UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Tenofovir and adefovir for the treatment of chronic HBV infection

Author
Anna SF Lok, MD
Section Editor
Rafael Esteban, MD
Deputy Editor
Jennifer Mitty, MD, MPH

INTRODUCTION

Tenofovir disoproxil fumarate, tenofovir alafenamide, and adefovir are nucleotide reverse transcriptase inhibitors (NRTIs) that are used for the treatment of chronic hepatitis B virus (HBV) infection. However, tenofovir has generally replaced adefovir because it is more potent.

This topic will focus on the efficacy and safety of NRTIs for the treatment of patients infected with HBV alone. Topic reviews that provide additional information on the treatment of HBV, as well as the use of tenofovir for the treatment of HIV, are presented elsewhere. (See "Hepatitis B virus: Overview of management" and "Overview of hepatitis B virus infection in children and adolescents" and "Treatment of chronic hepatitis B in the HIV-infected patient" and "Overview of antiretroviral agents used to treat HIV" and "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)

TENOFOVIR

Formulations — Tenofovir is an acyclic nucleotide diester analog of adenosine monophosphate, which is administered orally as the prodrug tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). The intracellular, pharmacologically active moiety is tenofovir-diphosphate. TDF (300 mg daily) has been used extensively for the treatment of HIV and chronic hepatitis B virus (HBV) infection. The newer formulation of tenofovir, TAF (25 mg daily), is also effective for the treatment of HIV and HBV and has fewer adverse effects on renal function and bone density [1,2]. (See 'Safety' below.)

Effect of tenofovir disoproxil fumarate on virologic outcomes — There is extensive experience demonstrating the virologic efficacy of tenofovir disoproxil fumarate (TDF) for the treatment of chronic HBV. TDF is effective regardless of the patient's HBeAg status, the presence or absence or cirrhosis, or prior use of nucleos(t)ide analogues.

A positive response to treatment is characterized by suppression of HBV DNA and loss of hepatitis B e antigen (HBeAg) (in patients who were initially HBeAg positive). This is followed by loss of hepatitis B surface antigen (HBsAg) in some patients during the course of follow-up.

                        
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: Dec 13, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
References
Top
  1. Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1:185.
  2. Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1:196.
  3. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008; 359:2442.
  4. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011; 140:132.
  5. 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; 381:468.
  6. Buti M, Tsai N, Petersen J, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci 2015; 60:1457.
  7. Chan HL, Chan CK, Hui AJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology 2014; 146:1240.
  8. Kuo A, Dienstag JL, Chung RT. Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin Gastroenterol Hepatol 2004; 2:266.
  9. Manns M, Jeffers L, Dalekos T, et al. The antiviral response to tenofovir disoproxil fumarate (TDF) is comparable in lamivudine (LAM)-naive and LAM-experienced subjects treatment for chronic hepatitis B (CHB) (abstract). J Hepatol 2008; (Suppl):S32.
  10. van Bömmel F, de Man RA, Wedemeyer H, et al. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology 2010; 51:73.
  11. Fung S, Kwan P, Fabri M, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2014; 146:980.
  12. van Bommel F, Mauss S, Schurmann D, et al. No evidence for tenofovir resistance in patients with lamivudine-resistant HBV infection during long-term treatment for up to 5 years (abstract). Hepatology 2006; 44(Suppl 1):549A.
  13. Wang HL, Lu X, Yang X, Ning Q. Efficacy of tenofovir-based rescue therapy in patients with lamivudine-resistant hepatitis B virus: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2016; 40:447.
  14. Fung S, Kwan P, Fabri M, et al. Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study. J Hepatol 2017; 66:11.
  15. van Bömmel F, Zöllner B, Sarrazin C, et al. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 2006; 44:318.
  16. van Bömmel F, Wünsche T, Mauss S, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 2004; 40:1421.
  17. van Bömmel F, Berg T. Reactivation of viral replication after replacement of tenofovir by adefovir. Hepatology 2005; 42:239.
  18. Schildgen O, Hartmann H, Gerlich WH. Replacement of tenofovir with adefovir may result in reactivation of hepatitis B virus replication. Scand J Gastroenterol 2006; 41:245.
  19. Berg T, Marcellin P, Zoulim F, et al. Tenofovir is effective alone or with emtricitabine in adefovir-treated patients with chronic-hepatitis B virus infection. Gastroenterology 2010; 139:1207.
  20. Berg T, Zoulim F, Moeller B, et al. Long-term efficacy and safety of emtricitabine plus tenofovir DF vs. tenofovir DF monotherapy in adefovir-experienced chronic hepatitis B patients. J Hepatol 2014; 60:715.
  21. Tan J, Degertekin B, Wong SN, et al. Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations. J Hepatol 2008; 48:391.
  22. van Bömmel F, Trojan J, Deterding K, et al. Evolution of adefovir-resistant HBV polymerase gene variants after switching to tenofovir disoproxil fumarate monotherapy. Antivir Ther 2012; 17:1049.
  23. Garg H, Sarin SK, Kumar M, et al. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology 2011; 53:774.
  24. Buti M, Fung S, Gane E, et al. Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years. Hepatol Int 2015; 9:243.
  25. Varbobitis I, Papatheodoridis GV. The assessment of hepatocellular carcinoma risk in patients with chronic hepatitis B under antiviral therapy. Clin Mol Hepatol 2016; 22:319.
  26. Kim WR, Loomba R, Berg T, et al. Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B. Cancer 2015; 121:3631.
  27. Kitrinos KM, Corsa A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology 2014; 59:434.
  28. Corsa AC, Liu Y, Flaherty JF, et al. No resistance to tenofovir disoproxil fumarate through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B. Clin Gastroenterol Hepatol 2014; 12:2106.
  29. Liu Y, Corsa AC, Buti M, et al. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment. J Viral Hepat 2017; 24:68.
  30. Shirvani-Dastgerdi E, Winer BY, Celià-Terrassa T, et al. Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy. J Hepatol 2017; 67:246.
  31. Sheldon J, Camino N, Rodés B, et al. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther 2005; 10:727.
  32. Delaney WE 4th, Ray AS, Yang H, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother 2006; 50:2471.
  33. Tourret J, Deray G, Isnard-Bagnis C. Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? J Am Soc Nephrol 2013; 24:1519.
  34. Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS 2008; 22:99.
  35. Verhelst D, Monge M, Meynard JL, et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis 2002; 40:1331.
  36. Gara N, Zhao X, Collins MT, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther 2012; 35:1317.
  37. Pipili C, Cholongitas E, Papatheodoridis G. Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. Aliment Pharmacol Ther 2014; 39:35.
  38. Lampertico P, Chan HL, Janssen HL, et al. Review article: long-term safety of nucleoside and nucleotide analogues in HBV-monoinfected patients. Aliment Pharmacol Ther 2016; 44:16.
  39. Wong GL, Tse YK, Wong VW, et al. Long-term safety of oral nucleos(t)ide analogs for patients with chronic hepatitis B: A cohort study of 53,500 subjects. Hepatology 2015; 62:684.
  40. Lok AS, McMahon BJ, Brown RS Jr, et al. Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta-analysis. Hepatology 2016; 63:284.
  41. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 2009; 49:S185.
  42. Gilson RJ, Chopra KB, Newell AM, et al. A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection. J Viral Hepat 1999; 6:387.
  43. Tsiang M, Rooney JF, Toole JJ, Gibbs CS. Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy. Hepatology 1999; 29:1863.
  44. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003; 348:808.
  45. Zeng M, Mao Y, Yao G, et al. A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology 2006; 44:108.
  46. 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.
  47. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003; 348:800.
  48. 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.
  49. Hadziyannis SJ, Sevastianos V, Rapti I, et al. 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.
  50. Xiong X, Flores C, Yang H, et al. Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro. Hepatology 1998; 28:1669.
  51. Perrillo R, Schiff E, Yoshida E, et al. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000; 32:129.
  52. Benhamou Y, Bochet M, Thibault V, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001; 358:718.
  53. Peters MG, Hann Hw Hw, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004; 126:91.
  54. Perrillo R, Hann HW, Mutimer D, et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004; 126:81.
  55. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006; 44:283.
  56. Ha NB, Ha NB, Garcia RT, et al. Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil. Hepatology 2009; 50:727.
  57. Angus P, Vaughan R, Xiong S, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 2003; 125:292.
  58. Villeneuve JP, Durantel D, Durantel S, et al. Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol 2003; 39:1085.
  59. Lacombe K, Ollivet A, Gozlan J, et al. A novel hepatitis B virus mutation with resistance to adefovir but not to tenofovir in an HIV-hepatitis B virus-co-infected patient. AIDS 2006; 20:2229.
  60. Borroto-Esoda K, Miller MD, Arterburn S. Pooled analysis of amino acid changes in the HBV polymerase in patients from four major adefovir dipivoxil clinical trials. J Hepatol 2007; 47:492.
  61. Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology 2008; 48:88.
  62. Locarnini S, Qi X, Arterburn S, et al. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil therapy for patients with chronic hepatitis B (abstract). J Hepatol 2005; 42 (Suppl 2):17A.