Navigating the Maze of Hepatitis B Treatments

Abstract

The ultimate goal of hepatitis B treatment is to prevent cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC). Because clinical outcomes arise only after decades of infection, surrogate end points are used to determine the success of hepatitis B treatment. Standardized definitions of treatment response were discussed in detail at the 2006 National Institutes of Health Workshop on “Management of Hepatitis B.”1Hoofnagle J.H. Doo E. Liang T.J. Fleischer R. Lok A.S.F. Management of hepatitis B: summary of a Clinical Research Workshop.Hepatology. 2007; (In press)Google Scholar Currently, there are 6 approved therapies for hepatitis B virus (HBV) infection including 2 formulations of interferon, standard interferon α-2b (IFN-α-2b) and pegylated interferon α-2a (pegIFN-α-2a), and 4 nucleos(t)ide analogues, lamivudine (Epivir), adefovir (Hepsera), entecavir (Baraclude), and telbivudine (Tyzeka). Despite these advances, approved treatments for hepatitis B do not eradicate hepatitis B virus. Thus, clinical benefit is dependent on the ability to maintain sustained suppression of HBV replication. However, long-term treatment with nucleos(t)ide analogues is associated with increasing rates of drug resistance, and the safety and efficacy of these therapies beyond 1–5 years have not been established. This review aims to help the reader navigate the maze of hepatitis B treatments. New therapies and molecular mechanisms of antiviral resistance are discussed in an accompanying article by Ghany and Liang.2Ghany M. Liang T.J. Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B.Gastroenterology. 2007; 132: 1574-1585Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar The short-term goals of hepatitis B treatment are to achieve suppression of HBV replication and to induce remission of liver disease. Table 1 summarizes the rates of response to the 6 approved therapies in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients.3Wong D.K. Cheung A.M. O’Rourke K. Naylor C.D. Detsky A.S. Heathcote J. Effect of α-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B A meta-analysis.Ann Intern Med. 1993; 119 (comments): 312-323Crossref PubMed Scopus (1035) Google Scholar, 4Cooksley W.G. Piratvisuth T. Lee S.D. Mahachai V. Chao Y.C. Tanwandee T. Chutaputti A. et al.Peginterferon α-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.J Viral Hepat. 2003; 10: 298-305Crossref PubMed Scopus (454) Google Scholar, 5Lau G.K. Piratvisuth T. Luo K.X. Marcellin P. Thongsawat S. Cooksley G. Gane E. et al.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695Crossref PubMed Scopus (1353) Google Scholar, 6Marcellin P. Lau G.K. Bonino F. Farci P. Hadziyannis S. Jin R. Lu Z.M. et al.Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2004; 351: 1206-1217Crossref PubMed Scopus (1047) Google Scholar, 7Janssen H.L. van Zonneveld M. Senturk H. Zeuzem S. Akarca U.S. Cakaloglu Y. Simon C. et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129Abstract Full Text Full Text PDF PubMed Scopus (1016) Google Scholar, 8Lai C.L. Chien R.N. Leung N.W. Chang T.T. Guan R. Tai D.I. Ng K.Y. et al.Asia Hepatitis Lamivudine Study GroupA one-year trial of lamivudine for chronic hepatitis B.N Engl J Med. 1998; 339 (comments): 61-68Crossref PubMed Scopus (1782) Google Scholar, 9Dienstag J.L. Schiff E.R. Wright T.L. Perrillo R.P. Hann H.W. Goodman Z. Crowther L. et al.Lamivudine as initial treatment for chronic hepatitis B in the United States.N Engl J Med. 1999; 341: 1256-1263Crossref PubMed Scopus (1326) Google Scholar, 10Marcellin P. Chang T. Lim S.G. Tong M. Sievert W. Schiffman M. Jeffers L. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med. 2003; 348: 808-816Crossref PubMed Scopus (1276) Google Scholar, 11Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. Chang T.T. Kitis G. Rizzetto M. Marcellin P. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.N Engl J Med. 2003; 348: 800-807Crossref PubMed Scopus (942) Google Scholar, 12Lai C.L. Shouval D. Lok A.S. Chang T.T. Cheinquer H. Goodman Z. DeHertogh D. et al.Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2006; 354: 1011-1020Crossref PubMed Scopus (1047) Google Scholar, 13Chang T.T. Gish R.G. de Man R. Gadano A. Sollano J. Chao Y.C. Lok A.S. et al.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010Crossref PubMed Scopus (1236) Google Scholar, 14Schalm S.W. Heathcote J. Cianciara J. Farrell G. Sherman M. Willems B. Dhillon A. et al.Lamivudine and α interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.Gut. 2000; 46 (comments): 562-568Crossref PubMed Scopus (512) Google Scholar, 15Lai C. Gane E. Liaw Y.-F. Thongawat S. Wang Y. Heathcote E. Rasenack J. et al.Telbivudine (LDT) vs. lamivudine for chronic hepatitis B: first-year results from the International Phase III Globe Trial.Hepatology. 2005; 42: 748ACrossref PubMed Scopus (1) Google Scholar Nucleos(t)ide analogues are more effective in decreasing serum HBV DNA levels, but they are less likely to lead to loss of HBeAg or hepatitis B surface antigen (HBsAg). A higher rate of HBeAg and HBsAg loss associated with IFN therapy, despite its less potent antiviral activity, is related to its ability to down-regulate viral protein expression and to achieve immune clearance of infected hepatocytes. Response after IFN therapy is also more durable than response after nucleos(t)ide analogue therapy. Among the nucleos(t)ide analogues, entecavir and telbivudine are more potent, followed by lamivudine and then adefovir.Table 1Responses to Approved Antiviral Therapies Among Nucleoside-Naive PatientsLamivudine 100 mg qd 48–52 WkPlaceboAdefovir 10 mg qd 48 WkPlaceboEntecavir 0.5 mg qd 48 WkTelbivudine 600 mg qd 52 WkPeg-IFN-α 180 μg qw 48 WkHBeAg-positive patients Loss of serum HBV DNAaLamivudine and entecavir: no or short duration of consolidation treatment; adefovir and telbivudine: most patients had consolidation treatment.40%–44%16%21%067%60%25% Loss of HBeAg17%–32%6%–11%24%11%22%26%30% HBeAg seroconversion16%–21%4%–6%12%6%21%22%27% Loss of HBsAg<1%0002%03% Normalization of ALT41%–75%7%–24%48%16%68%77%39% Histologic improvementbPosttreatment biopsies obtained on treatment for nucleos(t)ide analogues and 24 weeks after treatment for peg-IFN.49%–56%23%–25%53%25%72%65%38% Durability of responseaLamivudine and entecavir: no or short duration of consolidation treatment; adefovir and telbivudine: most patients had consolidation treatment.50%–80%–∼90%–69%∼80%naHBeAg-negative patients Loss of serum HBV DNA60%–73%na51%090%88%63% Normalization of ALT60%–79%na72%29%78%74%38% Histologic improvement60%–66%na64%33%70%67%48%bPosttreatment biopsies obtained on treatment for nucleos(t)ide analogues and 24 weeks after treatment for peg-IFN. Durability of response<10%–∼5%–nana∼20%NOTE. Adapted from Lok AS and McMahon.53Lok A.S. McMahon B. Practice guidelines: chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2114) Google Scholarqd, 4 times daily; qw, 4 times weekly; na, not available.a Lamivudine and entecavir: no or short duration of consolidation treatment; adefovir and telbivudine: most patients had consolidation treatment.b Posttreatment biopsies obtained on treatment for nucleos(t)ide analogues and 24 weeks after treatment for peg-IFN. Open table in a new tab NOTE. Adapted from Lok AS and McMahon.53Lok A.S. McMahon B. Practice guidelines: chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2114) Google Scholar qd, 4 times daily; qw, 4 times weekly; na, not available. For HBeAg-positive patients, a 1-year course of pegIFN is associated with HBeAg seroconversion in approximately 30% of patients compared with 12%–22% after a 1-year course of nucleos(t)ide analogue therapy.5Lau G.K. Piratvisuth T. Luo K.X. Marcellin P. Thongsawat S. Cooksley G. Gane E. et al.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695Crossref PubMed Scopus (1353) Google Scholar, 7Janssen H.L. van Zonneveld M. Senturk H. Zeuzem S. Akarca U.S. Cakaloglu Y. Simon C. et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129Abstract Full Text Full Text PDF PubMed Scopus (1016) Google Scholar, 8Lai C.L. Chien R.N. Leung N.W. Chang T.T. Guan R. Tai D.I. Ng K.Y. et al.Asia Hepatitis Lamivudine Study GroupA one-year trial of lamivudine for chronic hepatitis B.N Engl J Med. 1998; 339 (comments): 61-68Crossref PubMed Scopus (1782) Google Scholar, 9Dienstag J.L. Schiff E.R. Wright T.L. Perrillo R.P. Hann H.W. Goodman Z. Crowther L. et al.Lamivudine as initial treatment for chronic hepatitis B in the United States.N Engl J Med. 1999; 341: 1256-1263Crossref PubMed Scopus (1326) Google Scholar, 10Marcellin P. Chang T. Lim S.G. Tong M. Sievert W. Schiffman M. Jeffers L. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med. 2003; 348: 808-816Crossref PubMed Scopus (1276) Google Scholar, 13Chang T.T. Gish R.G. de Man R. Gadano A. Sollano J. Chao Y.C. Lok A.S. et al.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010Crossref PubMed Scopus (1236) Google Scholar, 14Schalm S.W. Heathcote J. Cianciara J. Farrell G. Sherman M. Willems B. Dhillon A. et al.Lamivudine and α interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.Gut. 2000; 46 (comments): 562-568Crossref PubMed Scopus (512) Google Scholar, 15Lai C. Gane E. Liaw Y.-F. Thongawat S. Wang Y. Heathcote E. Rasenack J. et al.Telbivudine (LDT) vs. lamivudine for chronic hepatitis B: first-year results from the International Phase III Globe Trial.Hepatology. 2005; 42: 748ACrossref PubMed Scopus (1) Google Scholar Furthermore, 6 months after discontinuation of treatment, HBeAg seroconversion rate increases slightly in patients who received pegIFN, whereas 20%–50% of patients who received nucleos(t)ide analogues revert back to HBeAg positivity.5Lau G.K. Piratvisuth T. Luo K.X. Marcellin P. Thongsawat S. Cooksley G. Gane E. et al.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695Crossref PubMed Scopus (1353) Google Scholar, 7Janssen H.L. van Zonneveld M. Senturk H. Zeuzem S. Akarca U.S. Cakaloglu Y. Simon C. et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129Abstract Full Text Full Text PDF PubMed Scopus (1016) Google Scholar, 16Dienstag J.L. Cianciara J. Karayalcin S. Kowdley K.V. Willems B. Plisek S. Woessner M. et al.Durability of serologic response after lamivudine treatment of chronic hepatitis B.Hepatology. 2003; 37: 748-755Crossref PubMed Scopus (211) Google Scholar, 17Song B.C. Suh D.J. Lee H.C. Chung Y.H. Lee Y.S. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.Hepatology. 2000; 32: 803-806Crossref PubMed Scopus (314) Google Scholar, 18Ryu S.H. Chung Y.H. Choi M.H. Kim J.A. Shin J.W. Jang M.K. Park N.H. et al.Long-term additional lamivudine therapy enhances durability of lamivudine-induced HBeAg loss: a prospective study.J Hepatol. 2003; 39: 614-619Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar The difference in HBeAg seroconversion rate between IFN and nucleos(t)ide analogue therapy is eliminated during subsequent years because nucleos(t)ide analogues are usually administered beyond 1 year. Thus, HBeAg seroconversion rates increase to 40% and 48% after 5 years of lamivudine and adefovir, respectively, and to 39% after 3 years of entecavir.19Lok A.S. Lai C.L. Leung N. Yao G.B. Cui Z.Y. Schiff E.R. Dienstag J.L. et al.Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology. 2003; 125: 1714-1722Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 20Chang T.T. Lai C.L. Chien R.N. Guan R. Lim S.G. Lee C.M. Ng K.Y. et al.Four years of lamivudine treatment in Chinese patients with chronic hepatitis B.J Gastroenterol Hepatol. 2004; 19: 1276-1282Crossref PubMed Scopus (222) Google Scholar, 21Marcellin P. Chang T. Lim S.G. Sievert W. Tong M. Arterburn S. Borroto-Esoda K. et al.Long-term efficacy and safety of adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B (CHB) patients.Hepatology. 2006; 44 (abstr 969): 548AGoogle Scholar, 22Chang T. Chao Y.-C. Kaymakoglu S. Cheinquer H. Pessoa M. Gish R. Poordad F. et al.Entecavir maintained virologic suppression through 3 years of treatment in antiviral naive HBeAg(+) Patients (ETV 022/901).Hepatology. 2006; 44 (abstr 109): 229AGoogle Scholar However, <50% of patients who meet stringent criteria for inclusion in clinical trials achieve HBeAg seroconversion after 5 years of continued therapy. For HBeAg-negative patients, virologic response rates during treatment are high, but posttreatment relapse occurs in >90% of patients who discontinue nucleos(t)ide analogue therapy and in approximately 80% of patients who discontinue IFN after 1 year of therapy.23Hadziyannis S. Tassopoulos N. Heathcote E.J. Chang T.T. Kitis G. Rizzetto M. Marcellin P. et al.Long-term (3-year) therapy with adefovir dipivoxil for the treatment of hepatitis B e antigen negative chronic hepatitis B.N Eng J Med. 2005; 352: 2673-2681Crossref PubMed Scopus (497) Google Scholar, 24Marcellin P. Bonino F. Lau G. Farci P. Yurdaydin C. Piratvisuth T. Luo K. et al.Suppression of HBV DNA in patients with HBeAg-negative CHB treated with peginterferon alfa-2A (40 KD) ± lamivudine: 2-year follow-up results.Hepatology. 2006; 44 (abstr 972): 550ACrossref PubMed Scopus (36) Google Scholar Continued treatment with lamivudine results in a progressively lower percentage of patients with maintained virologic response because of drug resistance, and continuation of adefovir leads to a slight increase in the percentage of patients with maintained virologic response up to year 4.25Papatheodoridis G.V. Dimou E. Laras A. Papadimitropoulos V. Hadziyannis S.J. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease.Hepatology. 2002; 36: 219-226Crossref PubMed Scopus (208) Google Scholar, 26Hadziyannis S. Tassopoulos N. Heathcote E. Chang T. Kitis G. Rizzetto M. Marcellin P. et al.Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.Gastroenterology. 2006; 131: 1743-1751Abstract Full Text Full Text PDF PubMed Scopus (774) Google Scholar Combination therapy has been advocated to improve antiviral activity and/or prevent drug resistance. Three studies evaluated the combination of nucleos(t)ide analogues. One study compared combination of lamivudine and adefovir to lamivudine alone in 115 HBeAg-positive patients.27Sung J.J.Y.L.J. Zeuzem S. Chow W.C. Heathcote E. Perrillo R. Brosgart C. et al.A randomized double-blind phase II study of lamivudine compared to lamivudine plus adefovir dipivoxil for treatment naïve patients with chronic hepatitis B: week 52 analysis.J Hepatol. 2003; 38 (abstr): 25Abstract Full Text PDF Google Scholar Responses at weeks 52 and 104 were not different between the 2 groups. Lamivudine-resistant mutations were detected in 15% and 43% of patients after 2 years of combination therapy and lamivudine monotherapy, respectively.28A phase II study of lamivudine compared to lamivudine plus adefovir dipivoxil for subjects with chronic hepatitis B. Available at: http://ctr.gsk.co.uk/Summary/lamivudine/II_NUC20912. Accessed December 1, 2006.Google Scholar Another study showed that combination of lamivudine and telbivudine was worse than telbivudine alone.29Lai C.L. Leung N. Teo E.K. Tong M. Wong F. Hann H.W. Han S. et al.A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B.Gastroenterology. 2005; 129: 528-536Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar A third study reported that combination of emtricitabine and adefovir was superior to adefovir alone, but the results likely reflect more potent antiviral activity of emtricitabine vs adefovir.30Lau G. Cooksley H. Ribeiro R.M. Powers K.A. Bowden S. Mommeja-Marin H. Mondou E. et al.Randomized, double-blind study comparing adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy versus ADV alone in HBeAg(+) chronic hepatitis B: efficacy and mechanisms of treatment response.Hepatology. 2004; 40 (abstr 245): 272ACrossref Scopus (2) Google Scholar The lack of additive or synergistic antiviral activity in these studies may be related to the common target (HBV polymerase) of the drugs used in combination. Studies comparing combination of pegIFN and lamivudine to pegIFN monotherapy and lamivudine monotherapy showed that combination therapy resulted in more marked on-treatment viral suppression, but responses assessed 6 months after discontinuation of treatment were similar to treatment with pegIFN alone and superior to that of lamivudine alone.5Lau G.K. Piratvisuth T. Luo K.X. Marcellin P. Thongsawat S. Cooksley G. Gane E. et al.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695Crossref PubMed Scopus (1353) Google Scholar, 6Marcellin P. Lau G.K. Bonino F. Farci P. Hadziyannis S. Jin R. Lu Z.M. et al.Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2004; 351: 1206-1217Crossref PubMed Scopus (1047) Google Scholar, 7Janssen H.L. van Zonneveld M. Senturk H. Zeuzem S. Akarca U.S. Cakaloglu Y. Simon C. et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129Abstract Full Text Full Text PDF PubMed Scopus (1016) Google Scholar Lamivudine resistance was less frequent but not completely prevented in the combination therapy group. Among the investigational therapies, tenofovir disoproxil fumarate, a nucleotide analogue that is structurally similar to adefovir, holds the most promise. In vitro studies showed that tenofovir and adefovir are equipotent and have activity against wild-type as well as lamivudine-resistant HBV and entecavir-resistant HBV.31Yang H. Qi X. Sabogal A. Miller M. Delaney IV, W.E. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV.Antivir Ther. 2005; 10: 625-633PubMed Google Scholar The approved dose of tenofovir is 30-fold higher than adefovir, accounting for its greater antiviral activity in vivo.32Peters M.G. Andersen J. Lynch P. Liu T. Alston-Smith B. Brosgart C.L. Jacobson J.M. et al.Viral hepatitis: randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127.Hepatology. 2006; 44: 1110-1116Crossref PubMed Scopus (162) Google Scholar, 33van Bommel S. Zollner B. Sarrazin C. Spengler U. Huppe D. Moller B. Feucht H.H. et al.Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy.Hepatology. 2006; 44: 318-325Crossref PubMed Scopus (249) Google Scholar Tenofovir, alone and in combination with emtricitabine as a single pill, has been approved for the treatment of human immunodeficiency virus (HIV) infection. Emtricitabine (FTC) is structurally similar to lamivudine (3TC) and is approved for the treatment of HIV infection. Clinical trials in patients with hepatitis B showed that FTC and 3TC have similar efficacy and resistance rates and select for the same resistant mutations.34Lim S.G. Ng T.M. Kung N. Krastev Z. Volfova M. Husa P. Lee S.S. et al.A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.Arch Intern Med. 2006; 166: 49-56Crossref PubMed Scopus (147) Google Scholar Clevudine is unique because viral suppression persists for up to 24 weeks even after very short courses of treatment.35Marcellin P. Mommeja-Marin H. Sacks S.L. Lau G.K. Sereni D. Bronowicki J.P. Conway B. et al.A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B.Hepatology. 2004; 40: 140-148Crossref PubMed Scopus (120) Google Scholar However, phase II clinical trials found that HBeAg seroconversion rate in clevudine-treated patients was not different compared with those who received placebo,36Lee Y. Suh D. Lim Y. Jung S. Kim K. Lee H. Chung Y. 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: 1385-1391Crossref PubMed Scopus (274) Google Scholar and in vitro studies suggest that clevudine is not effective against lamivudine-resistant HBV. IFN therapy is associated with many adverse effects, notably fatigue, bone marrow suppression, mood changes, and unmasking or exacerbation of autoimmune illnesses. The most dreaded adverse event is a severe hepatitis flare that is believed to be immune mediated and can lead to hepatic failure, particularly in older patients and those with cirrhosis or advanced hepatic fibrosis.37Hoofnagle J.H. Di Bisceglie A.M. Waggoner J.G. Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B.Gastroenterology. 1993; 104: 1116-1121PubMed Google Scholar, 38Perrillo R. Tamburro C. Regenstein F. Balart L. Bodenheimer H. Silva M. Schiff E. et al.Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus.Gastroenterology. 1995; 109: 908-916Abstract Full Text PDF PubMed Scopus (178) Google Scholar Nucleos(t)ide analogue therapies for hepatitis B have been very well tolerated even in patients with decompensated cirrhosis.39Fontana R.J. Hann H.W. Perrillo R.P. Vierling J.M. Wright T. Rakela J. Anschuetz G. et al.Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.Gastroenterology. 2002; 123: 719-727Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar Adefovir and tenofovir have been associated with renal dysfunction. Nephrotoxicity defined as an increase in serum creatinine by ≥0.5 mg/dL on 2 consecutive occasions has been reported in 3% of patients with compensated liver disease after 4–5 years of adefovir therapy.40Hadziyannis S. Tassopoulos N. Chang T.T. Heathcote J. Kitis G. Rizzetto M. Marcellin P. et al.Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy.Hepatology. 2005; 42: 754AGoogle Scholar A major concern with long-term nucleos(t)ide analogue treatment is the selection of antiviral-resistant mutations. The rate at which resistant mutants are selected is related to pretreatment serum HBV DNA level, rapidity of viral suppression, prior exposure to other HBV treatments (and presence of cross-resistant mutations), medication compliance, and potency of the drug and its genetic barrier to resistance. Table 2 summarizes the rates at which antiviral-resistant HBV mutants are detected in clinical trials.19Lok A.S. Lai C.L. Leung N. Yao G.B. Cui Z.Y. Schiff E.R. Dienstag J.L. et al.Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology. 2003; 125: 1714-1722Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar, 40Hadziyannis S. Tassopoulos N. Chang T.T. Heathcote J. Kitis G. Rizzetto M. Marcellin P. et al.Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy.Hepatology. 2005; 42: 754AGoogle Scholar, 41Colonno R. Rose R. Pokornowski K. Baldick C. Klesczewski K. Tenney D. Assessment at three years shows high barrier to resistance is maintained in entecavir-treated nucleoside naive patients while resistance emergence increases over time in lamivudine refractory patients.Hepatology. 2006; 44 (abstr 110): 229A-230ACrossref Scopus (317) Google Scholar, 42Lai C. Gane E. Hsu C.-W. Thonsgawat S. Wang Y. Chen Y. Heathcote E. et al.Two-year results from the Globe Trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine (LDT) vs. lamivudine.Hepatology. 2006; 44 (abstr 91): 222AGoogle Scholar It should be pointed out that the reported rates vary with the sensitivity of the methods used for detection of the mutants and the patient population studied.Table 2Rates of Antiviral-Resistant HBV Mutations Reported in Clinical TrialsAntiviral therapyRates of genotypic resistanceNucleoside-naïve patients Lamivudine15%–30% after 1 yr, ∼70% after 5 yr Adefovir0% after 1 yr, ∼30% after 5 yr Entecavir0% after 1 yr, ∼1% after 2 and 3 yr Telbivudine5%–11% after 1 yrLamivudine-resistant patients Adefovir∼20% after 2 yr Entecavir1%, 9%, ∼17% after 1, 2, and 3 yr, respectively Open table in a new tab Antiviral resistance is manifested as virologic breakthrough, increase in serum HBV DNA level by >1 log (10-fold) above nadir during treatment, in a medication compliant patient. Serum HBV DNA levels tend to be low initially because most antiviral-resistant mutants have decreased replication fitness compared with wild-type HBV. However, compensatory mutations that can restore replication fitness frequently emerge during continued treatment, leading to a progressive increase in serum HBV DNA that may exceed pretreatment levels. Biochemical breakthrough, defined as elevation in alanine aminotransferase (ALT) during treatment in a patient who had achieved initial normalization, can occur simultaneously with or months to years after virologic breakthrough. Emergence of antiviral-resistant mutations can lead to hepatitis flares and hepatic failure.19Lok A.S. Lai C.L. Leung N. Yao G.B. Cui Z.Y. Schiff E.R. Dienstag J.L. et al.Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology. 2003; 125: 1714-1722Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar A potential consequence of antiviral resistance is the selection of mutations that are cross-resistant to other drugs, limiting future treatment options. For example, patients with lamivudine-resistant HBV are more likely to acquire resistance to entecavir.43Sherman M. Martin P. Lee W. Yurdaydin C. Sollano J. Vaughan J. Hindes R. 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).Gastroenterology. 2006; 130 (abstr): A765Google Scholar Once selected, antiviral-resistant mutations are archived and can reemerge within a few months of reexposure to the same drug. 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