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Interferon alpha therapy in HBeAg-negative chronic hepatitis B: new data in support of long-term efficacy

2002; Elsevier BV; Volume: 36; Issue: 2 Linguagem: Inglês

10.1016/s0168-8278(01)00314-2

1600-0641

Stephanos J. Hadziyannis,

Liver Disease Diagnosis and Treatment

Chronic hepatitis B (CHB) is separable into two major forms: the HBeAg-positive and the HBeAg-negative [[1]Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar]. HBeAg-negative CHB has also been referred to as anti-HBe-positive and ‘precore mutant’ CHB [2Santantonio T. Mazzola M. Iacovazzi T. Miglietta A. Guastadisegni A. Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine.J Hepatol. 2000; 32: 300-306Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 3Tassopoulos N.C. Volpes R. Pastore G. Heathcote J. Buti M. Goldin R.D. et al.Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group.Hepatology. 1999; 29: 889-896Crossref PubMed Scopus (549) Google Scholar] but in most of the recent publications and in an international workshop on hepatitis B the designation HBeAg-negative CHB has been adopted [1Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 3Tassopoulos N.C. Volpes R. Pastore G. Heathcote J. Buti M. Goldin R.D. et al.Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group.Hepatology. 1999; 29: 889-896Crossref PubMed Scopus (549) Google Scholar, 4Chan H.L. Leung N.W. Hussain M. Wong M.L. Lok A.S. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.Hepatology. 2000; 31: 763-768Crossref PubMed Scopus (183) Google Scholar]. In HBeAg-negative CHB there is persistent or intermittent HBV replication demonstrable immunohistochemically (HBcAg in the liver) [[5]Hadziyannis S.J. Lieberman H.M. Karvountzis G.G. Shafritz D.A. Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg vs. anti-HBe positive carriers of hepatitis B virus.Hepatology. 1983; 3: 656-662Crossref PubMed Scopus (373) Google Scholar] by molecular hybridization techniques [[5]Hadziyannis S.J. Lieberman H.M. Karvountzis G.G. Shafritz D.A. Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg vs. anti-HBe positive carriers of hepatitis B virus.Hepatology. 1983; 3: 656-662Crossref PubMed Scopus (373) Google Scholar], and by quantitative PCR assays, with serum HBV DNA levels usually exceeding 105 and 106 molecule equivalents or copies/ml [[1]Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar]. The replicating HBV has been found to be unable to produce HBeAg as is the case with the most frequently detected precore mutation G1896A that creates a novel translational stop codon in the precore/core transcript [[6]Carman W.F. Jacyna M.R. Hadziyannis S. Karayiannis P. McGarvey M.J. Makris A. et al.Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection.Lancet. 1989; 2: 588-591Abstract PubMed Scopus (1106) Google Scholar]. The same is true for other rather rare missense or nonsense mutations in the precore region [[7]Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (458) Google Scholar]. Alternatively HBV may harbor mutations in the region of the basic core promoter (BCP) affecting HBeAg formation at the transcriptional level [[8]Okamoto H. Tsuda F. Akahane Y. Sugai Y. Yoshiba M. Moriyama K. et al.Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen.J Virol. 1994; 68: 8102-8110PubMed Google Scholar]. HBeAg-negative CHB is not acquired as an independent, ab initio mutant form of chronic HBV infection. The HBeAg-negative HBV mutants, which may be present from the early stages of chronic infection with the wild type, the HBeAg-positive HBV, become selected in the natural course of chronic infection during or after HBeAg seroconversion [[7]Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (458) Google Scholar]. For as yet unknown reasons, these mutants frequently retain or redevelop high replicative activity, which is inducing CHB immunologically [[7]Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (458) Google Scholar]. HBeAg-negative CHB is a potentially severe and progressive form of CHB prevailing in certain parts of the world such as in Southern Europe and the Mediterranean Area, the middle East and Asia [1Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 7Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (458) Google Scholar]. In these geographical areas 30–80% of patients with CHB are HBeAg-negative compared to Northern European countries and the USA, where only 10–40% of the CHB patients are lacking HBeAg [1Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 7Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (458) Google Scholar]. These differences may be related to several factors such as modes and age at acquisition of HBV infection, gender and immunosuppression, but their main determinant appears to be the infecting HBV genotype [[9]Lindh M. Andersson A.S. Gusdal A. Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus – large-scale analysis using a new genotyping method.J Infect Dis. 1997; 175: 1285-1293Crossref PubMed Scopus (428) Google Scholar]. Precore stop codon mutants (G1896A) can be selected only in chronic infection with those HBV genotypes harboring T at precore position 1858. These are genotypes B, D, E and a percentage of HBV strains with genotype C. HBV genotype A and a percentage of strains of genotype C and F harbor C and not T at 1858 [[9]Lindh M. Andersson A.S. Gusdal A. Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus – large-scale analysis using a new genotyping method.J Infect Dis. 1997; 175: 1285-1293Crossref PubMed Scopus (428) Google Scholar]. This precludes the selection of G1896A and reduces the possibility of development of HBeAg-negative CHB. The distribution of HBV genotypes varies geographically. As a consequence the relative frequencies of precore and other HBeAg-negative HBV mutants as well as of HBeAg-positive and -negative CHB also vary geographically. In the Mediterranean Area where the precore stop codon HBV mutant was first identified [6Carman W.F. Jacyna M.R. Hadziyannis S. Karayiannis P. McGarvey M.J. Makris A. et al.Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection.Lancet. 1989; 2: 588-591Abstract PubMed Scopus (1106) Google Scholar, 10Brunetto M.R. Stemler M. Bonino F. Schodel F. Oliveri F. Rizzetto M. et al.A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B.J Hepatol. 1990; 10: 258-261Abstract Full Text PDF PubMed Scopus (219) Google Scholar] and HBeAg-negative CHB largely predominates, HBV genotype D also predominates. In Greece it actually accounts for >90% of chronic HBV infections. Thus, reports from South Europe on the various features, the outcome of HBeAg-negative CHB and its response to interferon alfa (IFN-α), mainly concern precore mutant genotype D CHB and do not necessarily apply to other geographical areas where other virologic forms of HBeAg-negative CHB may prevail, e.g. BCP mutant HBV genotype A or C. As pointed out, HBeAg-negative CHB frequently attains a progressive course with severe persistent or intermittent HBV replication and liver disease activity, rarely if ever going spontaneously into sustained remission [11Bonino F. Rosina F. Rizzetto M. Rizzi R. Chiaberge E. Tardanico R. et al.Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe.Gastroenterology. 1986; 90: 1268-1273PubMed Google Scholar, 12Hadziyannis S.J. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment.Viral Hepat Rev. 1995; 1: 7-36Google Scholar]. It has been claimed to be complicated at a relatively high annual rate by the development of cirrhosis and hepatocellular carcinoma although the findings differ significantly among studies from various parts of the world [7Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (458) Google Scholar, 12Hadziyannis S.J. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment.Viral Hepat Rev. 1995; 1: 7-36Google Scholar]. On the other hand, suppression of HBV replication either by IFN-α or nucleoside analogues is almost always associated with remission in biochemical activity [2Santantonio T. Mazzola M. Iacovazzi T. Miglietta A. Guastadisegni A. Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine.J Hepatol. 2000; 32: 300-306Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 3Tassopoulos N.C. Volpes R. Pastore G. Heathcote J. Buti M. Goldin R.D. et al.Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group.Hepatology. 1999; 29: 889-896Crossref PubMed Scopus (549) Google Scholar, 12Hadziyannis S.J. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment.Viral Hepat Rev. 1995; 1: 7-36Google Scholar, 13Manesis E.K. Hadziyannis S.J. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.Gastroenterology. 2001; 121: 101-109Abstract Full Text PDF PubMed Scopus (241) Google Scholar]. Thus, an effective antiviral and/or immunomodulatory therapy is expected to improve its prognosis. Unfortunately, although IFN-α therapy has been reported to induce initial remission in almost 2/3 of the treated patients, its efficacy has been evaluated only in few randomized controlled trials (RCT) with small number of patients with IFN-α usually given for relatively short periods of time [14Fattovich G. Farci P. Rugge M. Brollo L. Mandas A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid interferon-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (174) Google Scholar, 15Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (142) Google Scholar, 16Lampertico P. Del Ninno E. Manzin A. Donato M.F. Rumi M.G. Lunghi G. et al.A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.Hepatology. 1997; 26: 1621-1625Crossref PubMed Scopus (190) Google Scholar, 17Pastore G. Santantonio T. Milella M. Monno L. Mariano N. Moschetta R. et al.Anti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6-month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (126) Google Scholar]. Moreover, because of a high frequency of relapses after cessation of treatment the results of therapy have generally been interpreted as negative, despite the fact that sustained response (SR) rates appeared to range between 10 and 30% [[1]Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar]. Probably because of the relatively low prevalence of HBeAg-negative CHB in most western countries priority to interferon therapy was given to the HBeAg-positive CHB and to chronic hepatitis C. However, regardless of these conjectures, it is obvious that the effect or no effect of IFN-α therapy on HBeAg-negative CHB and particularly on its long-term outcome has not been properly documented and has remained uncertain for years. In this issue of the Journal, Brunetto et al. report on the long-term outcome of a large group of IFN-α treated and untreated Italian patients with HBeAg-negative/anti-HBe-positive CHB [[18]Brunetto M.R. Oliveri F. Coco B. Leandro G. Colombatto P. Gorin J.M. et al.Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.J Hepatol. 2002; 36: 263-270Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar]. Drs F. Bonino and M. Brunetto and their group were of the first to recognize the need for IFN-α therapy in HBeAg-negative CHB and from the early 1990s have published a number of reports emphasizing the high initial response rates as well as the disappointingly high rates of relapse within a few months after cessation of IFN-α therapy [[19]Brunetto M.R. Oliveri F. Demartini A. Calvo P. Manzini P. Cerenzia M.T. et al.Treatment with interferon of chronic hepatitis B associated with antibody to hepatitis B e antigen.J Hepatol. 1991; 13: S8-S11Abstract Full Text PDF PubMed Scopus (24) Google Scholar]. On the other hand, some of their patients did achieve sustained biochemical remission and even loss of HBsAg. Four RCTs with 86 IFN-treated and 84 untreated patients conducted between 1989 and 1997 [14Fattovich G. Farci P. Rugge M. Brollo L. Mandas A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid interferon-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (174) Google Scholar, 15Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (142) Google Scholar, 16Lampertico P. Del Ninno E. Manzin A. Donato M.F. Rumi M.G. Lunghi G. et al.A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.Hepatology. 1997; 26: 1621-1625Crossref PubMed Scopus (190) Google Scholar, 17Pastore G. Santantonio T. Milella M. Monno L. Mariano N. Moschetta R. et al.Anti-HBe-positive chronic hepatitis B with HBV-DNA in the serum response to a 6-month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (126) Google Scholar] have been meta-analyzed recently by A. Alberti showing a 38–90% end of treatment response (ETR) rate compared to only 0–37% in the untreated controls [[1]Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar]. Most importantly there was a 10–47% (average 24%) SR rate at 12 months after cessation of therapy in treated vs. 0% in the untreated patients. This is similar to the results of the large number of small uncontrolled studies with approximately 1/5 of the patients achieving a SR, which became generally higher with longer duration of therapy (12 vs. 6 months) [1Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B: 2000 – summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 12Hadziyannis S.J. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment.Viral Hepat Rev. 1995; 1: 7-36Google Scholar]. The overall results of the study of Brunetto et al. [[18]Brunetto M.R. Oliveri F. Coco B. Leandro G. Colombatto P. Gorin J.M. et al.Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.J Hepatol. 2002; 36: 263-270Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar] with 9 MU of IFN-α twice weekly (tiw) given for 4–12 months to 57 of their patients or with other IFN regimens applied to 46 patients confirm the earlier impression of a beneficial effect of IFN-a therapy in HBeAg-negative CHB [[12]Hadziyannis S.J. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment.Viral Hepat Rev. 1995; 1: 7-36Google Scholar]. The ETR rate was 68.5% (71/103) without significant differences between patients with or without cirrhosis at baseline. The overall relapse rate among initial responders was 78% (71/103) and the SR rate, again among ETRs, was 21% (15/71). In addition, 10 of the 15 patients (66%) with SRs lost HBsAg and five of them (50%) also developed anti-HBs. In the largest series of the literature of 216 patients from a single center treated with IFN-α (3–6 MU tiw) for 5–12 months, approximately one-fifth (18%) of the treated and retreated patients achieved sustained biochemical and virologic remission. The duration of therapy was found, by multivariate analysis, to be inversely related to the relapse rate while 32% of the SRs lost HBsAg [[13]Manesis E.K. Hadziyannis S.J. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.Gastroenterology. 2001; 121: 101-109Abstract Full Text PDF PubMed Scopus (241) Google Scholar]. In an earlier study a 24 month course of treatment with 6 MU IFN-a led to sustained suppression of HBV in one-third of the patients and attenuated hepatitis in 81% of them [[16]Lampertico P. Del Ninno E. Manzin A. Donato M.F. Rumi M.G. Lunghi G. et al.A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.Hepatology. 1997; 26: 1621-1625Crossref PubMed Scopus (190) Google Scholar]. Brunetto et al. [[18]Brunetto M.R. Oliveri F. Coco B. Leandro G. Colombatto P. Gorin J.M. et al.Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.J Hepatol. 2002; 36: 263-270Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar] have also demonstrated that IFN-a treatment slowed down disease progression by 2.5 fold in comparison to untreated patients. Disease progression with development of cirrhosis and severe complications was actually found to be much more frequent in patients of an older age with higher serum HBV DNA levels and in unremitting disease. Nevertheless, liver disease improved in 16% of the IFN-α treated patients vs. 1.6% in the untreated ones. A similar analysis by Papatheodoridis et al. published recently in the Journal of Hepatology had also demonstrated that a SR compared to no treatment or no response was associated with lower rates of death (3.5 vs. 12.5%) and of development of HCC (1.7 vs. 10%) [[20]Papatheodoridis G.V. Manesis E. Hadziyannis S.J. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.J Hepatol. 2001; 34: 306-313Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar]. In HBeAg-negative CHB there is, as stressed, significant heterogeneity in the virus (genotypes, precore mutants, BCP mutation), in patterns of disease activity (continuous, fluctuating or intermittent), in age, sex mode and age at acquisition of HBV infection, immune status of the host and other variables. Moreover, different types and regimens of IFN-α have been applied and different assays of HBV DNA have been used. However, it is noteworthy that despite these differences a similar trend in long-term efficacy has emerged from the various studies, particularly those conducted in Greece and Italy, where as mentioned, most of the HBeAg-negative patients with CHB are HBV genotype D harboring the classical G1896A precore stop codon mutation. Nucleoside analogues have recently been introduced in the treatment not only of HBeAg-positive but also of HBeAg-negative CHB [2Santantonio T. Mazzola M. Iacovazzi T. Miglietta A. Guastadisegni A. Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine.J Hepatol. 2000; 32: 300-306Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 3Tassopoulos N.C. Volpes R. Pastore G. Heathcote J. Buti M. Goldin R.D. et al.Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group.Hepatology. 1999; 29: 889-896Crossref PubMed Scopus (549) Google Scholar, 7Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (458) Google Scholar]. Their short-term efficacy in suppressing viral B replication and inducing biochemical remission is quite satisfactory. However, soon after cessation of a 6 or 12 month or even longer course, the vast majority of initial responders experience both virologic and biochemical relapses, sometimes quite severe [[2]Santantonio T. Mazzola M. Iacovazzi T. Miglietta A. Guastadisegni A. Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine.J Hepatol. 2000; 32: 300-306Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar]. Only occasional instances of sustained remission after long-term lamivudine therapy may be observed. On the other hand, long-term lamivudine therapy is associated with the development of viral resistance in 60% of patients in the third year of therapy, with practically all virologic breakthroughs being followed by biochemical relapses as well [[21]Hadziyannis S.J. Papatheodoridis G.V. Dimou E. Laras A. Papaioannou C. Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2000; 32: 847-851Crossref PubMed Scopus (373) Google Scholar]. Other nucleoside analogues or combination therapies with two or more compounds may prove more effective in the future. However, for the time being, 1 year of IFN-a therapy appears to represent the most effective form of treatment for HBeAg-negative CHB with a good rate (approximately 60%) of ETRs and with 20–40% of them going into sustained remission. The new pegylated interferons, which appear to be more effective and more suitable for long-term administration, may significantly increase the rate of SR in HBeAg-negative CHB. A RCT comparing the efficacy of pegylated IFN monotherapy and of its combination with lamivudine is under way. The best lesson to take home from the study of Brunetto et al. [[18]Brunetto M.R. Oliveri F. Coco B. Leandro G. Colombatto P. Gorin J.M. et al.Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.J Hepatol. 2002; 36: 263-270Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar] and from the other recent publications on the same topic [13Manesis E.K. Hadziyannis S.J. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.Gastroenterology. 2001; 121: 101-109Abstract Full Text PDF PubMed Scopus (241) Google Scholar, 20Papatheodoridis G.V. Manesis E. Hadziyannis S.J. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.J Hepatol. 2001; 34: 306-313Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar] is that before rejecting an old treatment strategy and moving to a potentially ‘better’ one, it is important to have first proper documentation of its short- and long-term efficacy or non-efficacy. In respect to HBeAg-negative CHB it is obvious now that IFN-a therapy is indeed effective and improves the outcome of the disease in a number of patients and that prospective head to head comparisons of the newer interferons to nucleoside analogues and combination therapies are needed.