatitis B patients. HEPATOLOGY 2013;58:1888-1896.
CORRESPONDENCE
1797
3. Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology 2012;143:629-636 e621. 4. Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012;6:531-561.
C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27215 Potential conflict of interest: Nothing to report.
Entecavir Treatment Reduces Hepatic Events and Deaths in Chronic Hepatitis B Patients With Cirrhosis: Facts or Fiction? To the Editor: I read with interest the article by Wong et al. regarding longterm entecavir treatment in reduction of hepatic events and deaths in chronic hepatitis B patients with cirrhosis.1 This article is a retrospective-prospective cohort study based on two cohorts of patients during different periods. Some points require clarification. In the study, ultrasonography of the abdomen was performed every 1-2 years for surveillance of hepatocellular carcinoma (HCC) or, more frequently, if the alpha-fetoprotein level rose above 20 lg/ L. This appeared not to be in accord with the recommendations of screening intervals of every 6 months by the Asian Pacific Association for the Study of the Liver or American Association for the Study of liver Diseases.2,3 A high proportion of hepatic events were ascribed to variceal bleeding. If complied with the recommendations to prevent first variceal bleeding, these serious events could be effectively reduced.4,5 Most important, baseline clinical characteristics varied significantly between both cohorts. Though baseline data appeared to be milder disease in the entire untreated control cohort than entecavir-treated cohort, patients with cirrhosis in the untreated control cohort were more severe than the entecavir-treated cohort, as expressed by Child-Pugh’s score. There was no difference in hepatic events between both cohorts, except among patients with cirrhosis. Based on sensitivity analyses among patients with cirrhosis, the risk of hepatic events is greatly reduced by entecavir among patients with advanced liver disease, as reflected by low platelet counts, low serum albumin, high total bilirubin, higher Child-Pugh score, and Model for End-Stage Liver Disease score. These baseline clinical parameters were all worse in the untreated control cohort than the entecavirtreated cohort. Duration of follow-up was significantly longer in the untreated control cohort. All these factors may elicit significant bias between groups. Use of entecavir is proven to be beneficial for hepatitis B virus patients to reverse fibrosis and cirrhosis6; however, the evidence of reduction in hepatic events and incidence of HCC, as revealed by the current study and previous work,7 was still flawed with significant bias. Long-term follow-up of controlled studies would be more convincing.8
GIN-HO LO, M.D. Department of Medical Research Digestive Center E-DA Hospital Kaohsiung, Taiwan
References 1. Wong GLH, Chan HLY, Mak CWH, Lee SKY, Ip ZMY, Lam ATH, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with cirrhosis. HEPATOLOGY 2013;58:1537-1547. 2. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008;2:263-283. 3. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. HEPATOLOGY 2011;53:1020-1022. 4. de Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846-852. 5. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. HEPATOLOGY 2007;46:922-938. 6. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Longterm entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. HEPATOLOGY 2010;52:886-893. 7. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hapatocellular carcinoma incidence in patients with hepatitis B infection. HEPALOTOGY 2013;58:98-107. 8. Liaw YF, Sung JJY, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-1531.
C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27073 Potential conflict of interest: Nothing to report.
Reply: We thank Dr. Lo for his interest in our study.1 His first point related to the frequency of abdominal ultrasonography for surveillance of hepatocellular carcinoma every 1-2 years, instead of every 6 months, according to the international guidelines.2-4 This was the result of limited resources of radiology services in our public sector, which is often an issue in some regions.5 Instead, alphafetoprotein (AFP) was tested during every visit. In our recent analysis, the specificity of AFP was as high as 99% at a cut-off value of 20 mg/L in patients receiving entecavir.6
CORRESPONDENCE
however, that on multivariate analysis of lack of secondary prophylaxis, BCLC classification and liver failure as measured by ChildPugh score were independent predictors of death. We agree with the concerns that Drs. Chen and Hou express regarding the grouping of BCLC C/D patients. This was done due to the similarities in the survival curves of these patients (see Supporting fig. 1 of the article). Taking into account the subjective nature of some aspects of this classification, such as the performance status, it is possible that the difference between BCLC C and D patients is not so clear-cut. We would like to underline that not all patients received the standard secondary prophylaxis in our study. In Spain, standard secondary prophylaxis is done with a combination of beta-blockers and endoscopic band ligation.2 Many patients received only betablockers as secondary prophylaxis, and only a minority of patients received endoscopic treatment as the sole prophylactic measure. The reason for this is not clear, but it could be due to the fact that endoscopic band ligation is perceived as a more aggressive option than beta-blocker therapy. Unfortunately, our study cannot answer the question of whether the administration of beta-blockers without endoscopic band ligation offers a better risk-benefit balance than standard secondary prophylaxis. However, we disagree with the comment made by Drs. Chen and Hou regarding the possible association between beta-blocker use and poor survival in3 patients with more advanced liver failure. The study they refer to is also a retrospective study with major baseline differences between groups, including the presence or absence of varices, which has a wellknown impact on survival. In conclusion, we agree that the decision for secondary prophylaxis in patients with BCLC C/D should be made carefully, but our data suggest that secondary prophylaxis does offer a survival benefit in these patients. Physicians taking care of patients with advanced hepatocellular carcinoma should individualize therapies according to common sense and patient need. CRISTINA RIPOLL, M.D.1 JOAN GENESCA`, M.D.2 JAIME BOSCH, M.D.3 1 Servicio de Aparato Digestivo Hospital Universitario Gregorio Mara~ non
HEPATOLOGY, November 2014
IiSGM, CiberEHD Universidad Complutense Madrid, Spain 2 Servicio Medicina Interna-Hepatologıa Hospital Universitari Vall d’Hebron Universidad Aut onoma de Barcelona CiberEHD Barcelona, Spain 3 Hepatic Hemodynamic Laboratory, Liver Unit Hospital Clınic IDIBAPS, CiberEHD University of Barcelona Barcelona, Spain
References 1. Ripoll C, Genesca J, Araujo IK, Graupera I, Augustin S, Tejedor M, et al. Rebleeding prophylaxis improves outcomes in patients with hepatocellular carcinoma. A multicenter case-control study. HEPATOLOGY 2013;58:2079-2088. 2. Bosch J, Abraldes JG, Albillos A, Aracil C, Banares R, Berzigotti A, et al. [Portal hypertension: recommendations for evaluation and treatment: consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Center for Liver and Digestive Diseases(CIBERehd)]. Gastroenterol Hepatol 2012;35:421-450. 3. Serste T, Francoz C, Durand F, Rautou PE, Melot C, Valla D, et al. Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol 2011;55:794-799. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27119 Potential conflict of interest: Dr. Bosch consults for Gilead, Chiasma, and Norgine.
Finite Entecavir Therapy Is a Feasible Alternative to Indefinite Therapy To the Editor: We highly appreciate the editorial comments of Dr. Reijnders and Janssen1 on our study concerning off-therapy durability of response to entecavir therapy published in the December issue of HEPATOLOGY.2 They raised several points requiring clarification or further discussion. First, 193 patients were excluded because their off-therapy duration was 2 3 105 IU/mL as the predictor of the off-therapy relapse, the sensitivity was 79% and the specificity was 42.3%. Although the rates are not high enough, it was the only factor for clinical relapse in logistic analysis (P 5 0.012), and was able to carefully discriminate the cumulative incidence of clinical relapse (53 versus 29%, P 5 0.036), as shown in fig. 2 of the article.2 Fourth, they seem to suggest that clinical relapse occurred in approximately one-third of the patients, while longer consolidation duration is still too high. However, two-thirds of the patients had sustained remission and free of medication is in fact a
very promising finding to practicing physicians. The finding also indicates that the glass is not half empty! Fifth, indeed the spontaneous remission rate (21%) and hepatitis B virus surface antigen (HBsAg) clearance rate (4.2%) of our patients with clinical relapse was lower than 55% and 39%, respectively, in the patients of Hadziyannis et al.3 Besides much longer maintained remission in that study, different genotype and duration of HBV infection (perinatal versus horizontal) may also play some role in these differences. However, it remains to be studied using head-to-head comparisons. We have to emphasize that cirrhosis patients did not have a higher relapse rate and only one who failed to follow the monitoring schedule developed decompensation. This speaks against the notion that all cirrhosis patients require indefinite therapy if proper monitoring is provided. In conclusion, discontinuing entecavir therapy in HBeAgnegative patients by the stopping rule of Asian-Pacific guidelines4 is a feasible alternative to indefinite therapy, even in cirrhosis patients if proper off-therapy monitoring is provided. WEN-JUEI JENG, M.D.1-3 Liver Research Unit, Chang Gung Memorial Hospital Taipei, Taiwan
1
HEPATOLOGY, Vol. 60, No. 5, 2014
2
Division of Hepatology, Department of Hepatology and Gastroenterology, Linkou Medical Center Chang Gung Memorial Hospital, Taipei, Taiwan 3 College of Medicine, Chang Gung University Taipei, Taiwan
References 1. Reijnders JGP, Janssen HLA. Relapse of chronic hepatitis B after discontinuation of nucleos(t)ide analogues: Is the glass half full or half empty? HEPATOLOGY 2013;58:1885-1887. 2. Jeng W-J, Sheen IS, Chen Y-C, Hsu C-W, Chien R-N, Chu C-M, et al. Offtherapy durability of response to entecavir therapy in hepatitis B e antigennegative chronic hepatitis B patients. HEPATOLOGY 2013;58:1888-1896.
CORRESPONDENCE
1797
3. Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology 2012;143:629-636 e621. 4. Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012;6:531-561.
C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27215 Potential conflict of interest: Nothing to report.
Entecavir Treatment Reduces Hepatic Events and Deaths in Chronic Hepatitis B Patients With Cirrhosis: Facts or Fiction? To the Editor: I read with interest the article by Wong et al. regarding longterm entecavir treatment in reduction of hepatic events and deaths in chronic hepatitis B patients with cirrhosis.1 This article is a retrospective-prospective cohort study based on two cohorts of patients during different periods. Some points require clarification. In the study, ultrasonography of the abdomen was performed every 1-2 years for surveillance of hepatocellular carcinoma (HCC) or, more frequently, if the alpha-fetoprotein level rose above 20 lg/ L. This appeared not to be in accord with the recommendations of screening intervals of every 6 months by the Asian Pacific Association for the Study of the Liver or American Association for the Study of liver Diseases.2,3 A high proportion of hepatic events were ascribed to variceal bleeding. If complied with the recommendations to prevent first variceal bleeding, these serious events could be effectively reduced.4,5 Most important, baseline clinical characteristics varied significantly between both cohorts. Though baseline data appeared to be milder disease in the entire untreated control cohort than entecavir-treated cohort, patients with cirrhosis in the untreated control cohort were more severe than the entecavir-treated cohort, as expressed by Child-Pugh’s score. There was no difference in hepatic events between both cohorts, except among patients with cirrhosis. Based on sensitivity analyses among patients with cirrhosis, the risk of hepatic events is greatly reduced by entecavir among patients with advanced liver disease, as reflected by low platelet counts, low serum albumin, high total bilirubin, higher Child-Pugh score, and Model for End-Stage Liver Disease score. These baseline clinical parameters were all worse in the untreated control cohort than the entecavirtreated cohort. Duration of follow-up was significantly longer in the untreated control cohort. All these factors may elicit significant bias between groups. Use of entecavir is proven to be beneficial for hepatitis B virus patients to reverse fibrosis and cirrhosis6; however, the evidence of reduction in hepatic events and incidence of HCC, as revealed by the current study and previous work,7 was still flawed with significant bias. Long-term follow-up of controlled studies would be more convincing.8
GIN-HO LO, M.D. Department of Medical Research Digestive Center E-DA Hospital Kaohsiung, Taiwan
References 1. Wong GLH, Chan HLY, Mak CWH, Lee SKY, Ip ZMY, Lam ATH, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with cirrhosis. HEPATOLOGY 2013;58:1537-1547. 2. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008;2:263-283. 3. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. HEPATOLOGY 2011;53:1020-1022. 4. de Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846-852. 5. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. HEPATOLOGY 2007;46:922-938. 6. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Longterm entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. HEPATOLOGY 2010;52:886-893. 7. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hapatocellular carcinoma incidence in patients with hepatitis B infection. HEPALOTOGY 2013;58:98-107. 8. Liaw YF, Sung JJY, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-1531.
C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27073 Potential conflict of interest: Nothing to report.
Reply: We thank Dr. Lo for his interest in our study.1 His first point related to the frequency of abdominal ultrasonography for surveillance of hepatocellular carcinoma every 1-2 years, instead of every 6 months, according to the international guidelines.2-4 This was the result of limited resources of radiology services in our public sector, which is often an issue in some regions.5 Instead, alphafetoprotein (AFP) was tested during every visit. In our recent analysis, the specificity of AFP was as high as 99% at a cut-off value of 20 mg/L in patients receiving entecavir.6
