Comments on the EASL practice guidelines for the management of chronic hepatitis B: Controversies in interferon-based therapy
Authors: Harry L.A. Janssen, Erik H.C.J. Buster
Journal: Journal of Hepatology (2009)

With great interest we read the new EASL clinical practice guidelines for the management of chronic hepatitis B. First, we would, like to complement the authors with these concise and well-written guidelines. The manuscript provides valuable information and a firm helping hand for the many practicing clinicians around the globe struggling with different treatment modalities for chronic hepatitis B virus (HBV) infection. In particular, the distinction between sustained off-treatment response and treatment maintained response is of great importance. In addition, the clear recommendation for the strongest antivirals and the schedule for follow-up of antiviral therapy are important new concepts in these guidelines. There are however some concerns we would like to raise, particularly concerning the recommendations for interferon (IFN)-treated patients. The authors provided a clear overview of response rates after a 1-year course of therapy. It is well known that HBeAg loss rates increase with prolonged duration of nucleos(t)ide analogue (NA) therapy and may eventually exceed those achieved after one year of IFN-based therapy. However, we think it is important to mention that the risk of relapse may well be significantly higher after discontinuation of nucleoside analogue than IFN-based therapy [[1]van Nunen A.B. Hansen B.E. Suh D.J. Lohr H.F. Chemello L. Fontaine H. et al.Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase.Gut. 2003; 52: 420-424Crossref PubMed Scopus (158) Google Scholar]. Higher rates of sustained HBeAg negativity have been observed in nucleos(t)ide analogue treated patients who received several months of consolidation therapy compared to those who stopped therapy shortly after HBeAg loss. However, these data are available for relatively short periods only [1van Nunen A.B. Hansen B.E. Suh D.J. Lohr H.F. Chemello L. Fontaine H. et al.Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase.Gut. 2003; 52: 420-424Crossref PubMed Scopus (158) Google Scholar, 2Dienstag J.L. Cianciara J. Karayalcin S. Kowdley K.V. Willems B. Plisek S. et al.Durability of serologic response after lamivudine treatment of chronic hepatitis B.Hepatology. 2003; 37: 748-755Crossref PubMed Scopus (212) Google Scholar, 3Song 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 (317) Google Scholar, 4Chien R.N. Yeh C.T. Tsai S.L. Chu C.M. Liaw Y.F. Determinants for sustained HBeAg response to lamivudine therapy.Hepatology. 2003; 38: 1267-1273Crossref PubMed Scopus (188) Google Scholar, 5Gish R.G. Lok A.S. Chang T.T. de Man R.A. Gadano A. Sollano J. et al.Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B.Gastroenterology. 2007; 133: 1437-1444Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 6Poynard T. Hou J.L. Chutaputti A. Manns M. Naoumov N. Sustained durability of HBeAg seroconversion in chronic hepatitis B patients after treatment with telbivudine.J Hepatol. 2008; 48: S263-S264Abstract Full Text PDF Google Scholar, 7Ryu S.H. Chung Y.H. Choi M.H. Kim J.A. Shin J.W. 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The Long-Term Follow-up Investigator GroupThe European Study Group on Viral Hepatitis (EUROHEP)Executive Team on Anti-Viral TreatmentThe long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B.J Viral Hepat. 1998; 5: 389-397Crossref PubMed Scopus (96) Google Scholar, 11Lau D.T. Everhart J. Kleiner D.E. Park Y. Vergalla J. Schmid P. et al.Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa.Gastroenterology. 1997; 113: 1660-1667Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 12Marcellin P. Piratvisuth T. Brunetto M.R. Bonino F. Lau G.K. Farci P. et al.Virological and biochemical response in patients with HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40kD) with or without lamivudine: results of 4-year follow-up.J Hepatol. 2008; 48: S46Abstract Full Text PDF Google Scholar, 13van Zonneveld M. Honkoop P. Hansen B.E. Niesters H.G. Murad S.D. de Man R.A. et al.Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.Hepatology. 2004; 39: 804-810Crossref PubMed Scopus (304) Google Scholar]. Another important observation is that many HBeAg positive and HBeAg negative patients with sustained response after (PEG-)IFN therapy eventually also cleared serum HBsAg, while HBsAg loss hardly occurred in nucleos(t)ide analogue treated patients [8Buster E.H. Flink H.J. Cakaloglu Y. Simon K. Trojan J. Tabak F. et al.Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg positive patients treated with peginterferon alpha-2b.Gastroenterology. 2008; 135: 459-467Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 12Marcellin P. Piratvisuth T. Brunetto M.R. Bonino F. Lau G.K. Farci P. et al.Virological and biochemical response in patients with HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40kD) with or without lamivudine: results of 4-year follow-up.J Hepatol. 2008; 48: S46Abstract Full Text PDF Google Scholar, 13van Zonneveld M. Honkoop P. Hansen B.E. Niesters H.G. Murad S.D. de Man R.A. et al.Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.Hepatology. 2004; 39: 804-810Crossref PubMed Scopus (304) Google Scholar]. Nucleos(t)ide analogues are easy to use because they are generally well tolerated and can effectively suppress HBV replication in virtually all patients. In contrast, one would like to initiate PEG-IFN only in patients with a high likelihood of response because of its side effects and modest response rates. Knowledge of factors associated with an increased likelihood of response to IFN-based is therefore essential. Well known predictors of response to (PEG-)IFN include high baseline ALT and low baseline HBV DNA, which both seem linearly correlated with the chance of response [14Bonino F. Marcellin P. Lau G.K. Hadziyannis S. Jin R. Piratvisuth T. et al.Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B.Gut. 2007; 56: 699-705Crossref PubMed Scopus (237) Google Scholar, 15Janssen H.L. van Zonneveld M. Senturk H. Zeuzem S. Akarca U.S. Cakaloglu Y. 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 (1037) Google Scholar]. Cut-off levels for ALT and HBV DNA are therefore difficult to define. In our opinion, a cut-off level of 2 × ULN instead of 3 × ULN for ALT and of 2 × 108 IU/ml instead of 2 × 107 IU/ml for HBV DNA might have been more appropriate since these levels are widely used in clinical practice and have been recommended in several other international guidelines [16Hoofnagle J.H. Doo E. Liang T.J. Fleischer R. Lok A.S. Management of hepatitis B: summary of a clinical research workshop.Hepatology. 2007; 45: 1056-1075Crossref PubMed Scopus (541) Google Scholar, 17Liaw Y.F. Leung N. Kao J.H. Piratvisuth T. Gane E. Han K.H. et al.Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update.Hepatol Int. 2008; https://doi.org/10.1007/s12072-008-9080-3Crossref PubMed Scopus (829) Google Scholar, 18Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2166) Google Scholar]. We disagree that HBV genotype has a poor individual predictive value and that genotype alone should not override choice of treatment. Many previous studies have shown the importance of HBV genotype for IFN-based therapy [15Janssen H.L. van Zonneveld M. Senturk H. Zeuzem S. Akarca U.S. Cakaloglu Y. 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 (1037) Google Scholar, 19Hadziyannis S. Lau G.K.K. Marcellin P. Piratvisuth T. Cooksley G. Bonino F. et al.Sustained HBsAg seroconversion in patients with chronic hepatitis B treated with peginterferon alpha-2a (40 kDa) (Pegasys®).J Hepatol. 2005; 42: S178Google Scholar, 20Wai C.T. Chu C.J. Hussain M. Lok A.S. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.Hepatology. 2002; 36: 1425-1430PubMed Google Scholar, 21Erhardt A. Blondin D. Hauck K. Sagir A. Kohnle T. Heintges T. et al.Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D.Gut. 2005; 54: 1009-1013Crossref PubMed Scopus (221) Google Scholar, 22Hou J. Schilling R. Janssen H.L.A. Hansen B.E. Heijtink R. Sablon E. et al.Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-based HBeAg clearance.J Med Virol. 2007; 79: 1055-1063Crossref PubMed Scopus (35) Google Scholar, 23Kao J.H. Wu N.H. Chen P.J. Lai M.Y. Chen D.S. Hepatitis B genotypes and the response to interferon therapy.J Hepatol. 2000; 33: 998-1002Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, 24Cooksley W.G.E. Piratvisuth T. Lee S.D. Mahachai V. Chao Y.C. Tanwandee T. 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 (463) Google Scholar]. Recently, the two largest studies conducted so far showed that HBV genotype was actually the most important predictor of response in both HBeAg positive and HBeAg negative patients, in addition to ALT and HBV DNA [25Buster E.H. Hansen B.E. Lau G.K. Piratvisuth T. McCloud P.I. Button P. et al.Prediction of response to peginterferon-alfa in HBeAg positive chronic hepatitis B: a model based on 721 patients.Hepatology. 2008; 48: 723A-724ACrossref PubMed Scopus (96) Google Scholar, 26Erhardt A. Ludwig A.D. Brunetto M. van Boemmel F. Wolf E. Goebel T. et al.HBV genotypes are the stongest predictors of response to interferon-alfa treatment: multivariate evaluation in 1229 hepatitis B patients.Hepatology. 2008; 48: 700A-701AGoogle Scholar]. Since sustained off-treatment response can be achieved in only a quarter to one-third of PEG-IFN treated patients, being able to identify non-responders during the first weeks of therapy is important in order to reduce the number of patients needed to treat. The authors therefore suggest to determine serum HBV DNA at week 12 and 24. In case of primary non-response, defined as a <1log10 decline in serum HBV DNA from baseline after 12 weeks of therapy, they recommend to discontinue IFN-based therapy. In addition, they recommended to establish whether virological response (defined as an HBV DNA concentration of less than 2000 IU/ml) has been achieved after 24 weeks of IFN-based therapy. The consequence of the last finding is however not clear. To the best of our knowledge a solid stopping rule for suboptimal responders to IFN-based therapy has not been identified so far. In HBV genotype A infected patients, but not in those with other genotypes, absence of a 1log10 decline in HBV DNA at week 32 accurately predicted non-response [[27]ter Borg M.J. van Zonneveld M. Zeuzem S. Senturk H. Akarca U.S. Simon C. et al.Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response.Hepatology. 2006; 44: 721-727Crossref PubMed Scopus (58) Google Scholar]. Since patients with a delayed decline in HBV DNA, i.e. between weeks 32 and 52 of treatment or after treatment, still had a considerable chance of 27–31% to clear serum HBeAg it is difficult to decide on treatment (dis)continuation based on early HBV DNA measurements [[27]ter Borg M.J. van Zonneveld M. Zeuzem S. Senturk H. Akarca U.S. Simon C. et al.Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response.Hepatology. 2006; 44: 721-727Crossref PubMed Scopus (58) Google Scholar]. Quantitative HBsAg and HBeAg decline during therapy may more accurately predict (non-)response to PEG-IFN than HBV DNA levels [[28]Fried M.W. Piratvisuth T. Lau G.K. Marcellin P. Chow W.C. Cooksley G. et al.HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B.Hepatology. 2008; 47: 428-434Crossref PubMed Scopus (215) Google Scholar], but many clinicians do not have access to these quantitative assays. For HBeAg-positive patients who do not achieve HBeAg seroconversion during antiviral therapy the authors state that sustained undetectable HBV DNA is the next most desirable endpoint. We fully agree that optimal HBV DNA suppression is desirable in all patients. Disease progression can be significantly diminished or possibly even prevented if persistent HBV DNA suppression can be achieved [[29]Liaw Y.F. Sung J.J. Chow W.C. Farrell G. Lee C.Z. Yuen H. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (2013) Google Scholar]. While undetectable HBV DNA is a feasible endpoint for nucleos(t)ide analogue treated patients who remain HBeAg positive, undetectable serum HBV DNA can hardly be achieved in those who remain HBeAg positive after IFN-based therapy. PEG-IFN induced response was persistent in the majority of those who underwent HBeAg seroconversion. Although the proportion of PEG-IFN-treated patients with undetectable HBV DNA increased with longer duration of post-treatment follow-up and most of them were in the inactive carrier state, the majority of patients still had detectable HBV DNA in the long-term [[8]Buster E.H. Flink H.J. Cakaloglu Y. Simon K. Trojan J. Tabak F. et al.Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg positive patients treated with peginterferon alpha-2b.Gastroenterology. 2008; 135: 459-467Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar]. Prevention of antiviral resistance is crucial in nucleos(t)ide analogue-treated patients. In adefovir-treated patients detectable serum HBV DNA at week 48 was strongly associated with a higher risk of antiviral resistance in the long term [[30]Locarnini S. Qi X. Arterburn S. Snow A. Brosgart C.L. Currie G. et al.Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B.J Hepatol. 2005; 42: A17Google Scholar]. Therefore, modification of the treatment regimen is recommended in suboptimal responders to adefovir therapy. The authors now also recommend using this strategy in patients receiving entecavir or tenofovir. One might hypothesize that detectable HBV DNA after 48 weeks of therapy is associated with an increased risk of antiviral resistance in the long term in these patients as well. So far, suboptimal responders to entecavir seem however to do well on continued therapy and tenofovir resistance has not yet been reported. We therefore suggest to modify entecavir or tenofovir therapy only in case of virological breakthrough in patients who are fully compliant [31Sherman M. Rizzetto M. Lai C.L. Liaw Y.F. Gadano A. Jacobson I.M. et al.Long-term follow-up of entecavir treated protocol-defined non-responders in rollover study ETV-901.Hepatology. 2007; 46: 682ACrossref PubMed Scopus (23) Google Scholar, 32Marcellin P. Buti M. Krastev Z. Gurel S. Balabanska R.I. Dusheiko G. et al.Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-negative patients with chronic hepatitis B (study 102), preliminary results.Hepatology. 2008; 48: 370ACrossref Scopus (266) Google Scholar, 33Heathcote E.J. Gane E.J. de Man R.A. Chan S. Sievert W. Mauss S. et al.Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-positive patients with chronic hepatitis B (study 103), preliminary analysis.Hepatology. 2008; 48: 376AGoogle Scholar]. We conclude that the updated EASL recommendations provide valuable support for the many physicians faced with the complex management of patients chronically infected with the hepatitis B virus. Treatment strategies for chronic hepatitis B have dramatically improved in the last decade, but many aspects have not been fully elucidated and controversies persist. To allow for identification of good candidates for PEG-IFN therapy determination of HBV genotype is important in all patients in whom sustained off-treatment response is pursued.