Finite Antiviral Therapy in Chronic Hepatitis B Patients with Cirrhosis

Abstract

Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.

Keywords

functional cure - hepatitis B surface antigen - hepatic decompensation - hepatocellular carcinoma - nucleos(t)ide analogues

Author Contribution

Contributed equally.

Authors Disclosure

Both authors have no conflicts.

Publikationsverlauf

Artikel online veröffentlicht:
28. Juni 2021

• References

• 1 Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988; 8 (03) 493-496
• 2 Fattovich G, Brollo L, Giustina G. et al. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991; 32 (03) 294-298
• 3 Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130 (03) 678-686
• 4 Chu CM, Liaw YF. Hepatitis B virus-related cirrhosis: natural history and treatment. Semin Liver Dis 2006; 26 (02) 142-152
• 5 Yang HI, Yeh SH, Chen PJ. et al; REVEAL-HBV Study Group. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst 2008; 100 (16) 1134-1143
• 6 Peng CY, Chien RN, Liaw YF. Hepatitis B virus-related decompensated liver cirrhosis: benefits of antiviral therapy. J Hepatol 2012; 57 (02) 442-450
• 7 Chevaliez S, Hézode C, Bahrami S, Grare M, Pawlotsky JM. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol 2013; 58 (04) 676-683
• 8 Liaw YF. Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift. Hepatol Int 2019; 13 (06) 665-673
• 9 Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Liver 1989; 9 (04) 235-241
• 10 Weissberg JI, Andres LL, Smith CI. et al. Survival in chronic hepatitis B. An analysis of 379 patients. Ann Intern Med 1984; 101 (05) 613-616
• 11 de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992; 103 (05) 1630-1635
• 12 Realdi G, Fattovich G, Hadziyannis S. et al; The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP). Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. J Hepatol 1994; 21 (04) 656-666
• 13 Fattovich G, Giustina G, Schalm SW. et al; The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. Hepatology 1995; 21 (01) 77-82
• 14 Fattovich G, Pantalena M, Zagni I, Realdi G, Schalm SW, Christensen E. European Concerted Action on Viral Hepatitis (EUROHEP). Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol 2002; 97 (11) 2886-2895
• 15 Liaw YF, Chen JJ, Chen TJ. Acute exacerbation in patients with liver cirrhosis: a clinicopathological study. Liver 1990; 10 (03) 177-184
• 16 Chen CJ, Yang HI, Su J. et al; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295 (01) 65-73
• 17 Kato Y, Nakata K, Omagari K. et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses. Cancer 1994; 74 (08) 2234-2238
• 18 Chien J, Liu J, Lee MH. et al. Risk and predictors of hepatocellular carcinoma for chronic hepatitis B patients with newly developed cirrhosis. J Gastroenterol Hepatol 2016; 31 (12) 1971-1977
• 19 Fattovich G, Giustina G, Sanchez-Tapias J. et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol 1998; 93 (06) 896-900
• 20 Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology 2002; 123 (04) 1084-1089
• 21 Chung HT, Lai CL, Lok AS. Pathogenic role of hepatitis B virus in hepatitis B surface antigen-negative decompensated cirrhosis. Hepatology 1995; 22 (01) 25-29
• 22 Lin SM, Yu ML, Lee CM. et al. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 2007; 46 (01) 45-52
• 23 Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm SW. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology 1997; 26 (05) 1338-1342
• 24 Chang TT, Liaw YF, Wu SS. et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52 (03) 886-893
• 25 Marcellin P, Gane E, Buti M. et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013; 381 (9865): 468-475
• 26 Liaw YF. Reversal of cirrhosis: an achievable goal of hepatitis B antiviral therapy. J Hepatol 2013; 59 (04) 880-881
• 27 Lampertico P, Invernizzi F, Viganò M. et al. The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: a 12-year prospective cohort study. J Hepatol 2015; 63 (05) 1118-1125
• 28 Su TH, Hu TH, Chen CY. et al; C-TEAM study group and the Taiwan Liver Diseases Consortium. Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. Liver Int 2016; 36 (12) 1755-1764
• 29 Liu K, Choi J, Le A. et al. Tenofovir disoproxil fumarate reduces hepatocellular carcinoma, decompensation and death in chronic hepatitis B patients with cirrhosis. Aliment Pharmacol Ther 2019; 50 (09) 1037-1048
• 30 Liaw YF, Sung JJ, Chow WC. et al; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351 (15) 1521-1531
• 31 Chen YC, Peng CY, Jeng WJ, Chien RN, Liaw YF. Clinical outcomes after interruption of entecavir therapy in HBeAg-negative chronic hepatitis B patients with compensated cirrhosis. Aliment Pharmacol Ther 2015; 42 (10) 1182-1191
• 32 Papatheodoridis GV, Idilman R, Dalekos GN. et al. The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology 2017; 66 (05) 1444-1453
• 33 Sinn DH, Lee J, Goo J. et al. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology 2015; 62 (03) 694-701
• 34 Kim JH, Sinn DH, Kang W. et al. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment. Hepatology 2017; 66 (02) 335-343
• 35 Zoutendijk R, Reijnders JG, Zoulim F. et al; VIRGIL Surveillance Study Group. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut 2013; 62 (05) 760-765
• 36 Jang JW, Choi JY, Kim YS. et al. Long-term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus-related cirrhosis. Hepatology 2015; 61 (06) 1809-1820
• 37 Chang ML, Cheng JS, Chien RN, Liaw YF. Hepatitis flares are associated with better outcomes than no flare in patients with decompensated cirrhosis and chronic hepatitis B virus infection. Clin Gastroenterol Hepatol 2020; 18 (09) 2064-2072.e2
• 38 Shim JH, Lee HC, Kim KM. et al. Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol 2010; 52 (02) 176-182
• 39 Liaw YF, Sheen IS, Lee CM. et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 2011; 53 (01) 62-72
• 40 Liaw YF, Raptopoulou-Gigi M, Cheinquer H. et al. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study. Hepatology 2011; 54 (01) 91-100
• 41 Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology 1999; 30 (02) 567-572
• 42 Liaw YF, Lee CM, Chien RN, Yeh CT. Switching to adefovir monotherapy after emergence of lamivudine-resistant mutations in patients with liver cirrhosis. J Viral Hepat 2006; 13 (04) 250-255
• 43 Core Working Party for Asia-Pacific Consensus on Hepatitis B and C. Consensus statements on the prevention and management of hepatitis B and hepatitis C in the Asia-Pacific region. J Gastroenterol Hepatol 2000; 15 (08) 825-841
• 44 Liaw YF, Kao JH, Piratvisuth T. et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 2012; 6 (03) 531-561
• 45 Chen CH, Lee CM, Lu SN. et al. Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants. J Hepatol 2004; 41 (03) 454-461
• 46 Kuo YH, Chen CH, Wang JH. et al. Extended lamivudine consolidation therapy in hepatitis B e antigen-positive chronic hepatitis B patients improves sustained hepatitis B e antigen seroconversion. Scand J Gastroenterol 2010; 45 (01) 75-81
• 47 Jeng WJ, Sheen IS, Chen YC. et al. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology 2013; 58 (06) 1888-1896
• 48 Jeng WJ, Chen YC, Sheen IS. et al. Clinical relapse after cessation of tenofovir therapy in hepatitis B e antigen-negative patients. Clin Gastroenterol Hepatol 2016; 14 (12) 1813-1820.e1
• 49 Hung CH, Wang JH, Lu SN, Hu TH, Lee CM, Chen CH. Hepatitis B surface antigen loss and clinical outcomes between HBeAg-negative cirrhosis patients who discontinued or continued nucleoside analogue therapy. J Viral Hepat 2017; 24 (07) 599-607
• 50 Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2018; 68 (02) 425-434
• 51 Van Hees S, Bourgeois S, Van Vlierberghe H. et al; Belgian NA Stop Study Group. Stopping nucleos(t)ide analogue treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates and fatal outcomes. Aliment Pharmacol Ther 2018; 47 (08) 1170-1180
• 52 Kuo MT, Hu TH, Hung CH. et al. Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir. Aliment Pharmacol Ther 2019; 49 (02) 218-228
• 53 Jeng WJ, Sheen IS, Chen YC, Hsu CW, Chien RN, Liaw YF. Entecavir retreatment for HBeAg negative patients with clinical relapse after stopping entecavir therapy. Hepatol Int 2013; 7: S1-S754
• 54 Marcellin P, Wong DK, Sievert W. et al. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int 2019; 39 (10) 1868-1875
• 55 Shin JW, Jung SW, Lee SB. et al. Medication nonadherence increases hepatocellular carcinoma, cirrhotic complications, and mortality in chronic hepatitis B patients treated with entecavir. Am J Gastroenterol 2018; 113 (07) 998-1008
• 56 Lee J, Cho S, Kim HJ. et al. High level of medication adherence is required to lower mortality in patients with chronic hepatitis B taking entecavir: a nationwide cohort study. J Viral Hepat 2021; 28 (02) 353-363
• 57 Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut 2002; 51 (04) 597-599
• 58 Kim GA, Lim YS, An J. et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut 2014; 63 (08) 1325-1332
• 59 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 (03) 629-636.e1
• 60 Chi H, Hansen BE, Yim C. et al. Reduced risk of relapse after long-term nucleos(t)ide analogue consolidation therapy for chronic hepatitis B. Aliment Pharmacol Ther 2015; 41 (09) 867-876
• 61 Lok AS, Zoulim F, Dusheiko G. et al. Durability of hepatitis B surface antigen loss with nucleotide analogue and peginterferon therapy in patients with chronic hepatitis B. Hepatol Commun 2019; 4 (01) 8-20
• 62 Arase Y, Ikeda K, Suzuki F. et al. Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B. Am J Med 2006; 119 (01) 71.e9-71.e16
• 63 Choi J, Yoo S, Lim YS. Comparison of long-term clinical outcomes between spontaneous and therapy-induced HBsAg seroclearance. Hepatology 2020;
• 64 Chang ML, Liaw YF, Hadziyannis SJ. et al. Systemic review: cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Aliment Pharmacol THer 2015; 42 (03) 243-257
• 65 Chang ML, Jeng WJ, Liaw YF. Clinical events after cessation of lamivudine therapy in patients recovered from hepatitis B flare with hepatic decompensation. Clin Gastroenterol Hepatol 2015; 13 (05) 979-986
• 66 Liu YC, Jeng WJ, Liaw YF. EARLIER and more severe off-tenofovir hepatitis flares than off-entecavir flares in hepatitis B e antigen-negative patients. Hepatology 2020; 72: 481A-481A
• 67 Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management. J Hepatol 2014; 61 (06) 1407-1417
• 68 Höner Zu Siederdissen C, Rinker F, Maasoumy B. et al. Viral and host responses after stopping long-term nucleos(t)ide analogue therapy in HBeag-negative chronic hepatitis B. J Infect Dis 2016; 214 (10) 1492-1497
• 69 Liaw YF. Hepatitis B flare after cessation of nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B: to retreat or not to retreat. Hepatology 2021; Feb 73 (02) 843-852
• 70 Peng CW, Jeng WJ, Chien RN. et al. Clinical relapse pattern in HBeag negative chronic hepatitis B can be changed by switching to another nucleos(t)ide analogues before cessation. Hepatology 2020; 72: 478A-479A
• 71 Chen YC, Chu CM, Yeh CT, Liaw YF. Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study. Hepatol Int 2007; 1 (01) 267-273
• 72 Ahn J, Lee HM, Lim JK. et al. Entecavir safety and effectiveness in a national cohort of treatment-naïve chronic hepatitis B patients in the US - the ENUMERATE study. Aliment Pharmacol Ther 2016; 43 (01) 134-144
• 73 Chen CH, Chen CY, Wang JH. et al. Comparison of incidence of hepatocellular carcinoma between chronic hepatitis B patients with cirrhosis treated with entecavir or tenofovir in Taiwan - a retrospective study. Am J Cancer Res 2020; 10 (11) 3882-3895
• 74 Yip TC, Chan HL, Tse YK. et al. On-treatment improvement of MELD score reduces death and hepatic events in patients with hepatitis B-related cirrhosis. Am J Gastroenterol 2018; 113 (11) 1629-1638
• 75 Sohn HR, Min BY, Song JC. et al. Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs. BMC Infect Dis 2014; 14: 439