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Current Hepatology Reports
Published in: Current Hepatology Reports 3/2019

01-09-2019 | Hepatitis B | Hepatitis B (JK Lim, Section Editor)

Management of Virologic Failure in Patients with Chronic Hepatitis B Treated with Nucleos(t)ide Analogues

Authors: Zaid H. Tafesh, Robert S. Brown Jr

Published in: Current Hepatology Reports | Issue 3/2019

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Abstract

Purpose of the Review

Poorly controlled hepatitis B increases the risk for liver-related morbidity. Although there are now six approved nucleos(t)ide analogues (NA) for the treatment of chronic hepatitis B (CHB), drug resistance and thus virologic breakthrough still exist. This review outlines a systematic approach to the management of virologic failure in patients with CHB treated with NAs.

Recent Findings

Current NAs can be divided into older generation and newer generation agents, with newer generation agents associated with lower rates of virologic breakthrough. Both tenofovir dipovoxil fumarate (TDF) and tenofovir alafenamide (TAF) are equally as effective in addressing virologic breakthrough while on all other NAs. Entecavir is an effective treatment option for NA naïve patients only, with high rates of resistance to entecavir in those exposed to older NAs.

Summary

The management of virologic breakthroughs should focus on identifying risk factors for future drug resistance and escalation to appropriate newer generation drug options to avoid long-term liver-related morbidity.
Literature
1.
2.
Wasley A, Kruszon-Moran D, Kuhnert W, Simard EP, Finelli L, McQuillan G, et al. The prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis. 2010;202(2):192–201.CrossRef
3.
Kowdley KV, Wang CC, Welch S, Roberts H, Brosgart CL. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology. 2012;56(2):422–33.CrossRef
4.
Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99.CrossRef
5.
European Association for the Study of the Liver. Electronic address, e.e.e. and L. European Association for the Study of the, EASL. Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol, 2017. 2017;67(2):370–98.
6.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261–83.CrossRef
7.
Lok AS, et al. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology. 2016;63(1):284–306.CrossRef
8.
Lee S, Ahn SH, Jung KS, Kim DY, Kim BK, Kim SU, et al. Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance. J Viral Hepat. 2017;24(2):141–7.CrossRef
9.
Papatheodoridis GV, Chan HLY, Hansen BE, Janssen HLA, Lampertico P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol. 2015;62(4):956–67.CrossRef
10.
Su TH, Hu TH, Chen CY, Huang YH, Chuang WL, Lin CC, et al. Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. Liver Int. 2016;36(12):1755–64.CrossRef
11.
Agarwal K, Brunetto M, Seto WK, Lim YS, Fung S, Marcellin P, et al. 96weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018;68(4):672–81.CrossRef
12.
Terrault N. Is low level viremia acceptable during antiviral therapy of patients with HBV infection and decompensated cirrhosis? Clin Gastroenterol Hepatol. 2018;16(12):1876–8.CrossRef
13.
Sheppard-Law S, Zablotska-Manos I, Kermeen M, Holdaway S, Lee A, Zekry A, et al. Factors associated with HBV virological breakthrough. Antivir Ther. 2017;22(1):53–60.CrossRef
14.
Shin JW, Jung SW, Lee SB, Lee BU, Park BR, Park EJ, et al. Medication nonadherence increases hepatocellular carcinoma, cirrhotic complications, and mortality in chronic hepatitis B patients treated with entecavir. Am J Gastroenterol. 2018;113(7):998–1008.CrossRef
15.
Salpini R, Alteri C, Cento V, Pollicita M, Micheli V, Gubertini G, et al. Snapshot on drug-resistance rate and profiles in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice. J Med Virol. 2013;85(6):996–1004.CrossRef
16.
Kim JH, et al. Molecular diagnosis and treatment of drug-resistant hepatitis B virus. World J Gastroenterol. 2014;20(19):5708–20.CrossRef
17.
Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology. 2009;137(5):1593–608 e1–2.CrossRef
18.
Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, 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(4):980–8.CrossRef
19.
Lok AS, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125(6):1714–22.CrossRef
20.
Papatheodoridis GV, Dimou E, Laras A, Papadimitropoulos V, Hadziyannis SJ. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease. Hepatology. 2002;36(1):219–26.CrossRef
21.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, 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(5):1503–14.CrossRef
22.
Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, Jeon WK, et al. Rescue therapy for lamivudine-resistant chronic hepatitis B: comparison between entecavir 1.0 mg monotherapy, adefovir monotherapy and adefovir add-on lamivudine combination therapy. J Gastroenterol Hepatol. 2010;25(8):1374–80.CrossRef
23.
Huang ZB, Zhao SS, Huang Y, Dai XH, Zhou RR, Yi PP, et al. Comparison of the efficacy of lamivudine plus adefovir versus entecavir in the treatment of lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Clin Ther. 2013;35(12):1997–2006.CrossRef
24.
Chung GE, Kim W, Lee KL, Hwang SY, Lee JH, Kim HY, et al. Add-on adefovir is superior to a switch to entecavir as rescue therapy for lamivudine-resistant chronic hepatitis B. Dig Dis Sci. 2011;56(7):2130–6.CrossRef
25.
Seto WK, Liu K, Fung J, Wong DKH, Yuen JCH, Hung IFN, et al. Outcome of lamivudine-resistant chronic hepatitis B after up to 5 years of combination therapy with adefovir. Antivir Ther. 2012;17(7):1255–62.CrossRef
26.
Park JH, Jung SW, Park NH, Park BR, Kim MH, Kim CJ, et al. Efficacy of tenofovir-based rescue therapy in lamivudine-resistant chronic hepatitis B patients with failure of lamivudine and adefovir combination. Clin Ther. 2015;37(7):1433–42.CrossRef
27.
Fung S, Kwan P, Fabri M, Horban A, Pelemis M, Hann HW, et al. Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: a 5-year randomised study. J Hepatol. 2017;66(1):11–8.CrossRef
28.
Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang T–T, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131(6):1743–51.CrossRef
29.
Marcellin P, Chang TT, Lim SGL, Sievert W, Tong M, Arterburn S, 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(3):750–8.CrossRef
30.
Lee YS, Suh DJ, Lim YS, Jung SW, Kim KM, Lee HC, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43(6):1385–91.CrossRef
31.
Park JW, Kim HS, Seo DD, Jang JS, Shin WG, Kim KH, et al. Long-term efficacy of entecavir in adefovir-refractory chronic hepatitis B patients with prior lamivudine resistance. J Viral Hepat. 2011;18(10):e475–81.CrossRef
32.
Shim JH, Suh DJ, Kim KM, Lim YS, Lee HC, Chung YH, et al. Efficacy of entecavir in patients with chronic hepatitis B resistant to both lamivudine and adefovir or to lamivudine alone. Hepatology. 2009;50(4):1064–71.CrossRef
33.
van Bommel F, et al. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology. 2010;51(1):73–80.CrossRef
34.
Berg T, Zoulim F, Moeller B, Trinh H, Marcellin P, Chan S, 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(4):715–22.CrossRef
35.
Lim YS, Yoo BC, Byun KS, Kwon SY, Kim YJ, An J, et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. Gut. 2016;65(6):1042–51.CrossRef
36.
Lee YB, Lee JH, Lee DH, Cho H, Ahn H, Choi WM, et al. Efficacy of entecavir-tenofovir combination therapy for chronic hepatitis B patients with multidrug-resistant strains. Antimicrob Agents Chemother. 2014;58(11):6710–6.CrossRef
37.
Petersen J, Ratziu V, Buti M, Janssen HLA, Brown A, Lampertico P, et al. Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: an international multicenter cohort study. J Hepatol. 2012;56(3):520–6.CrossRef
38.
Lim YS, Byun KS, Yoo BC, Kwon SY, Kim YJ, An J, et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut. 2016;65(5):852–60.CrossRef
39.
Liu Y, Miller MD, Kitrinos KM. Tenofovir alafenamide demonstrates broad cross-genotype activity against wild-type HBV clinical isolates and maintains susceptibility to drug-resistant HBV isolates in vitro. Antivir Res. 2017;139:25–31.CrossRef
40.
Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, 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(3):185–95.CrossRef
41.
Koklu S, et al. Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis. Clin Gastroenterol Hepatol. 2013;11(1):88–94.CrossRef
42.
Cho WH, Lee HJ, Bang KB, Kim SB, Song IH. Development of tenofovir disoproxil fumarate resistance after complete viral suppression in a patient with treatment-naive chronic hepatitis B: a case report and review of the literature. World J Gastroenterol. 2018;24(17):1919–24.CrossRef
43.
Park ES, Lee AR, Kim DH, Lee JH, Yoo JJ, Ahn SH, et al. Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients. J Hepatol. 2019;70(6):1093–102.CrossRef
44.
Kwon H, Lok AS. Hepatitis B therapy. Nat Rev Gastroenterol Hepatol. 2011;8(5):275–84.CrossRef
45.
Kim SS, Hwang JC, Lim SG, Ahn SJ, Cheong JY, Cho SW. Effect of virological response to entecavir on the development of hepatocellular carcinoma in hepatitis B viral cirrhotic patients: comparison between compensated and decompensated cirrhosis. Am J Gastroenterol. 2014;109(8):1223–33.CrossRef
46.
Kim JH, Sinn DH, Kang W, Gwak GY, Paik YH, Choi MS, et al. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment. Hepatology. 2017;66(2):335–43.CrossRef
47.
Jang JW, Choi JY, Kim YS, Yoo JJ, Woo HY, Choi SK, et al. Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis. Clin Gastroenterol Hepatol. 2018;16(12):1954–63 e3.CrossRef
Metadata
Title
Management of Virologic Failure in Patients with Chronic Hepatitis B Treated with Nucleos(t)ide Analogues
Authors
Zaid H. Tafesh
Robert S. Brown Jr
Publication date
01-09-2019
Publisher
Springer US
Published in
Current Hepatology Reports / Issue 3/2019
Electronic ISSN: 2195-9595
DOI
https://doi.org/10.1007/s11901-019-00483-z

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