Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B
Edward J. Gane
New Zealand Liver Unit, Auckland City Hospital, Auckland, New Zealand
Search for more papers by this authorYuming Wang
Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
Search for more papers by this authorYun-Fan Liaw
Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
Search for more papers by this authorJinLin Hou
Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
Search for more papers by this authorSatawat Thongsawat
Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorMoBin Wan
Department of Infectious Diseases, Shanghai Changhai Hospital, Shanghai, China
Search for more papers by this authorYoung M. Moon
Department of Internal Medicine, Kwan Dong University College of Medicine, Goyang, Korea
Search for more papers by this authorJiDong Jia
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorYou C. Chao
Division of Gastroenterology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
Search for more papers by this authorJunqi Niu
Department of Liver Diseases, First Hospital, University of Jilin, Changchun, China
Search for more papers by this authorNancy Leung
Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China
Search for more papers by this authorDidier Samuel
AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
Search for more papers by this authorChao Wei Hsu
Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
Search for more papers by this authorEdward J. Gane
New Zealand Liver Unit, Auckland City Hospital, Auckland, New Zealand
Search for more papers by this authorYuming Wang
Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
Search for more papers by this authorYun-Fan Liaw
Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
Search for more papers by this authorJinLin Hou
Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
Search for more papers by this authorSatawat Thongsawat
Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorMoBin Wan
Department of Infectious Diseases, Shanghai Changhai Hospital, Shanghai, China
Search for more papers by this authorYoung M. Moon
Department of Internal Medicine, Kwan Dong University College of Medicine, Goyang, Korea
Search for more papers by this authorJiDong Jia
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Search for more papers by this authorYou C. Chao
Division of Gastroenterology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
Search for more papers by this authorJunqi Niu
Department of Liver Diseases, First Hospital, University of Jilin, Changchun, China
Search for more papers by this authorNancy Leung
Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China
Search for more papers by this authorDidier Samuel
AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
Search for more papers by this authorChao Wei Hsu
Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
Search for more papers by this authorAbstract
Background: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB).
Aims: To investigate the long-term efficacy and safety of telbivudine in the telbivudine-treated cohort from the GLOBE trial.
Methods: Virological and biochemical responses were assessed in 213 HBeAg-positive and 186 HBeAg-negative CHB patients who continued telbivudine treatment for 3 years.
Results: Undetectable hepatitis B virus DNA and HBeAg seroconversions were achieved by 77 and 37% of HBeAg-positive patients respectively. Cumulative HBeAg seroconversion rate was 46%. HBeAg seroconversion was sustained at 52 weeks off therapy in 84% of the patients enrolled in the off-treatment follow-up arm of the study. Undetectable viraemia and normal alanine aminotransferase (ALT) levels at 3 years were achieved by 85 and 83% of HBeAg-negative patients respectively. Genotypic resistance rates for the study population who continued therapy during the third year were 11.3 in HBeAg-positive and 6.5% in HBeAg-negative patients. Patients with undetectable viraemia at treatment week 24 had optimal outcomes at 3 years. In the HBeAg-positive population, cumulative HBeAg seroconversion occurred in 58%. Resistance rates for HBeAg-positive and HBeAg-negative patients were 3.6 and 6.2% respectively. The telbivudine safety profile during prolonged therapy was similar to that in the GLOBE trial.
Conclusions: Three years of telbivudine treatment yielded high rates of viral suppression and ALT normalization with a favourable safety profile. High rates of HBeAg seroconversion were achieved with prolonged telbivudine therapy and were sustained in the majority of patients over 52 weeks off therapy.
References
- 1 Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007; 357: 2576–88.
- 2 Lee HW, Kim HJ, Kim MH. Entecavir induced HBV DNA suppression at 12 weeks in treatment-naive patients with chronic hepatitis B is a good predictive factor for virological response at 48 weeks (abstract no. 969). Hepatology 2008; 48 (Suppl. 1): 741A.
- 3 Locarnini S, Qi X, Arterburn S, et al. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB) (abstract no. 36). J Hepatol 2005; 42 (Suppl. 2): 17.
- 4 Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology 2003; 37: 1309–19.
- 5 van der Eijk AA, Hansen BE, Niesters HG, et al. Viral dynamics during tenofovir therapy in patients infected with lamivudine-resistant hepatitis B virus mutants. J Viral Hepat 2005; 12: 364–72.
- 6 van der Eijk AA, Niesters HG, Hansen BE, et al. Quantitative HBV DNA levels as an early predictor of nonresponse in chronic HBe-antigen positive hepatitis B patients treated with interferon-alpha. J Viral Hepat 2006; 13: 96–103.
- 7 Yuen MF, Sablon E, Hui CK, et al. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 2001; 34: 785–91.
- 8 Yurdaydin C, Sollano J, Hadziyannis S, et al. Entecavir results in continued virologic and biochemical improvement and HBeAg seroconversion through 96 weeks of treatment in lamivudine-refractory, HBeAg(+)chronic hepatitis B patients (ETV-026) (abstract no. 80). J Hepatol 2006; 44 (Suppl. 2): S36.
- 9 European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2009; 50: 227–42.
- 10 Liaw Y-F, Leung N, Kao J-H, et al. For the Chronic Hepatitis B Guideline Working Party of the Asian-Pacific Association for the Study of the Liver Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008; 2: 263–83.
- 11 Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50: 661–2.
- 12 Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009; 136: 486–95.
- 13 Zeuzem S, Gane E, Liaw YF, et al. Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B. J Hepatol 2009; 51: 11–20.
- 14 Locarnini S, Hatzakis A, Heathcote J, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther 2004; 9: 679–93.
- 15 National Institute of Allergy and Infectious Diseases. Division of AIDS Table for Grading Severity of Adult Adverse Experiences. Bethesda, MD: National Institute of Allergy and Infectious Diseases, 1992.
- 16 Keeffe EB, Zeuzem S, Koff RS, et al. Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol 2007; 5: 890–7.
- 17 Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006; 130: 678–86.
- 18 Liaw Y-F. HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B. Hepatol Int 2009; 3: 425–33.
- 19 Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521–31.
- 20 Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007; 133: 1437–44.
- 21 Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006; 131: 1743–51.
- 22 Heathcote E, Gane EJ, deMan RA. Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-positive patients with chronic hepatitis B (study 103) (abstract no. 158). Hepatology 2008; 48 (Suppl. 1): 376A.
- 23 Lau DT, Khokhar MF, Doo E, et al. Long-term therapy of chronic hepatitis B with lamivudine. Hepatology 2000; 32: 828–34.
- 24 Dienstag JL, Cianciara J, Karayalcin S, et al. Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology 2003; 37: 748–55.
- 25 Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005; 352: 2673–81.
- 26 Marcelin P, Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-negative patients with chronic hepatitis B (study 102), preliminary analysis (abstract no. 146). Hepatology 2008; 48 (Suppl. 4): 370A.
- 27 Shouval D, Lai CL, Chang TT, et al. Relapse of hepatitis B in HBeAg-negative chronic hepatitis B patients who discontinued successful entecavir treatment: the case for continuous antiviral therapy. J Hepatol 2009; 50: 289–95.
- 28 Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med 2004; 116: 829–34.
- 29 Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002; 35: 1522–27.
- 30 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: 45–52.
- 31 Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996; 334: 1422–7.
- 32 Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002; 347: 168–74.
- 33 Piratvisuth T, Lau G, Chao Y. Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Hepatol Int 2008; 2: 102–10.
- 34 Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006; 354: 1001–10.
- 35 Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008; 48: 750–8.
- 36 Leung N, Peng CY, Sollano J, et al. Entecavir (ETV) results in higher HBV DNA reduction versus Adefovir (ADV) in antivial-naive HBeAg(+) adults with high HBV DNA: week 96 results (E.A.R.L.Y. study). J Hepatol 2008; 48 (Suppl. 4): S373–4.
- 37 Yao G-B, Xu DZ, Ren H. Three years of continuous treatment with entecavir results in high proportions of Chinese nucleoside-naive patients with undetectable HBV DNA results from studies ETV-023 and -050. J Hepatol 2008; 48 (Suppl. 4): S266–7.
- 38 Yao G, Chen C-W, Lu W-L, et al. Virologic, serologic, and biochemical outcomes through 2 years of treatment with entecavir and lamivudine in nucleoside-naïve Chinese patients with chronic hepatitis B: a randomized, multicenter study. Hepatol Int 2008; 2: 486–93.
- 39 Evans A, Riva A, Cooksley H, et al. Programmed death 1 expression during antiviral treatment of chronic hepatitis B: impact of hepatitis B e-antigen seroconversion. Hepatology 2008; 48: 759–69.
- 40 Wu Z, Yan W, Guo W, et al. Telbivudine preserves Th1 cytokine and inhibits Th2 cytokine production in MHV-3 induced viral hepatitis model (poster no. 945). Hepatology 2008; 48 (Suppl. 1): 731A.
- 41 Zoulim F, Perrillo R. Hepatitis B. Reflections on the current approach to antiviral therapy. J Hepatol 2008; 48 (Suppl. 4): S2–19.
- 42 Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 2009; 49: 1503–14.
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