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INTERFERON ALPHA FOR HBeAg POSITIVE CHRONIC HEPATITIS B: SYSTEMATIC REVIEW

Antonio Craxì, Danilo Di Bona, Calogero Cammà, Cattedra di Gastroenterologia, Istituto di Clinica Medica, University of Palermo, Italy and ISMEDA-CNR, Palermo, Italy

BACKGROUND

Hepatitis B virus (HBV) infection, together with hepatitis C and alcohol abuse, is among the leading causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide (1,2). It thus represents a relevant cause of morbidity and mortality (3-5), and induces substantial direct and indirect social costs. Effective treatment of HBV-related conditions would significantly reduce the global burden of chronic liver disease.

a interferon has been the mainstay of therapy for chronic hepatitis B since the early 80’s. Meta-analyses (6-9) of randomized clinical trials (RCTs) conclusively prove its effectiveness in normalizing alanine aminotransferases (ALT) and clearing HBeAg and HBV-DNA from blood in 25-40% of patients treated. No definite data are available from these reviews on improvements of liver histology. Standardized response criteria have been set by the use of these “surrogate” markers of cure (10, 11), on the ground of clinical and biological plausibility. “True” disease endpoints (i.e. progression to cirrhosis, to hepatocellular carcinoma and death) cannot usually be assessed in short-term trials of IFN due to the slow natural course of chronic hepatitis B. A major issue of concern is the fact that RCTs of IFN for chronic hepatitis B have been mostly performed in patients without advanced fibrosis or cirrhosis. The transferability of results to the whole spectrum of subjects with chronic liver disease due to HBV is hence questionable.

Since IFN is today in widespread use, in alternative to lamivudine, as the first-line therapy for chronic hepatitis B (1, 2, 10, 11), no additional prospective cohort studies on the course of untreated disease will be feasible. Long-term retrospective or prospective studies to evaluate the benefits of IFN therapy on true endpoints, i.e. prevention of cirrhosis, liver failure, HCC and death, will also difficult to perform due to the prolonged and slow course of the disease.

The aim of this meta-analysis is to review and update the available evidence in order to estimate the effectiveness of alfa-IFN in chronic on “surrogate markers” of response and its long-term benefit.

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MATERIALS AND METHODS

The meta-analysis was performed according to the criteria set by Lau et al. (12). The primary source of studies reviewed was the MEDLINE data-base (1985-2002) (key words: chronic hepatitis, hepatitis B, interferon alpha, RCT, randomized, clinical trial, long-term study). Reference lists of all available review articles and primary studies were also checked in order to identify other studies not found by computer search. Potentially relevant papers were initially classified into two subsets (1: RCTs; 2: cohort studies).

Studies allocated to subset 1 were included in the meta-analysis if they were truly randomized and had a crossover or a parallel design comparing different schedules of treatment to a control group receiving no treatment; if they had been published in English as full length papers; if they included adult patient (older than 18 years) with biopsy-proven chronic hepatitis B with or without cirrhosis, and with abnormal aminotransferases levels for at least 3 months, without evidence of HDV superinfection and HIV co-infection or of HCV coinfection (since 1990 beyond); if they had used a interferon (recombinant a2a or a2b, human lymphoblastoid aN1 or human leucocyte derived aN3) in naïve patients. Studies were excluded if they used IFN in combination with other antiviral or immunomodulatory agents (except steroid induction); if they had not been published in English or as a preliminary report subsequently published as final paper; if they randomized only primary responders, or pooled randomized with nonrandomized patients. Duplicate reports, as well as studies reported solely in abstracts, letters and preliminary reports were also excluded. Abstracts were excluded because of the potential risk for duplication of the results and a substantial and uninterpretable bias could be introduced. 24 RCTs (13-35) from subset 1 were included in the meta-analysis (Table 1). Main sociodemographic features of patients and the schedules of treatment were analysed in order to verify their actual comparability. Abstraction of data was independently performed by two readers (D. D. B. and C.C.), who compared results and then achieved consensus.

The evaluation of therapeutic efficacy was performed by an “intention to treat” strategy. Treatment effectiveness was assessed on “surrogate markers” of response such as stable normalization of ALT, sustained loss of HBV-DNA, clearance of HBeAg and loss of HBsAg at 6-12 months of follow-up. In order to obtain an overall measure of treatment efficacy, we calculated the overall risk difference and its 95% confidence interval (95% CI) between frequencies of events in both treated and untreated patients, according to the method of DerSimonian and Laird (36). If the confidence intervals between treated and untreated patients do not overlap, the results are statistically significant. The assumption of heterogeneity implied by the use of random effect models is plausible because of the differences in eligibility criteria, baseline characteristic of patients, treatment modalities and outcome measures. In addition to within-study variance, the random-effects model considers heterogeneity among studies. The overall risk difference was tested for significance using a Mantel-Haenszel c2 test (37). We excluded each study at a time to ensure that no single trial would be solely responsible for the significance of any result (so-called robust analysis). All our analyses were computed using a program (courtesy of Professor Joseph Lau, Tufts University, USA). The number of patients needing treatment (NNT) to prevent one event, deriving from the inverse of the risk difference, was given as a measure of treatment effect (38, 39).

Subset 2 included 12 cohort studies (40-51) reporting data on loss of HBsAg, disease decompensation (i.e. ascites, jaundice, encephalopathy, portal hypertensive bleeding, and liver transplantation), development of HCC and death (Table 2). The cohorts of patients in this subset were reviewed to assess the overall likelihood of loss of HBsAg, disease decompensation, development of HCC and death by the Confidence Profile Method (52) using the Fast*Pro software (53). This is a bayesian method for combining evidence (“meta-analysis”) to estimate a probability distribution for a parameter. The result is a posterior distribution for the parameters of interest.

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EVALUATION OF AVAILABLE EVIDENCE

When assessing treatment options for chronic hepatitis B, some important issues must be addressed.

1. What effects has IFN therapy of chronic hepatitis B on “surrogate” markers of response?

The 24 RCTs included a total of 1299 patients, 444 not receiving any active treatment. Overall, IFN treatment had a favourable, statistically significant effect on all 4 end points in comparison to no treatment. Meta-analysis showed the following risk differences, all in favour of IFN:

  • persistent ALT normalization (fig. 1): + 26.2% (95% CI 18.3%-34.0%, p < 0.00001); NNT 3.8
  • clearance of HBeAg (fig. 2): + 24.3% (95% CI 8.3%-30.4%, p < 0.00001); NNT 4.1
  • sustained loss of HBV-DNA (fig. 3): + 23.4% (95% CI 17.9%-28.8%, p < 0.00001); NNT 4.3
  • clearance of HBsAg (fig. 4): + 5.6% (95% CI 3.5%-7.6%, p < 0.00001); NNT 18.

Few RCTs were planned to assess the effects of IFN on liver histology. In these RCTs (19, 21, 22, 27) , an histologic improvement was observed. However, the histologic approach to the evaluation of IFN response in chronic hepatitis B has several important limitations and sources of bias:

  • the histological picture of chronic hepatitis B is mild to moderate in most cases. Therefore, the relatively small change induced by IFN can be difficult to assess with accuracy and reliability
  • many factors might influence the interpretation of histology: inconsistency in the definition of pathological features, technical processing of the specimens, sampling variation
  • none of the trials reported a preliminary assessment of the intra/interobserver variations inherent to the semiquantitative evaluation of histological lesions. This can be a particularly important source of bias in cooperative studies, or in studies where the biopsy specimens were observed by different pathologists
  • the biopsy specimens reflect just one time-point in a long-term dynamic process, developing at variable speed.

Taking these limitations into account, we regard the IFN-induced histologic changes reported as an approximate, although important, indication of treatment effect, far from being a precise quantitative estimate. Significant histological improvement was usually observed among patients who normalized ALT and cleared serum HBV-DNA, but complete healing of liver lesions was only seen among subjects rebiopsied after many years from seroconversion (41, 47, 51, 54, 55). Many of these had also lost serum HBsAg.

An alternative approach to chronic HBV infection is based on the induction of a brief period of immunosuppression by steroids (56-57), then a withdrawal to provoke an abrupt ALT elevation due to the host immune reconstitution, and a subsequent decline of HBV-DNA. IFN administration is then started 2-4 weeks after stopping steroids. The sequential schedule has been studied in some RCTs and their results have been pooled in a meta-analysis (58). The overall rate of HBeAg loss in 7 RCTs was comparable between the prednisone-IFN and IFN monotherapy groups (41% vs. 35%, OR 1.20; 95% CI, 0.8-1.7). Similar results were observed for sustained ALT normalization (44.5% vs. 38%; OR, 1.19; 95% CI, 0.6-2.0). Analysis of HBeAg clearance stratifying the patients according to pre-treatment ALT levels showed that prednisone-IFN treated cases had a significantly higher proportion of clearance (47.9% vs. 18.4%, p < 0.01) only when ALT were low before starting therapy. Even if there could be an advantage in pre-treatment with steroids of this subset of patients, this must be balanced against the risk of flare of liver disease after steroid withdrawal. A severe, often fatal “seroconversion hepatitis” has been in fact reported in subjects with pre-existing cirrhosis (59,60).

The amount of IFN used was clearly an important point. Subjects receiving a total dose of < 200 MU had a 1.37 odds ratio (OR, 95% CI 0.95-1.98) of HBeAg clearance above controls, while those who received >200 MU had an OR of 2.05 (95% CI 1.5-2.78) (61, 62).

Overall experience suggests that the optimal cost-effectiveness ratio on surrogate end-points is reached by treating HBeAg positive patients with 9-10 MU IFN tiw for 4 to 6 months. Predictive factors of a favourable response (8, 9, 28, 29, 25, 63, 64, 56) are:

  • low serum HBV-DNA (< 100 pg/ml)
  • low amounts of HBcAg in the liver
  • high levels of ALT
  • high HAI grade at biopsy
  • infection in the adult age and/or a history of acute hepatitis
  • non-Asian ethnic origin.

2. What are the long-term benefits of IFN treatment for chronic hepatitis B?

The clinical course and outcome of patients enrolled in studies in subset 2 is shown in Table 2. The 12 studies (11 prospective and 1 retrospective) included a total of 1975 patients, 1210 not receiving active treatment. Length of follow-up ranged from 2.1 to 8.9 years (mean 6.1).

Meta-analysis showed the following distribution of probabilities:

  • Loss of HBsAg (fig. 5): treated 11.4% (95% CI 9.1%-13.7%), controls 2.6% (95% CI 1.8%-3.4%); RD 8.8; NNT 11.4;
  • Disease decompensation (fig. 6): treated 9.9% (95% CI 7.7%-12.1%), controls 13.3 % (95% CI 10.1%-16.4%);
  • Development of HCC (fig. 7): treated 1.9% (95% CI 0.8%-3.0%), controls 3.16% (95% CI 1.8%-4.5%);
  • Liver-related death (fig. 8): treated 4.9% (95% CI 3.3%-6.5%), controls 8.7 % (95% CI 6.1%-11.3%);

The rate of clearance of HBsAg in untreated patients was generally low, and a statistically significant advantage was observed for IFN-treated patients. HBsAg clearance was seen mostly among subjects infected as adults, among those with more active disease at onset, and on average 2 to 4 years after HBeAg/HBV-DNA clearance.

Data on the protective effects of IFN against development of HCC are less encouraging: studies show a strong heterogeneity, which makes the reliability of conclusions of individual studies questionable. On this basis, there is no firm ground to recommend IFN to prevent HCC in HBV-related cirrhosis. It has been suggested from retrospective and prospective studies that IFN treatment might have a protective effect against HCC development in patients with chronic HBV infection independently from viral clearance or resolution of necroinflammation (65). Obviously, IFN-induced viral clearance remains a major outcome for patients with HBV-related chronic liver disease and indirectly reduces the risk of cancer. Some cases of HBV-associated HCC are observed in the absence of cirrhosis (mostly young males with perinatal infection), and have a very aggressive clinical course. No information on the effectiveness of IFN in preventing this subtype of HCC can be gathered from the available studies.

All the data on disease events (i.e liver decompensation and HCC) and on liver-related mortality coming from studies with prolonged follow-up must be considered with caution, since possible biases can originate errors in estimates through:

  • data collected from both prospective and retrospective studies conducted in tertiary care centres with limited generalizability
  • lack of randomization reducing the internal and the external validity of the studies
  • heterogeneity of patients enrolled, both in respect of clinical and demographic features and of possible co-factors
  • slow and prolonged course of the disease not allowing an inception cohort;
  • few clinically relevant events, relatively small sample size and duration of follow-up less than 8-10 years
  • high mortality from non-hepatic causes
  • selection and increased surveillance for cases with more severe disease and unfavourable course
  • progressive shift over the years of the global spectrum of the disease due to intervening factors (e.g. new diagnostic tests and screening programs; new treatments).

Overall, IFN treatment had a favourable, statistically significant effect only on loss of HBsAg in comparison to no treatment. In contrast, IFN treatment has failed to show statistically significant effects on disease decompensation, development of HCC and liver-related death, albeit favorable trends for all these points are observed.

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CONCLUSIONS

The available evidence from RCTs or cohort studies of alfa-IFN treatment for chronic HbeAg positive hepatitis B is sufficient to conclude that:

  • IFN therapy significantly improve clearance of HbeAg (NNT 4.1) and loss of HBV-DNA (NNT 4.3) compared with no treatment
  • The rate of clearance of HBsAg is significantly higher in the IFN treated than in untreated patients (NNT 17.8 ). The magnitude of the overall effect is small but clinically relevant
  • There is no clear evidence of a protective effect of IFN against HCC
  • IFN treatment could help to delay or prevent disease decompensation and liver-related deaths, but further large-scale, multicenter longitudinal studies are needed to prove this point.

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REFERENCES

  1. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34(6):1225-41.
  2. Lok AS, Heathcote J, Hoofnagle JH. Management of hepatitis B: 2000—Summary of a workshop. Gastroenterology 2001; 120 (7):1828-p1853.
  3. Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988, 8: 493-6.
  4. De Jongh FE, Janssen HLA, De Man RA, Hop WCJ, Schalm SW, Van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992,103:1630-5.
  5. Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, Christensen E et al. Occurrence of hepatocellular carcinoma and decompensation in western european patients with cirrhosis type B. Hepatology 1995,21:77-82.
  6. Almasio P, Cammà C, Giunta M, Craxì A. Treatment of chronic hepatitis B: an evidence-based review. In: “Evidence-based Gastroenterology and Hepatology”. JWD McDonald, A Burroughs, BG Feagan eds, BMJ publ, London, 1999, pp. 305-321.
  7. Wong JB, Koff RS, Tiné F, Pauker SG. Cost-effectiveness of interferon-alpha 2b treatment for hepatitis B e antigen-positive chronic hepatitis B. Ann Intern Med 1995,122:664-75.
  8. Tiné F, Liberati A, Craxì A, Almasio P and Pagliaro L. Interferon treatment in patients with chronic hepatitis B: A meta-analysis of the published literature. J Hepatol 1993,18:154-162.
  9. Wong DK, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993, 119:312-23.
  10. Evans AA. and London WT. Interferon for chronic hepatitis B. Annals of Internal Medicine 1996;124:276.
  11. Carithers RL,Jr. Effect of interferon on hepatitis B. Lancet 1998; 351:157.
  12. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997, 127:820-826.
  13. Alexander GJ, Brahm J, Fagan EA, Smith HM, Daniels HM, Eddleston AL, Williams R. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet, 1987; 8550: 66-9.
  14. Carreño V, Porres JC, Mora I, Gutiez J, Quiroga JA, Ramón y Cajal S, Oliva H, Compernolle C, Bartolomé J. A controlled study of treatment with recombinant interferon alpha in chronic hepatitis B virus infection: induction and maintenance schedules. Antiviral Res, 1987; 3: 125-37.
  15. McDonald JA, Caruso L, Karayiannis P, Scully LJ, Harris JR, Forster GE, Thomas HC. Diminished responsiveness of male homosexual chronic hepatitis B virus carriers with HTLV-III antibodies to recombinant alpha-interferon. Hepatology 1987;7(4):719-23.
  16. Hoofnagle JH, Peters M, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Hallahan C, Park Y, Meschievitz C, Jones EA. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology, 1988; 95: 1318-25.
  17. Lok AS, Lai CL, Wu PC, Leung EK. Long-term follow-up in a randomised controlled trial of recombinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection. Lancet, 1988 2: 298-302.
  18. Porres JC, Carreño V, Mora I, Gutiez J, Moreno A, Cajal SR, Marron JA, Bartolomé J. Different doses of recombinant alpha interferon in the treatment of chronic hepatitis B patients without antibodies against the human immunodeficiency virus. Hepatogastroenterology, 1988 6: 300-3.
  19. Pastore G; Santantonio T; Monno L; Milella M; Luchena N; Angarano G. Permanent inhibition of viral replication induced by low dosage of human leukocyte interferon in patients with chronic hepatitis B. Hepatogastroenterology, 1988 35:2: 57-61.
  20. Brook MG, McDonald JA, Karayiannis P, Caruso L, Forster G, Harris JR, Thomas HC. Randomised controlled trial of interferon alfa 2A (rbe) (Roferon-A) for the treatment of chronic hepatitis B virus (HBV) infection: factors that influence response. Gut, 1989 Aug, 30:1116-22.
  21. Brook MG, Chan G, Yap I, Karayannis P, Lever AML, Jacyna M, Main J, Thomas HC. Randomised controlled trial of lymphoblastoid IFN alfa in Europid men with chronic hepatitis B virus infection. BMJ 1989; 299: 652-656.
  22. Saracco G, Mazzella G, Rosina F, Cancellieri C, Lattore V, Raise E, Rocca G, Giorda L, Verme G, Gasbarrini G. A controlled trial of human lymphoblastoid interferon in chronic hepatitis B in Italy. Hepatology, 1989; 10: 336-41.
  23. Fattovich G; Brollo L; Boscaro S; Pontisso P; Giustina G; Criscuolo D; Maladorno D; Alberti A; Realdi G; Ruol A. Long-term effect of low dose recombinant interferon therapy in patients with chronic hepatitis B. J Hepatol, 1989 Nov, 9:3, 331-7
  24. Müller R, Baumgarten R, Markus R, Schulz M, Wittenberg H, Hintsche-Kilger B, Fengler JD, Von Wussow P, Meisel H, Klein, H. Treatment of chronic hepatitis B with interferon alfa-2b. J Hepatol, 1990; 11 Suppl 1:, S137-40.
  25. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC Jr, Lindsay K, Payne J, Dienstag JL, O'Brien C, Tamburro C, Jacobson IM. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med, 1990; 323:295-301.
  26. Williams SJ, Craig PI, Cooksley WG, Bye WA, Bilous M, Grierson JM, Nightingale BN, Burnett L, Hensley WJ, Batey RG. Randomised controlled trial of recombinant human interferon -alpha A for chronic active hepatitis B. Aust N Z J Med, 1990 20: 9-19.
  27. Waked I, Amin M, Abd el Fattah S, Osman LM, Sabbour MS. Experience with interferon in chronic hepatitis B in Egypt. J Chemother, 1990; 2: 310-8.
  28. Realdi G, Fattovich G, Pastore G, Caredda F, Noventa F, Santantonio T, Moroni M, Criscuolo D, Maladorno D, Rugge M. Problems in the management of chronic hepatitis B with interferon: experience in a randomized, multicentre study. J Hepatol, 1990, 11 Suppl 1: S129-32.
  29. Lok AS, Wu PC, Lai CL, Lau JY, Leung EK, Wong LS, Ma OC, Lauder IJ, Ng CP, Chung HT. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology, 1992 Jun, 102:6, 2091-7.
  30. Di Bisceglie AM, Fong TL, Fried MW, Swain MG, Baker B, Korenman J, Bergasa NV, Waggoner JG, Park Y, Hoofnagle JH. A randomized, controlled trial of recombinant alpha-interferon therapy for chronic hepatitis B. Am J Gastroenterol, 1993; 88:1887-92.
  31. Bayraktar Y, Uzunalimoglu B, Arslan S, Koseoglu T, Kayhan B, Telatar H. Effects of recombinant alpha interferon on chronic active hepatitis B: preliminary results. Gut 1993;34(2 Suppl):S101.
  32. Müller R, Baumgarten R, Markus R, Schulz M, Wittenberg H, Hintsche-Kilger B, Fengler JD, von Wussow P, Meisel H, Klein H. Low dose alpha interferon treatment in chronic hepatitis B virus infection. Gut, 1993; 34: Suppl, S97-8.
  33. Wong DK, Yim C, Naylor CD, Chen E, Sherman M, Vas S, Wanless IR, Read S, Li H, Heathcote EJ. Interferon alfa treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population. Gastroenterology, 1995; 108: 165-71.
  34. Sarin SK, Guptan RC, Thakur V, Malhotra S, Malhotra V, Banerjee K, Khandekar P. Efficacy of low-dose alpha interferon therapy in HBV-related chronic liver disease in Asian Indians: a randomized controlled trial. J Hepatol, 1996 24: 391-6.
  35. Janssen HL, Gerken G, Carreno V, Marcellin P, Naoumov NV, Craxì A, Ring-Larsen H, Kitis G, van Hattum J, de Vries RA, Michielsen PP, ten Kate FJ, Hop WC, Heijtink RA, Honkoop P, Schalm SW. Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology. 1999 Jul;30(1):238-43.
  36. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Tials. 1986;7:177-88.
  37. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48.
  38. Laupacis A, Sackett DL, Roberts RS. An assesment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988; 318:1728-33
  39. Laupacis A, Naylor CD, Sackett DL. How should the results of clinical trials be presented to clinicians? [Editorial]. ACP J Club. 1992; 116(Suppl 3)A12-14.
  40. Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, Haussinger D. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996,334:1422-7.
  41. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology. 1999 Mar;29(3):971-5.
  42. Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm SW. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology. 1997 Nov;26(5):1338-42.
  43. Di Marco V, Lo Iacono O, Camma C, Vaccaro A, Giunta M, Martorana G, Fuschi P, Almasio PL, Craxì A. The long-term course of chronic hepatitis B. Hepatology. 1999 Jul;30(1):257-64.
  44. Yuen MF, Hui CK, Cheng CC, Wu CH, Lai YP, Lai CL. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology. 2001 Jul;34(1):139-45.
  45. Chen DK, Yim C, O'Rourke K, Krajden M, Wong DK, Heathcote EJ. Long-term follow-up of a randomized trial of interferon therapy for chronic hepatitis B in a predominantly homosexual male population. J Hepatol. 1999 Apr;30(4):557-63.
  46. Evans AA, Fine M, London WT. Spontaneous seroconversion in hepatitis B e antigen-positive chronic hepatitis B: implications for interferon therapy. J Infect Dis. 1997 Oct;176(4):845-50.
  47. Korenman J, Baker B, Waggoner J, Everhart JE, Di Bisceglie AM, Hoofnagle JH. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med. 1991 Apr 15;114(8):629-34.
  48. Lok AS, Chung HT, Liu VW, Ma OC. Long-term follow-up of chronic hepatitis B patients treated with interferon alfa. Gastroenterology. 1993 Dec;105(6):1833-8.
  49. Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, Hoofnagle JH. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology. 1997 Nov;113(5):1660-7.
  50. Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, Schalm SW. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut. 2000 Mar;46(3):420-6.
  51. Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, Liaw YF. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002 Jun;35(6):1522-7.
  52. Eddy MD, Hasselblad V, Shacter R. An introduction to a bayesian method for meta-analysis: the confidence profile method. Med Decis Making 1990; 10:15-23.
  53. Eddy MD, Hasselblad V, Shacter R. Meta-analysis by the confidence profile method. The statistical synthesis of evidence. Appendix B. Fast*Pro demo: a demonstration of teh confidence profile method with an attached disk. Boston: Academic Press, 1992; 371-419.
  54. Lok ASF, Ma OCK and Lau JYN. Interferon alfa therapy in patients with chronic hepatitis B virus infection. Effects on hepatitis B virus DNA in the liver. Gastroenterology 1991;100:756-761.
  55. Di Bisceglie AM. Long-term outcome of interferon-alpha therapy for chronic hepatitis B. J.Hepatol. 1995; 22 Suppl. 1:65-67.
  56. Krogsgaard K. Does corticosteroid pretreatment enhance the effect of alfa interferon treatment in chronic hepatitis B. J.Hepatol. 1994; 20:159-162.
  57. Krogsgaard K, Marcellin P, Trepo C, Berthelot P, Sanchez-Tapias JM, Bassendine M, Tran A, Ouzan D, Ring-Larsen H, Lindberg J, Enriquez J, Benhamou JP, Bindslev N, Bertet S, Boyer N, Brind A, Civeira MP, Housset C, Lund-Laursen A, Mas A, Pol S, Prieto J, Quedens J and Rampal P. Prednisolone withdrawal therapy enhances the effect of human lymphoblastoid interferon in chronic hepatitis B. Journal of Hepatology 1996; 25:803-813.
  58. Cohard M, Poynard T, Mathurin P, Zarski JP. Prednisone-interferon combination in the treatment of chronic hepatitis B: direct and indirect metanalysis. Hepatology 1994; 20: 1390-8.
  59. Perrillo R, Tamburro C, Regenstein F, Balart L, Bodenheimer H, Silva M, Schiff E, Bodicky C, Miller B, Denham C, Brodeur C, Roach K and Albrecht J. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 1995; 109:908-916.
  60. Perrillo RP. Chronic hepatitis B: Problem patients (including patients with decompensated disease). J.Hepatol. 1995; 22 Suppl. 1:45-48.
  61. Krogsgaard K, Bindslev N, Christensen E, Craxì A, Schlichting P, Schalm S, Carreno V, Trepo C, Gerken G, Thomas HC, Andersen PK, Ring-Larsen H and EUROHEP, The treatment effect of alpha interferon in chronic hepatitis B is independent of pre-treatment variables. Results based on individual patient data from 10 clinical controlled trials. J.Hepatol. 1994; 21:646-655.
  62. Krogsgaard K, Christensen E, Bindslev N, Schalm S, Andersen PK, Ring-Larsen H, Carreno V, Craxì A, Gerken G, Schlichting P, Thomas HC and Trepo C. Relation between treatment efficacy and cumulative dose of alpha interferon in chronic hepatitis B. Journal of Hepatology 1996; 25:795-802.
  63. Thomas HC, Karayiannis P and Brook G. Treatment of hepatitis B virus infection with interferon. Factors predicting response to interferon. J.Hepatol. 1991; 13 Suppl. 1:S4-S7.
  64. Carreño V, Castillo I, Molina J, Porres JC and Bartolomé J. Long-term follow-up of hepatitis B chronic carriers who responded to interferon therapy. J.Hepatol. 1992;15:102-106.
  65. Benvegnù L, Chemello L, Noventa F, Fattovich G, Pontisso P and Alberti A. Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis. Cancer 1998; 83:901-909.

Acknowledgment: we thank Pietro Lampertico, MD (Angela Maria e Antonio Migliavacca Center for Liver Disease, Institute of Internal Medicine, IRCCS Ospedale Maggiore, Milan, Italy) for his help.

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