Tenofovir for the treatment of adults with chronic HBV infection
- Anna SF Lok, MD
Anna SF Lok, MD
- Professor of Medicine
- University of Michigan Medical School
Tenofovir disoproxil fumarate and tenofovir alafenamide are nucleotide reverse transcriptase inhibitors that are approved for the treatment of HIV infection and the treatment of chronic hepatitis B virus (HBV) infection. This topic will focus on the efficacy and safety of these agents in patients infected with HBV alone. Additional information on the use of tenofovir in the management of patients with chronic HBV infection (including those coinfected with HIV and HBV) is presented elsewhere. (See "Hepatitis B virus: Overview of management" and "Treatment of chronic hepatitis B in the HIV-infected patient".)
Tenofovir is an acyclic nucleotide diester analog of adenosine monophosphate, which is administered orally as the prodrug tenofovir disoproxil fumarate (tenofovir DF) or tenofovir alafenamide (tenofovir AF). The intracellular, pharmacologically active moiety is tenofovir-diphosphate. Tenofovir DF (300 mg daily) has been used extensively for the treatment of HIV and chronic HBV infection. The newer formulation of tenofovir, tenofovir AF (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 ON VIROLOGIC OUTCOMES
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.
Tenofovir disoproxil fumarate — There is extensive experience demonstrating the virologic efficacy of tenofovir disoproxil fumarate (tenofovir DF) for the treatment of chronic HBV. Tenofovir DF is effective regardless of the patient’s HBeAg status, the presence or absence or cirrhosis, or prior use of nucleos(t)ide analogues.
Patients with HBeAg-positive chronic hepatitis B — Tenofovir DF is effective for the treatment of chronic HBV in patients who are HBeAg-positive. However, patients in the immune-tolerant phase of infection (ie, a high viral load, and a normal alanine aminotransferase [ALT]) should generally not be treated because efficacy is lower in this setting. Indications for the treatment of chronic HBV are discussed elsewhere. (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.)
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Kuo A, Dienstag JL, Chung RT. Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin Gastroenterol Hepatol 2004; 2:266.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- van Bömmel F, Berg T. Reactivation of viral replication after replacement of tenofovir by adefovir. Hepatology 2005; 42:239.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS 2008; 22:99.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 2009; 49:S185.
- EFFECT ON VIROLOGIC OUTCOMES
- Tenofovir disoproxil fumarate
- - Patients with HBeAg-positive chronic hepatitis B
- - Patients with HBeAg-negative chronic hepatitis B
- - Patients with previous exposure to other nucleos(t)ide analogues
- Lamivudine resistance
- Adefovir resistance
- - Patients with spontaneous exacerbation
- - In combination with other drugs
- Tenofovir alafenamide
- Regression of fibrosis and cirrhosis
- Reduced risk of hepatocellular carcinoma
- RISK OF RESISTANCE
- Renal insufficiency and renal tubular dysfunction
- Bone density
- SUMMARY AND RECOMMENDATIONS