Management of Antiviral Resistance in Chronic Hepatitis B

Young-Suk Lim, Young-Suk Lim

Abstract

The primary goal of therapy for chronic hepatitis B (CHB) is to prevent liver disease progression. Hepatitis B surface antigen (HBsAg) seroclearance or seroconversion is regarded as an optimal endpoint to discontinue treatment. However, HBsAg seroclearance occurs very rarely with nucleos(t)ide analog (NUC) treatment, and long-term, almost indefinite, NUC treatment is required for the majority of patients. In patients with drug-resistant hepatitis B virus (HBV), a combination of tenofovir disoproxil fumarate (TDF) and entecavir (ETV), which is currently regarded as the strongest combination therapy against HBV, would be potentially safe to prevent the emergence of additional HBV resistance mutations. However, long-term tolerance data are lacking, and cost may be an issue for combination therapies. Several recent, well-designed, randomized controlled trials have shown that TDF monotherapy provides similar antiviral efficacy compared with the combination of TDF and ETV. Furthermore, no additional HBV resistance mutations emerged during TDF monotherapy for up to 96 weeks. Considering a comparable antiviral efficacy, extremely low risk of TDF-resistance, lower cost, and better safety potential, TDF monotherapy would be a reasonable choice for the treatment of drug-resistant patients with CHB.

Keywords: Adefovir; Entecavir; Lamivudine; Monotherapy; Tenofovir.

Conflict of interest statement

CONFLICTS OF INTEREST

Y.S.L. is an advisory board member of Bayer Healthcare, Bristol-Myers Squibb, and Gilead Sciences, and receives research funding from Bayer Healthcare, Bristol-Myers Squibb, Gilead Sciences, and Novartis.

Figures

Fig. 1
Fig. 1
Cumulative incidence of hepatitis B virus resistance in pivotal trials. Adapted from EASL clinical practice guidelines. J Hepatol 2012;57:167–185.
Fig. 2
Fig. 2
Evolution of drug-resistant hepatitis B virus. Adapted from Bartholomeusz A, et al. Semin Liver Dis 2006;26:162–170.; Fournier C, et al. Clin Liver Dis 2007;11:869–892. LAM, lamivudine; LdT, telbivudine; CLV, clevudine; ETV, entecavir; ADV, adefovir dipivoxil; W, wild type HBV strain; R, resistant HBV strain.
Fig. 3
Fig. 3
Virologic response (hepatitis B virus [HBV] DNA et al. Gastroenterology 2014;146:980–988.e1, with permission from El-sevier. FTC, emtricitabine.
Fig. 4
Fig. 4
Virologic response (hepatitis B virus [HBV] DNA et al. Gut 2016;65:852–860.
Fig. 5
Fig. 5
Virologic response (hepatitis B virus [HBV] DNA et al. Gut 2016;65:1042–1051.

References

    1. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73. doi: 10.1001/jama.295.1.65.
    1. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–686. doi: 10.1053/j.gastro.2005.11.016.
    1. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531. doi: 10.1056/NEJMoa033364.
    1. Gordon SC, Lamerato LE, Rupp LB, et al. Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population. Clin Gastroenterol Hepatol. 2014;12:885–893. doi: 10.1016/j.cgh.2013.09.062.
    1. Eun JR, Lee HJ, Kim TN, Lee KS. Risk assessment for the development of hepatocellular carcinoma: according to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease. J Hepatol. 2010;53:118–125. doi: 10.1016/j.jhep.2010.02.026.
    1. Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology. 2005;42:121–129. doi: 10.1002/hep.20760.
    1. Yuen MF, Seto WK, Chow DH, et al. Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease. Antivir Ther. 2007;12:1295–1303.
    1. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98–107. doi: 10.1002/hep.26180.
    1. Wong GL, Chan HL, Mak CW, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;58:1537–1547. doi: 10.1002/hep.26301.
    1. Lim YS, Han S, Heo NY, Shim JH, Lee HC, Suh DJ. Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine. Gastroenterology. 2014;147:152–161. doi: 10.1053/j.gastro.2014.02.033.
    1. Wu CY, Lin JT, Ho HJ, et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology. 2014;147:143–151.e5. doi: 10.1053/j.gastro.2014.03.048.
    1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227–242. doi: 10.1016/j.jhep.2008.10.001.
    1. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315–1341. doi: 10.1016/j.cgh.2008.08.021.
    1. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–662. doi: 10.1002/hep.23190.
    1. Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51:422–430. doi: 10.1002/hep.23327.
    1. 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;59:434–442. doi: 10.1002/hep.26686.
    1. Zoulim F, Locarnini S. Management of treatment failure in chronic hepatitis B. J Hepatol. 2012;56(Suppl 1):S112–S122. doi: 10.1016/S0168-8278(12)60012-9.
    1. Yim HJ, Hussain M, Liu Y, Wong SN, Fung SK, Lok AS. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology. 2006;44:703–712. doi: 10.1002/hep.21290.
    1. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol. 2006;44:283–290. doi: 10.1016/j.jhep.2005.10.018.
    1. Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385–1391. doi: 10.1002/hep.21189.
    1. Yeon JE, Yoo W, Hong SP, et al. Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil. Gut. 2006;55:1488–1495. doi: 10.1136/gut.2005.077099.
    1. Tenney DJ, Rose RE, Baldick CJ, et al. Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007;51:902–911. doi: 10.1128/AAC.00833-06.
    1. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–1514. doi: 10.1002/hep.22841.
    1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–185. doi: 10.1016/j.jhep.2012.02.010.
    1. Korean Association for the Study of the Liver. KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol. 2012;18:109–162. doi: 10.3350/cmh.2012.18.2.109.
    1. 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;6:531–561. doi: 10.1007/s12072-012-9365-4.
    1. 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;139:1207–1217. doi: 10.1053/j.gastro.2010.06.053.
    1. 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;60:715–722. doi: 10.1016/j.jhep.2013.11.024.
    1. 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;146:980–988.e1. doi: 10.1053/j.gastro.2013.12.028.
    1. Patterson SJ, George J, Strasser SI, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247–254. doi: 10.1136/gut.2010.223206.
    1. Lim YS, Byun KS, Yoo BC, 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;65:852–860. doi: 10.1136/gutjnl-2014-308353.
    1. Lim YS, Yoo BC, Byun KS, 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;65:1042–1051. doi: 10.1136/gutjnl-2014-308435.
    1. Peters MG, Hann HW, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004;126:91–101. doi: 10.1053/j.gastro.2003.10.051.
    1. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2:263–283. doi: 10.1007/s12072-008-9080-3.
    1. Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology. 2007;45:307–313. doi: 10.1002/hep.21534.
    1. Lampertico P, Viganò M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445–1451. doi: 10.1053/j.gastro.2007.08.079.
    1. 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;12:2106–2112.e1. doi: 10.1016/j.cgh.2014.05.024.
    1. Chang TT, Gish RG, Hadziyannis SJ, et al. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology. 2005;129:1198–1209. doi: 10.1053/j.gastro.2005.06.055.
    1. Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130:2039–2049. doi: 10.1053/j.gastro.2006.04.007.
    1. Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother. 2004;48:3498–3507. doi: 10.1128/AAC.48.9.3498-3507.2004.
    1. Villet S, Ollivet A, Pichoud C, et al. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol. 2007;46:531–538. doi: 10.1016/j.jhep.2006.11.016.
    1. Pan CQ, Hu KQ, Yu AS, Chen W, Bunchorntavakul C, Reddy KR. Response to tenofovir monotherapy in chronic hepatitis B patients with prior suboptimal response to entecavir. J Viral Hepat. 2012;19:213–219. doi: 10.1111/j.1365-2893.2011.01533.x.
    1. Yip B, Chaung K, Wong CR, et al. Tenofovir monotherapy and tenofovir plus entecavir combination as rescue therapy for entecavir partial responders. Dig Dis Sci. 2012;57:3011–3016. doi: 10.1007/s10620-012-2402-2.
    1. Leemans WF, Niesters HG, van der Eijk AA, Janssen HL, Schalm SW, de Man RA. Selection of an entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: successful rescue therapy with tenofovir. Eur J Gastroenterol Hepatol. 2008;20:773–777. doi: 10.1097/MEG.0b013e3282f793d6.
    1. Zoulim F, Jablkowski MS, Diculescu M, et al. The safety and efficacy of entecavir and tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure: week 96 results of the ENTEBE study. Hepatology. 2014;60(Suppl 4):314A–315A.
    1. Villet S, Pichoud C, Villeneuve JP, Trépo C, Zoulim F. Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient. Gastroenterology. 2006;131:1253–1261. doi: 10.1053/j.gastro.2006.08.013.
    1. 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;39:1085–1089. doi: 10.1016/j.jhep.2003.09.022.
    1. 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;125:292–297. doi: 10.1016/S0016-5085(03)00939-9.
    1. Heo NY, Lim YS, Lee HC, Chung YH, Lee YS, Suh DJ. Lamivudine plus adefovir or entecavir for patients with chronic hepatitis B resistant to lamivudine and adefovir. J Hepatol. 2010;53:449–454. doi: 10.1016/j.jhep.2010.03.020.
    1. Shim JH, Suh DJ, Kim KM, et al. Efficacy of entecavir in patients with chronic hepatitis B resistant to both lamivudine and adefovir or to lamivudine alone. Hepatology. 2009;50:1064–1071. doi: 10.1002/hep.23145.
    1. Brunelle MN, Jacquard AC, Pichoud C, et al. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology. 2005;41:1391–1398. doi: 10.1002/hep.20723.
    1. Villet S, Pichoud C, Billioud G, et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol. 2008;48:747–755. doi: 10.1016/j.jhep.2008.01.027.
    1. Qi X, Xiong S, Yang H, Miller M, Delaney WE., 4th In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther. 2007;12:355–362.
    1. 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;51:73–80. doi: 10.1002/hep.23246.
    1. Petersen J, Ratziu V, Buti M, et al. Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: an international multicenter cohort study. J Hepatol. 2012;56:520–526. doi: 10.1016/j.jhep.2011.09.018.
    1. 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;63:1325–1332. doi: 10.1136/gutjnl-2013-305517.
    1. 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;58:676–683. doi: 10.1016/j.jhep.2012.11.039.
    1. Pawlotsky JM. Is hepatitis virus resistance to antiviral drugs a threat? Gastroenterology. 2012;142:1369–1372. doi: 10.1053/j.gastro.2011.12.060.
    1. Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261–283. doi: 10.1002/hep.28156.
    1. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organization; 2015.
    1. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1–98. doi: 10.1007/s12072-015-9675-4.
    1. Korean Association for the Study of Liver. KASL clinical practice guidelines: management of chronic hepatitis B. Seoul: Korean Association for the Study of Liver; 2015.
    1. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442–2455. doi: 10.1056/NEJMoa0802878.
    1. Bartholomeusz A, Locarnini SA. Antiviral drug resistance: clinical consequences and molecular aspects. Semin Liver Dis. 2006;26:162–170. doi: 10.1055/s-2006-939758.
    1. Fournier C, Zoulim F. Antiviral therapy of chronic hepatitis B: prevention of drug resistance. Clin Liver Dis. 2007;11:869–892. ix. doi: 10.1016/j.cld.2007.08.013.

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