Treatment of HBeAg-negative chronic hepatitis B with interferon or pegylated interferon
2003; Elsevier BV; Volume: 39; Linguagem: Inglês
10.1016/s0168-8278(03)00329-5
ISSN1600-0641
AutoresMaurizia Rossana Brunetto, Filippo Oliveri, P. Colombatto, B. Coco, P. Ciccorossi, Ferruccio Bonino,
Tópico(s)Liver Disease Diagnosis and Treatment
Resumo1. IntroductionAnti-HBe-positive chronic hepatitis B was first described and characterized in patients of the Mediterranean area, where about 20% of hepatitis B surface antigen (HBsAg) carriers with antibody to hepatitis B 'e' antigen (HBeAg) show detectable serum levels of hepatitis B virus (HBV) DNA by hybridization assays and intrahepatic necro-inflammation [1Bonino F. Hoyer B. Nelson J. Engle R. Verme G. Gerin J. Hepatitis B virus DNA in the sera of HBsAg carriers – a marker of active hepatitis B virus replication in the liver.Hepatology. 1981; 1: 386-391Crossref PubMed Scopus (258) Google Scholar, 2Hadziyannis S.J. Lieberman H.M. Karvountzis G.G. Shafritz D.A. Analysis of liver, nuclear HBcAg, viral replication and hepatitis B virus DNA in liver and serum of HBeAg versus anti-HBe positive carriers of hepatitis B virus.Hepatology. 1983; 3: 656-662Crossref PubMed Scopus (358) Google Scholar]. They are infected with HBV variants with mutations in the pre-core region which hamper HBeAg production. The G to A mutation at nucleotide 1896 of the pre-core region is the most commonly described [3Brunetto M.R. Stemler M. Schoedel F. Will H. Ottobrelli A. Rizetto M. et al.Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis.Ital J Gastroenterol. 1989; 21: 151-154Google Scholar, 4Carman W.F. Jacyna M.R. Hadziyannis S.J. Karayiannis P. McGarvey M.J. Makri A. Thomas H.C. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection.Lancet. 1989; i: 588-590Abstract Scopus (1074) Google Scholar]. Liver disease runs an indolent course for 3–4 decades reaching the stage of histological cirrhosis at a median age of 45 years [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar]; thereafter about 25% of the patients progress to end stage complications within 10 years [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar].In recent years several reports suggest a worldwide incidence of HBeAg-negative chronic hepatitis B [6Lok A.S. Heathcote 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 (728) Google Scholar, 7Chan H.L. Leung N.W. Hussain M. Wong M.L. Lok A.S. Hepatitis Be antigen-negative chronic hepatitis B in Hong Kong.Hepatology. 2000; 31: 763-768Crossref PubMed Scopus (183) Google Scholar]. However, further virological and clinical studies are needed to warrant a complete characterization of the disease and to understand whether it shares common features with the anti-HBe-positive chronic hepatitis B observed in Mediterranean patients, who are infected with HBV genotype D, bearing the stop codon at nucleotide 1896 [[8]Hadziyannis S.J. Interferon alpha in HBeAg negative chronic hepatitis B: new data in support of long term efficacy.J Hepatol. 2002; 36: 280-282Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. Because of the progressive course of HBeAg-negative/anti-HBe-positive chronic hepatitis B, alpha-interferon (IFN) treatment was attempted as soon as the drug became available for treatment of chronic HBV infection [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 10Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alpha-2b treatment of HBeAg negative/serum HBV-DNA positive chronic hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar]. Most studies about interferon treatment of anti-HBe-positive chronic hepatitis B were performed in southern Europe [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 10Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alpha-2b treatment of HBeAg negative/serum HBV-DNA positive chronic hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar, 13Brunetto M.R. Oliveri F. Colombatto P. Capalbo M. Barbera C. Bonino F. Treatment of chronic anti-HBe positive hepatitis B with interferon-alpha.J Hepatol. 1995; 22: 42-44PubMed Google Scholar, 14Lampertico P. Del Ninno E. Manzin A. Donato M.R. Rumi M.G. Lunghi G. et al.A randomized, controlled trial of 24-month course of interferon alpha 2b in patients with chronic hepatitis B who had hepatitis virus DNA without hepatitis B e antigen in serum.Hepatology. 1997; 26: 1621-1625Crossref PubMed Scopus (190) Google Scholar] and more recently a few reports had been published from Asia [15Karasawa T. Aizawa Y. Zeniya M. Kuramoto A. Shirasawa T. Toda G. Genetic heterogeneity in the pre-core region of HBV in hepatitis B e antigen-negative chronic hepatitis B patients: spontaneous seroconversion and interferon-induced seroconversion.J Med Virol. 1995; 45: 373-380Crossref PubMed Scopus (16) Google Scholar, 16Guptan R.C. Thakur V. Malhotra V. Sarin S.K. Low dose recombinant interferon therapy in anti-HBe positive chronic hepatitis B in Asian Indians.J Gastroenterol Hepatol. 1998; 13: 675-679Crossref PubMed Scopus (18) Google Scholar, 17Lin C.C. Wu J.C. Chang T.T. Huang Y.H. Wang Y.J. Tsay S.H. et al.Long term evaluation of recombinant interferon alpha 2b in the treatment of patients with hepatitis B e antigen negative chronic hepatitis B in Taiwan.J Viral Hepat. 2001; 8: 438-446Crossref PubMed Scopus (18) Google Scholar].2. Aims of antiviral treatment and monitoring criteriaIn chronic hepatitis B antiviral treatment is aimed to cure liver disease by a sustained control of HBV infection. This can be obtained in progressive steps: inhibition of viral replication, HBeAg to anti-HBe seroconversion and eventually clearance of HBsAg and seroconversion to anti-HBs [6Lok A.S. Heathcote 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 (728) Google Scholar, 18Hoofnagle J.H. Di Bisceglie A.M. The treatment of chronic viral hepatitis.N Engl J Med. 1997; 336: 347-353Crossref PubMed Scopus (987) Google Scholar]. Since HBsAg to anti-HBs seroconversion occurs months or years after the control of HBV replication it cannot be used as a short-term marker of response to treatment [19Koreman J. Baker B. Waggoner J. Everhart J.E. Di Bisceglie A.M. Hoofnagle J.H. Long term remission of chronic hepatitis B after alpha-interferon therapy.Ann Intern Med. 1991; 114: 629-634Crossref PubMed Scopus (380) Google Scholar, 20Wong D.K.H. Cheung A.M. O'Rourke K. Naylor C.D. Detsky A.S. Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B.Ann Intern Med. 1993; 119: 312-323Crossref PubMed Scopus (1039) Google Scholar]. Therefore, in HBeAg-positive patients HBeAg to anti-HBe seroconversion is considered the hallmark of a successful control of HBV replication and it is used to monitor response to antiviral treatment. In anti-HBe-positive chronic hepatitis B, however, HBeAg to anti-HBe seroconversion has already occurred and a general consensus on alternative criteria to be used to monitor treatment has never been reached.In addition, anti-HBe-positive chronic hepatitis B shows variable profiles characterized by major fluctuations of both viremia and alanine aminotransferase (ALT) levels (HBV DNA can fall below the 105 genomes/ml and ALT may be normal temporarily) in >50% of patients [5Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar, 6Lok A.S. Heathcote 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 (728) Google Scholar]. These features hamper the precise diagnosis of disease or disease relapse when the detection limits for HBV DNA are 105–106 genomes/ml, unless surrogate markers of HBV induced liver damage (anti-HBc IgM) and stringent monitoring criteria are used [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar]. These factors have significantly contributed to the different response rate to interferon therapy reported in the literature [[21]Oliveri F. Santantonio T. Bellati G. Colombatto P. Colloredo-Mels G. Carriero L. et al.Long term response to therapy of chronic anti-HBe positive hepatitis B is poor independent of type and schedule of interferon.Am J Gastroenterol. 1999; 94: 1366-1372PubMed Google Scholar].3. Interferon schedules and evaluation of efficacyIn anti-HBe-positive chronic hepatitis B two different treatment strategies were used. Between 1986 and 1990, when IFN was first introduced for treatment of chronic hepatitis B, medium-to-high doses (5–10 MU) of recombinant or lymphoblastoid IFN were given for 16–24 weeks, according to the schedules adopted for chronic HBeAg-positive hepatitis B [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 13Brunetto M.R. Oliveri F. Colombatto P. Capalbo M. Barbera C. Bonino F. Treatment of chronic anti-HBe positive hepatitis B with interferon-alpha.J Hepatol. 1995; 22: 42-44PubMed Google Scholar, 21Oliveri F. Santantonio T. Bellati G. Colombatto P. Colloredo-Mels G. Carriero L. et al.Long term response to therapy of chronic anti-HBe positive hepatitis B is poor independent of type and schedule of interferon.Am J Gastroenterol. 1999; 94: 1366-1372PubMed Google Scholar]. Thereafter, longer treatment courses (12–24 months) were attempted with medium interferon doses (5–6 MU) [14Lampertico P. Del Ninno E. Manzin A. Donato M.R. Rumi M.G. Lunghi G. et al.A randomized, controlled trial of 24-month course of interferon alpha 2b in patients with chronic hepatitis B who had hepatitis virus DNA without hepatitis B e antigen in serum.Hepatology. 1997; 26: 1621-1625Crossref PubMed Scopus (190) Google Scholar, 22Manesis 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 (236) Google Scholar, 23Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar, 24Papatheodoridis 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 (273) Google Scholar]. Therefore, to assess the efficacy of IFN and its impact on disease outcome, the duration of treatment has to be considered in addition to factors such as disease variability and the different monitoring criteria used in different studies.On-treatment response (OTR) has been described to be associated, independently of the IFN schedule, with a progressive decrease of serum HBV DNA levels, paralleled by a slower ALT decrease [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 10Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alpha-2b treatment of HBeAg negative/serum HBV-DNA positive chronic hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 22Manesis 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 (236) Google Scholar]. ALT flares, like those described in HBeAg-positive responders during month 2–4 on treatment, have been described only in one study, where in 42% of responders serum HBV DNA clearance was preceded by an ALT flare at least two times higher than the median pre-treatment value [[12]Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar].End-of-treatment response (ETR) (Fig. 1) is achieved in 57–90% of treated patients, when defined as a decrease of HBV DNA levels below 1–10 pg/ml and normal ALT at the end of treatment [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 10Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alpha-2b treatment of HBeAg negative/serum HBV-DNA positive chronic hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar, 13Brunetto M.R. Oliveri F. Colombatto P. Capalbo M. Barbera C. Bonino F. Treatment of chronic anti-HBe positive hepatitis B with interferon-alpha.J Hepatol. 1995; 22: 42-44PubMed Google Scholar]. In only one study where more stringent criteria (HBV DNA 90% of relapses occurring within the first year of follow-up, when monthly monitoring was adopted.The hepatitis relapse was associated with an ALT flare in 50–86% of patients [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 10Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alpha-2b treatment of HBeAg negative/serum HBV-DNA positive chronic hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 13Brunetto M.R. Oliveri F. Colombatto P. Capalbo M. Barbera C. Bonino F. Treatment of chronic anti-HBe positive hepatitis B with interferon-alpha.J Hepatol. 1995; 22: 42-44PubMed Google Scholar, 21Oliveri F. Santantonio T. Bellati G. Colombatto P. Colloredo-Mels G. Carriero L. et al.Long term response to therapy of chronic anti-HBe positive hepatitis B is poor independent of type and schedule of interferon.Am J Gastroenterol. 1999; 94: 1366-1372PubMed Google Scholar]. Three studies report a persistent clearance of markers of viral replication and biochemical remission after the hepatitis relapse, showing the possibility of a 'second intention' disease resolution [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 13Brunetto M.R. Oliveri F. Colombatto P. Capalbo M. Barbera C. Bonino F. Treatment of chronic anti-HBe positive hepatitis B with interferon-alpha.J Hepatol. 1995; 22: 42-44PubMed Google Scholar, 21Oliveri F. Santantonio T. Bellati G. Colombatto P. Colloredo-Mels G. Carriero L. et al.Long term response to therapy of chronic anti-HBe positive hepatitis B is poor independent of type and schedule of interferon.Am J Gastroenterol. 1999; 94: 1366-1372PubMed Google Scholar] (Fig. 3) .Fig. 3Control of HBV infection and resolution of chronic hepatitis following a relapse after the end of IFN treatment.View Large Image Figure ViewerDownload (PPT)Interestingly, the only study where a short course of IFN resulted in a lower relapse rate (37%), was the only one that reported the unusual association of ALT flares with treatment response [[12]Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar]. This finding suggests a possible bias through the selection of patients enrolled in the study and the heterogeneity of the anti-HBe-positive patient population.Data from a 24-month treatment show a relapse rate of only 25% at 22 months median follow-up [[14]Lampertico P. Del Ninno E. Manzin A. Donato M.R. Rumi M.G. Lunghi G. et al.A randomized, controlled trial of 24-month course of interferon alpha 2b in patients with chronic hepatitis B who had hepatitis virus DNA without hepatitis B e antigen in serum.Hepatology. 1997; 26: 1621-1625Crossref PubMed Scopus (190) Google Scholar]. A longer follow-up (54 months) of 101 patients treated with the same schedule demonstrated a slightly higher relapse rate of 35% [[23]Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar]. These data are consistent with the results of a multivariate analysis of 216 patients where a 1.64 times higher probability of sustained remission was found when 12 month courses were compared to shorter treatment [[22]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 (236) Google Scholar]. All the findings suggest that longer treatment increases the remission time and the rate of sustained response.Overall the sustained response rate after 2–4 years of follow-up are 10–15% in patients treated for 4–6 months (usually with 9–10 MU of IFN), 22 and 30% when 5 MU of IFN were given for 12 and 24 months, respectively.Untreated patients, despite frequent temporary remissions, resolve their liver disease very rarely. The only study where a significant number of untreated patients showed a sustained remission (10% after 6 months, 17% after 18 months); a 6-month treatment also resulted in an unusually high rate of sustained response of 53% [[12]Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar].During post-treatment follow-up (median 4.5–7 years) 31.6–66.6% of sustained responders lost serum HBsAg, followed by anti-HBs seroconversion in 50–77% [5Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar, 22Manesis 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 (236) Google Scholar, 23Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar, 24Papatheodoridis 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 (273) Google Scholar]. Interestingly, >50% of patients who cleared serum HBsAg had HBV DNA levels <400 copies/ml as compared to 25% of sustained responders who did not clear HBsAg [[22]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 (236) Google Scholar], suggesting a stronger control of HBV replication in patients who clear HBsAg.4. Long-term impact of interferon treatmentLong-term studies to evaluate the effect of IFN therapy on disease outcome should analyze separately the early and late phase of the disease, as the impact of many factors, including treatment, may vary during such a prolonged course of the disease. In addition, the heterogeneity of criteria used to monitor the patients and to define response to therapy may made it difficult to compare the results from different studies. Furthermore, all studies with an untreated control group were not randomized; the data, therefore, have to interpreted cautiously. To date, the impact of IFN on the progression of anti-HBe-positive chronic hepatitis B had been analyzed in three studies that followed 669 patients (413 treated, 256 untreated) for 4.5–6 years [5Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar, 23Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar, 24Papatheodoridis 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 (273) Google Scholar].In the study that defined a sustained response as persistently undetectable HBV DNA (<10 pg/ml) and anti-HBc IgM as well as normal ALT interferon treatment, independently of the response, reduces disease progression 2.5-fold as well as terminal events [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar]. None of the long-term responders showed disease progression, that occurred in 20% of relapsers or non-responders. This difference was not statistically significant, however, because of the low rate of sustained response (14.6%). IFN proved useful to reduce the progression of chronic hepatitis to cirrhosis [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar] and the occurrence of end-stage complications in cirrhotic patients [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar]. Improved long-term outcome and reduction of liver-related morbidity had been confirmed in biochemical [[24]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 (273) Google Scholar] as well as in biochemical and virological [[23]Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar] sustained responders in the other two studies. The impact of therapy on the development of hepatocellular carcinoma (HCC) is unclear [23Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar, 24Papatheodoridis 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 (273) Google Scholar]. The cumulative analysis of the available data [5Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar, 23Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar, 24Papatheodoridis 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 (273) Google Scholar] indicates that 3/102 of sustained responders (2.9%) developed HCC as compared to 27/311 (8.7%) patients with relapse or no response (P=0.086, χ2 2.954). Therefore, studies in larger cohorts of patients with adequate follow-up and stratification by diagnosis at baseline (chronic hepatitis and cirrhosis) are needed to see whether IFN reduces HCC incidence by slowing the progression of chronic hepatitis to cirrhosis or by interfering with oncogenic mechanisms in cirrhotic patients.5. Factors influencing disease outcome and predicting response to interferonWhen factors influencing disease progression were evaluated by multivariate analysis, older age predicted the worst outcome in treated and untreated patients [5Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar, 24Papatheodoridis 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 (273) Google Scholar]. In addition, when chronic hepatitis and cirrhotic patients were analyzed separately, high levels of viral replication (more frequently observed in those patients with an unremitting biochemical disease profile) and steatosis were associated with progression of chronic hepatitis to cirrhosis. Flares of anti-HBc IgM levels, a hallmark of hepatitis B exacerbation, were associated with progression of cirrhosis to end stage complications [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar].Factors predicting an IFN response are not well defined. In a pilot study, starting therapy at the time of increasing anti-HBc IgM levels was associated with a higher sustained response rate [[25]Lobello S. Lorenzoni U. Vian A. Floreani A. Brunetto M.R. Chiaramonte M. Interferon treatment in hepatitis B surface antigen-positive hepatitis e antibody-positive chronic hepatitis B: role of hepatitis B core antibody IgM titre in patients selection and treatment monitoring.J Viral Hepat. 1998; 5: 61-66Crossref PubMed Scopus (8) Google Scholar]. Recently, a larger study showed a correlation between a high sustained response, high anti-HBc IgM levels and undetectable HBV DNA [[23]Lampertico P. Del Ninno E. Viganò M. Romeo R. Donato M.F. Sablon E. et al.Extended interferon therapy increases hepatitis suppression and reduces liver-related morbidity of hepatitis B e antigen negative chronic active hepatitis B.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar]. In addition, when baseline HBV DNA levels were measured by quantitative PCR, median baseline levels were significantly lower in sustained responders [[22]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 (236) Google Scholar]. These findings suggest that starting treatment immediately after a hepatitis flare may increase the chance of a sustained response. During treatment an early virologic and biochemical response was associated with a 3.45 times higher probability of a sustained response [[22]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 (236) Google Scholar].6. Conclusions and perspectivesIn conclusion, IFN is the standard treatment for anti-HBe-positive chronic hepatitis B. However, optimization of treatment schedules is awaited.Early treatment appears to be indicated in patients with disease profiles associated with faster progression. IFN also appears to reduce end-stage complications in patients with cirrhosis.Pegylated IFN as monotherapy or in combination with antivirals could improve the suppression of HBV replication or may result in a more efficacious control of HBV infection. Future studies should address the kinetics of both viral replication and immune response during combination therapy to assess the antiviral and the immune-modulatory activities of IFN. In addition, it should be investigated whether treatment initiation after flares, for example, could increase the sustained response rate.It is unclear at present whether IFN reduces the hepatocellular carcinoma incidence. To answer this question prospective studies are needed. 1. IntroductionAnti-HBe-positive chronic hepatitis B was first described and characterized in patients of the Mediterranean area, where about 20% of hepatitis B surface antigen (HBsAg) carriers with antibody to hepatitis B 'e' antigen (HBeAg) show detectable serum levels of hepatitis B virus (HBV) DNA by hybridization assays and intrahepatic necro-inflammation [1Bonino F. Hoyer B. Nelson J. Engle R. Verme G. Gerin J. Hepatitis B virus DNA in the sera of HBsAg carriers – a marker of active hepatitis B virus replication in the liver.Hepatology. 1981; 1: 386-391Crossref PubMed Scopus (258) Google Scholar, 2Hadziyannis S.J. Lieberman H.M. Karvountzis G.G. Shafritz D.A. Analysis of liver, nuclear HBcAg, viral replication and hepatitis B virus DNA in liver and serum of HBeAg versus anti-HBe positive carriers of hepatitis B virus.Hepatology. 1983; 3: 656-662Crossref PubMed Scopus (358) Google Scholar]. They are infected with HBV variants with mutations in the pre-core region which hamper HBeAg production. The G to A mutation at nucleotide 1896 of the pre-core region is the most commonly described [3Brunetto M.R. Stemler M. Schoedel F. Will H. Ottobrelli A. Rizetto M. et al.Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis.Ital J Gastroenterol. 1989; 21: 151-154Google Scholar, 4Carman W.F. Jacyna M.R. Hadziyannis S.J. Karayiannis P. McGarvey M.J. Makri A. Thomas H.C. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection.Lancet. 1989; i: 588-590Abstract Scopus (1074) Google Scholar]. Liver disease runs an indolent course for 3–4 decades reaching the stage of histological cirrhosis at a median age of 45 years [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar]; thereafter about 25% of the patients progress to end stage complications within 10 years [[5]Brunetto M.R. Oliveri F. Coco B. Leandro L. Colombatto P. Monti Gorin J. Bonino F. Outcome of anti-HBe positive chronic hepatitis 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 (324) Google Scholar].In recent years several reports suggest a worldwide incidence of HBeAg-negative chronic hepatitis B [6Lok A.S. Heathcote 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 (728) Google Scholar, 7Chan H.L. Leung N.W. Hussain M. Wong M.L. Lok A.S. Hepatitis Be antigen-negative chronic hepatitis B in Hong Kong.Hepatology. 2000; 31: 763-768Crossref PubMed Scopus (183) Google Scholar]. However, further virological and clinical studies are needed to warrant a complete characterization of the disease and to understand whether it shares common features with the anti-HBe-positive chronic hepatitis B observed in Mediterranean patients, who are infected with HBV genotype D, bearing the stop codon at nucleotide 1896 [[8]Hadziyannis S.J. Interferon alpha in HBeAg negative chronic hepatitis B: new data in support of long term efficacy.J Hepatol. 2002; 36: 280-282Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. Because of the progressive course of HBeAg-negative/anti-HBe-positive chronic hepatitis B, alpha-interferon (IFN) treatment was attempted as soon as the drug became available for treatment of chronic HBV infection [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 10Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alpha-2b treatment of HBeAg negative/serum HBV-DNA positive chronic hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar]. Most studies about interferon treatment of anti-HBe-positive chronic hepatitis B were performed in southern Europe [9Brunetto M.R. Oliveri F. Rocca G. Criscuolo D. Chiaberge E. Capalbo M. et al.Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.Hepatology. 1989; 10: 198-202Crossref PubMed Scopus (225) Google Scholar, 10Hadziyannis S. Bramou T. Makris A. Moussoulis G. Zignego L. Papaioannou C. Interferon alpha-2b treatment of HBeAg negative/serum HBV-DNA positive chronic hepatitis type B.J Hepatol. 1990; 11: S133-S136Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 11Pastore G. Santantonio T. Milella N. Monno L. Moschetta R. Pollice L. Anti-HBe positive chronic hepatitis B with HBV-DNA in the serum: response to a six month course of lymphoblastoid interferon.J Hepatol. 1992; 14: 221-225Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Fattovich G. Farci P. Rugge M. Brollo L. Mandes A. Pontisso P. et al.A randomized controlled trial of lymphoblastoid IFN-alpha in patients with chronic hepatitis B lacking HBeAg.Hepatology. 1992; 15: 584-589Crossref PubMed Scopus (170) Google Scholar, 13Brunetto M.R. Oliveri F. Colombatto P. Capalbo M. Barbera C. Bonino F. Treatment of chronic anti-HBe positive hepatitis B with interferon-alpha.J Hepatol. 1995; 22: 42-44PubMed Google Scholar, 14Lampertico P. Del Ninno E. Manzin A. Donato M.R. Rumi M.G. Lunghi G. et al.A randomized, controlled trial of 24-month course of interferon alpha 2b in patients with chronic hepatitis B who had hepatitis virus DNA without hepatitis B e antigen in serum.Hepatology. 1997; 26: 1621-1625Crossref PubMed Scopus (190) Google Scholar] and more recently a few reports had been published from Asia [15Karasawa T. Aizawa Y. Zeniya M. Kuramoto A. Shirasawa T. Toda G. Genetic heterogeneity in the pre-core region of HBV in hepatitis B e antigen-negative chronic hepatitis B patients: spontaneous seroconversion and interferon-induced seroconversion.J Med Virol. 1995; 45: 373-380Crossref PubMed Scopus (16) Google Scholar, 16Guptan R.C. Thakur V. Malhotra V. Sarin S.K. Low dose recombinant interferon therapy in anti-HBe positive chronic hepatitis B in Asian Indians.J Gastroenterol Hepatol. 1998; 13: 675-679Crossref PubMed Scopus (18) Google Scholar, 17Lin C.C. Wu J.C. Chang T.T. Huang Y.H. Wang Y.J. Tsay S.H. et al.Long term evaluation of recombinant interferon alpha 2b in the treatment of patients with hepatitis B e antigen negative chronic hepatitis B in Taiwan.J Viral Hepat. 2001; 8: 438-446Crossref PubMed Scopus (18) Google Scholar].
Referência(s)