Chronic Hepatitis B: A Critical Appraisal of Current Approaches to Therapy
2006; Elsevier BV; Volume: 4; Issue: 2 Linguagem: Inglês
10.1016/s1542-3565(05)00983-3
ISSN1542-7714
AutoresRobert P. Perrillo, Robert G. Gish, Marion G. Peters, Emmet B. Keeffe, A. Albertí, Marı́a Buti, W. Graham E. Cooksley, Michael Fried, Stephanos J. Hadziyannis, Yun‐Fan Liaw,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoBackground & Aims: Treatment of chronic hepatitis B (CHB) involves a number of complex and controversial issues. Expert opinions may differ from those of practicing hepatologists and gastroenterologists. We aimed to explore this issue further after a critical review of the literature. Methods: A panel of 14 international experts graded the strength of evidence for 16 statements addressing 3 content areas: patient selection, therapeutic end points, and treatment options. Available data relating to the statements were reviewed critically in 3 small work groups. After discussion of each statement with the entire panel, the experts voted anonymously to accept or reject statements based on the strength of evidence and their experience. A total of 241 members of the American Association for the Study of Liver Diseases (AASLD) responded to the same statements and their responses were compared with those of the experts. A discordant response was defined as a difference of more than 20% in any of the 5 graded levels of response (accept or reject) between the 2 groups. Results: With the exception of 2 statements, the experts’ responses were relatively uniform. However, the responses of the AASLD members were discordant from the experts in 12 statements, spanning all 3 content areas. Conclusions: Several areas of disagreement on the management of CHB exist between experts and AASLD members. Our results indicate a potential knowledge gap among practicing hepatologists. Better educational efforts are needed to meet the challenge of managing this complex disorder in which even expert opinion occasionally may disagree. Background & Aims: Treatment of chronic hepatitis B (CHB) involves a number of complex and controversial issues. Expert opinions may differ from those of practicing hepatologists and gastroenterologists. We aimed to explore this issue further after a critical review of the literature. Methods: A panel of 14 international experts graded the strength of evidence for 16 statements addressing 3 content areas: patient selection, therapeutic end points, and treatment options. Available data relating to the statements were reviewed critically in 3 small work groups. After discussion of each statement with the entire panel, the experts voted anonymously to accept or reject statements based on the strength of evidence and their experience. A total of 241 members of the American Association for the Study of Liver Diseases (AASLD) responded to the same statements and their responses were compared with those of the experts. A discordant response was defined as a difference of more than 20% in any of the 5 graded levels of response (accept or reject) between the 2 groups. Results: With the exception of 2 statements, the experts’ responses were relatively uniform. However, the responses of the AASLD members were discordant from the experts in 12 statements, spanning all 3 content areas. Conclusions: Several areas of disagreement on the management of CHB exist between experts and AASLD members. Our results indicate a potential knowledge gap among practicing hepatologists. Better educational efforts are needed to meet the challenge of managing this complex disorder in which even expert opinion occasionally may disagree. Chronic hepatitis B (CHB) is a potentially serious illness that can result in cirrhosis, liver failure, and hepatocellular carcinoma. Significant medical advances in the treatment of this disorder have occurred in the past decade. Unfortunately, treatment involves a number of complex issues, including patient variability in the immunologic response to hepatitis B virus (HBV), nonstandardized testing for serum HBV DNA, and treatment options with different mechanisms of action.1Perrillo R.P. Overview of treatment of hepatitis B key approaches and clinical challenges.Semin Liver Dis. 2004; 24: 23-29Crossref PubMed Scopus (31) Google Scholar Nucleos(t)ide analogue and interferon (IFN)–based strategies for treating CHB have been evolving over the past several years. The complexities involved in the management of hepatitis B possibly have contributed to a knowledge gap among treating physicians. Three sets of international guidelines have been published to elucidate optimal treatment strategies.2Lok A.S. McMahon B.J. Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD)Chronic hepatitis B update of recommendations.Hepatology. 2004; 39: 857-861Crossref PubMed Scopus (491) Google Scholar, 3de Franchis R. Hadengue A. Lau G. et al.EASL JuryEASL International Consensus Conference on Hepatitis B.J Hepatol. 2003; 39 (September 13-14, 2002 Geneva, Switzerland. Consensus statement (long version)): S3-S25PubMed Google Scholar, 4Liaw Y.-F. Leung N. Guan R. et al.Asian-Pacific consensus statement on the management of chronic hepatitis B a 2005 update.Liver Int. 2005; 25: 472-489Crossref PubMed Scopus (327) Google Scholar Although these guidelines have undergone periodic modifications to keep pace with noteworthy new findings, there are several areas that remain controversial. Furthermore, as evidence-based instruments, the guidelines cannot address all individual patient circumstances. Given the controversies involving the treatment of CHB, a meeting of an international panel of experts was convened to critically evaluate the published literature on treatment and provide an in-depth analysis of clinical issues associated with this disorder. Rather than proposing new treatment guidelines, the meeting assessed the evidence-based opinions of experts regarding patient selection criteria, the clinical significance of certain therapeutic end points, and the overall management of this disorder. The primary goal of the meeting was to provide practicing physicians with a current and critical appraisal of the relative uniformity or divergence of expert opinion on issues that fell outside, and within, the established treatment guidelines. A secondary objective was to compare the responses of the expert panel with those of the members of the American Association for the Study of Liver Diseases (AASLD). The international expert panel included 14 investigators from Australia, Greece, Italy, Spain, Taiwan, the United Kingdom, and the United States. An additional investigator from the Netherlands provided background materials for a workshop statement but was unable to take part in the meeting. Each of the 14 expert panel members had extensive basic or clinical research background in the management of CHB. Their primary fields of study included immunopathogenesis, molecular virology, and antiviral therapy. The content areas included patient selection, therapeutic end points, and treatment options. Workshops in each of these areas were a critical part of the meeting. Before the meeting, the chairman (R.P.) and the 3 workshop leaders (E.K., M.P., and R.G.) developed 16 clinically relevant statements that formed the basis for workshop data review and discussions. Each workshop focused on 5 or 6 statements. The statements related to patient-selection raised issues on the appropriateness of treating patients who fell outside the current guidelines. Statements dealing with therapeutic end points were focused on their clinical significance. The statements regarding treatment options were designed to assess the optimal approaches for different types of patients. The meeting was conducted in 3 phases. During the first phase, the 3 workshop leaders provided state-of-the-art overviews for their assigned areas in a general session of all participants, serving as a framework for subsequent discussions. In the second phase, 3 simultaneously conducted workshops, composed of a leader and 3 or 4 content experts, served as a forum for each individual to present the evidence for 1 or 2 of the statements. When the data were presented, primary attention was given to study methodology, the number of patients enrolled, and outcome events. After each statement, workshop members discussed the evidence presented, graded the strength of the evidence, and assigned the statement a consensus numeric grade for “Nature of the Evidence” and “Grade of Recommendation” (Table 1). The level of acceptance or rejection for a statement was based on group consensus after review of the evidence and open discussion. There were no predefined criteria for distinguishing fair, good, or poor evidence. In the third phase, all 14 members of the panel reassembled, reviewed the workshop summaries, and discussed each statement further. After each discussion, all participants anonymously voted for their level of support for the statements (Table 2).Table 1Grading Scheme for WorkshopsCategoryNature of evidenceI Evidence obtained from at least 1 well-designed, randomized, controlled trialII Evidence obtained from well-designed cohort or case-controlled studiesIII Evidence obtained from case series, case reports, or flawed, clinical trialsIV Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committeesV Insufficient evidence to form an opinionLevel of workshop group support for statementA There is good evidence to support the statementB There is fair evidence to support the statementC There is poor evidence to support the statement, but recommendations may be made on other groundsD There is fair evidence to reject the statementE There is good evidence to reject the statementGrading scheme according to Sharma et al.78Sharma P. McQuaid K. Dent J. et al.A critical review of the diagnosis and management of Barrett’s esophagus the AGA Chicago Workshop.Gastroenterology. 2004; 127: 310-330Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar Open table in a new tab Table 2Grading Scheme for General Session Level of Support for Each StatementAAccept recommendation completelyBAccept recommendation with some reservationsCAccept recommendation with major reservationsDReject recommendation with reservationsEReject recommendation completelyGrading scheme according to Sharma et al.78Sharma P. McQuaid K. Dent J. et al.A critical review of the diagnosis and management of Barrett’s esophagus the AGA Chicago Workshop.Gastroenterology. 2004; 127: 310-330Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar Open table in a new tab Grading scheme according to Sharma et al.78Sharma P. McQuaid K. Dent J. et al.A critical review of the diagnosis and management of Barrett’s esophagus the AGA Chicago Workshop.Gastroenterology. 2004; 127: 310-330Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar Grading scheme according to Sharma et al.78Sharma P. McQuaid K. Dent J. et al.A critical review of the diagnosis and management of Barrett’s esophagus the AGA Chicago Workshop.Gastroenterology. 2004; 127: 310-330Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar Before the meeting, the same statements and response options outlined in Table 2 were sent electronically to 1800 AASLD members. In addition, they were asked the following 4 questions: how many patients in their practice had liver disease; of those with liver disease, what percentage were cases of hepatitis B; how many new cases of hepatitis B had they seen in the past 6 months; and, of this number, what percentage had they treated? This article outlines the meeting proceedings, including the results of the general session voting and the comparison of responses from the experts and AASLD members. Responses to the 16 statements were returned by 241 AASLD members (13%) who received the survey. A total of 185 members not only completed the survey but provided requested information on their degrees and countries of practice (Table 3). As seen in Table 4, the AASLD members who responded to the survey predominantly were hepatologists and gastroenterologists who routinely cared for patients with CHB.Table 3Composition of AASLD Membership RespondentsGeographic region of practiceNumber (% of total)Physician number, %aTwenty-six held additional PhD degrees.NonphysicianbIncludes PhD (1), degree in pharmacy (1), osteopathic medicine (1), nurse practitioner (8), or physician assistant (4).United States95 (51)80 (84)15 (16)Europe36 (19)34 (100)0Asia, Australia26 (14)26 (100)0Central, South America13 (7)13 (100)0Middle East11 (6)11 (100)0Canada4 (2)4 (100)0NOTE. Based on 185 of 241 respondents who provided information on locations and degrees.a Twenty-six held additional PhD degrees.b Includes PhD (1), degree in pharmacy (1), osteopathic medicine (1), nurse practitioner (8), or physician assistant (4). Open table in a new tab Table 4AASLD Membership Experience With Hepatitis BPatients with liver disease in practiceChronic hepatitis B/liver diseaseNumber of hepatitis B patients in previous 6 moPercentage of hepatitis B patients treatedCategoryResponseCategoryResponseCategoryResponseCategoryResponse0–24%11.8%0–24%78.5%0–1024.9%aPercentage answering yes.0–24%28.7%25–49%14.8%25–49%13.5%11–2027.9%25–49%31.2%50–74%20.3%50–74%4.6%21–3013.9%50–74%19.4%75–100%52%75–100%2.1%31–5013.5%5–100%19.0%51+18.1%NOTE. Based on all 241 respondents to survey.a Percentage answering yes. Open table in a new tab NOTE. Based on 185 of 241 respondents who provided information on locations and degrees. NOTE. Based on all 241 respondents to survey. Current treatment guidelines established threshold limits of serum HBV DNA and alanine transaminase (ALT) for treatment. An arbitrary value of greater than 105 copies/mL of HBV DNA was chosen as a criterion for the treatment of CHB at a National Institutes of Health workshop.5Lok 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 (730) Google Scholar Although all current guidelines recognize this level as an appropriate threshold for both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative forms of the disease,2Lok A.S. McMahon B.J. Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD)Chronic hepatitis B update of recommendations.Hepatology. 2004; 39: 857-861Crossref PubMed Scopus (491) Google Scholar, 3de Franchis R. Hadengue A. Lau G. et al.EASL JuryEASL International Consensus Conference on Hepatitis B.J Hepatol. 2003; 39 (September 13-14, 2002 Geneva, Switzerland. Consensus statement (long version)): S3-S25PubMed Google Scholar, 4Liaw Y.-F. Leung N. Guan R. et al.Asian-Pacific consensus statement on the management of chronic hepatitis B a 2005 update.Liver Int. 2005; 25: 472-489Crossref PubMed Scopus (327) Google Scholar a value of 104 copies/mL recently was suggested for HBeAg-negative CHB.6Keeffe E.B. Dieterich D.T. Han S.-H.B. et al.A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.Clin Gastroenterol Hepatol. 2004; 2: 87-106Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar By using polymerase chain reaction (PCR), it has been shown that 96% of samples from HBeAg-positive patients equal or exceed 105 copies/mL, but approximately 30%–45% of individuals with HBeAg-negative hepatitis occasionally may have values less than this level.7Chu C.J. Hussain M. Lok A.S. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection.Hepatology. 2002; 36: 1408-1415PubMed Google Scholar The published guidelines also advocate an arbitrary ALT limit of greater than 2 times the upper limit of normal as an appropriate threshold for considering therapy. This decision is based on 2 factors: a presumed lower likelihood of significant liver disease with minor increases of ALT and a lower level of sustained virologic response in patients with ALT values less than twice normal irrespective of type of treatment.8Hoofnagle J.H. di Bisceglie A.M. The treatment of chronic viral hepatitis.N Engl J Med. 1997; 336: 347-356Crossref PubMed Scopus (991) Google Scholar, 9Perrillo R.P. Lai C.L. Liaw Y.F. et al.Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.Hepatology. 2002; 36: 186-194Crossref PubMed Scopus (286) Google Scholar All guidelines also advocate the treatment of individuals with moderate or severe hepatitis on liver biopsy examination. However, this is not defined specifically by a scoring system for grade and stage of disease. Serum HBV DNA levels greater than 1 × 105 copies/mL has been used as a criterion for patient selection in phase III clinical trials of peginterferon (PEG-IFN) and nucleos(t)ide analogues.1Perrillo R.P. Overview of treatment of hepatitis B key approaches and clinical challenges.Semin Liver Dis. 2004; 24: 23-29Crossref PubMed Scopus (31) Google Scholar However, there is relatively limited information on whether patients with lower levels of serum HBV DNA may be in need of treatment. It was noted that 4% of HBeAg-positive CHB patients have transient serum HBV DNA values less than 105 copies/mL.7Chu C.J. Hussain M. Lok A.S. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection.Hepatology. 2002; 36: 1408-1415PubMed Google Scholar Because of the relatively limited data, the workshop members concluded it was important to consider the statement in conjunction with ALT levels. They uniformly agreed that before excluding treatment as a possibility, liver biopsy should be performed whenever ALT level is increased and serum HBV DNA level is 105 or less copies/mL because the level of serum HBV DNA associated with disease is not known. Some patients present with lower serum HBV DNA levels and substantial liver injury caused by CHB. There was uniform agreement that patients with normal ALT levels and subthreshold amounts (≤105 copies/mL) of circulating HBV DNA should not undergo a biopsy examination and most likely are inactive HBV carriers. The workshop concluded that there was fair evidence to support the statement, but patients who have levels of serum HBV DNA of less than 105 copies/mL occasionally may need treatment based on the results of liver biopsy examination. In the general session voting, most expert panel members (85%) accepted the statement. The majority of AASLD respondents (71%) also accepted the statement. Discordance, however, was seen in the number of respondents who accepted the statement with some reservations (41% vs 64%, respectively, Table 5).Table 5Conclusions of Workshop Summary, Expert Panel Consensus, and AASLD Membership Response to SurveyStatementNature of evidenceSubgroup support% Accept completely% Accept/some reservations% Accept/ major reservations% Reject/reservations% Reject/completelyCategoryCategoryEAEAEAEAEAPatient selection 1. Patients with HBeAg (+) chronic hepatitis B are candidates for therapy only if serum HBV DNA is >105 copies/mLI, III, IVB141464417161418011 2. Patients with HBeAg (−) chronic hepatitis B are candidates for therapy only if serum HBV DNA is >104 copies/mLIII and IVE0147497112117649 3. Patients with high levels of viral replication (>105 or >104) should undergo liver biopsy to assess need for therapy only if serum ALT levels are increased above the upper limit of normalI and IIE72202771021256416 4. Patients with high levels of viral replication (>105 or >104) and minimal hepatitis on liver biopsy are candidates for therapy if serum ALT levels are > 2-fold increasedII and IIIA3645363814414904 5. If liver biopsy is performed in patients with chronic HBV infection, only patients with at least grade 2, stage 2 disease are candidates for therapyII and IIIE7873014914235731Therapeutic end points 6. In HBeAg (+) chronic hepatitis B, HBeAg seroconversion rather than HBeAg loss should be the primary end point of therapyIA for nucleoside analogues D for interferon0436431219141204 7. In HBeAg (−) chronic hepatitis B, nondetectability of HBV DNA by PCR for a minimum of 6 months should be the end point of therapyI and IIIE7337412952911299 8. HBsAg seroconversion is more important than HBeAg seroconversion with regard to retarding disease progressionIIA7936212206021014 9. Chronic HBV infection can be controlled but not curedIIIA7135143314501401310. Therapeutic end points for nucleos(t)ide analogues and IFN-based therapies are differentIA36274336042115018Therapeutic options11. Long-term treatment with a nucleos(t)ide analogue with a low rate of resistance is the initial treatment of choice for HBeAg (−) CHBIII and IVD026733012432150712. PEG-IFN alfa is the initial treatment of choice for HBeAg (+) CHBI and IIA716643571421260913. PEG-IFN alfa monotherapy is as effective as combined therapy with PEG-IFN alfa and a nucleos(t)ide analogue in the treatment of CHBIB034573329814170814. Newer more potent nucleos(t)ide analogues will offer greater therapeutic efficacy over currently licensed agents for the treatment of CHBI and IIIB735794014130100115. Combination nucleos(t)ide analogue therapy is preferable to monotherapy as an initial treatment strategy for CHBI and IIE0120202111713672016. Adefovir should be added to LAM maintenance, rather than replace it, in cases of clinically significant LAM resistanceI and IVD for clinically stable; C for decompensated liver disease021292729113625716NOTE. Values in boldface differ between groups by more than 20%. Subgroup support categories: A, accept recommendation completely; B, accept recommendation with some reservations; C, accept recommendation with major reservations; D, reject recommendation with reservations; E, reject recommendation completely.E, expert panel; A, AASLD membership. Open table in a new tab NOTE. Values in boldface differ between groups by more than 20%. Subgroup support categories: A, accept recommendation completely; B, accept recommendation with some reservations; C, accept recommendation with major reservations; D, reject recommendation with reservations; E, reject recommendation completely. E, expert panel; A, AASLD membership. The workshop members noted there was good evidence to reject the statement because serum HBV DNA levels often are 1–2 log values lower in HBeAg-negative CHB (Table 5). Levels have been shown to range from 103 to 108,7Chu C.J. Hussain M. Lok A.S. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection.Hepatology. 2002; 36: 1408-1415PubMed Google Scholar and fluctuations in serum HBV DNA levels (and ALT levels) are common.10Hadziyannis S.J. Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624Crossref PubMed Scopus (454) Google Scholar In addition, it was emphasized that it may be difficult without a liver biopsy to distinguish between an inactive hepatitis B surface antigen (HBsAg) carrier and HBeAg-negative CHB with normal ALT level based on serum HBV DNA level alone because of overlap in the lower range of values. Reference was made to data from a retrospectively studied cohort of 134 patients with HBeAg-negative CHB, in which it was shown that serum HBV DNA values were less than 3 × 104 copies/mL in 10% of the entire group and in 20% of those with normal baseline ALT levels.11Manesis E.K. Papatheodoridis G.V. Sevastianos V. et al.Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection.Am J Gastroenterol. 2003; 98: 2261-2267PubMed Google Scholar Only 2 expert panel members accepted the statement, with neither one accepting it completely. Instead, most of the panel members (64%) rejected the statement completely. In contrast, 74% of AASLD respondents accepted the statement, most with only some reservations (49% vs 7% for the expert panel). Only 9% rejected the statement completely (Table 5). The workshop discussed the findings of a large randomized controlled clinical trial of lamivudine (LAM) maintenance vs placebo in patients with advanced fibrosis (Ishak score of ≥4).12Liaw Y.-F. Sung J.J.Y. Chow W.C. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (1982) Google Scholar Approximately 20% of patients enrolled in this study had normal ALT levels and 80% of the total group had HBV DNA levels detectable by signal amplification (lower limit of 7 × 105 copies/mL). Patients with normal ALT levels had less disease progression on LAM maintenance (personal communication with Y. F. Liaw, 2004). The workshop also raised the question of what constitutes a normal ALT level because this test is dependent on age, sex, and body mass index, and correlates with a number of other factors such as blood pressure and cigarette smoking.13Prati D. Taioli E. Zanella A. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1113) Google Scholar, 14Piton A. Poynard T. Imbert-Bismut F. et al.MULTIVIRC GroupFactors associated with serum alanine transaminase activity in healthy subjects consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C.Hepatology. 1998; 27: 1213-1219Crossref PubMed Scopus (268) Google Scholar The results were cited for a large Korean medical insurance study in which the risk for liver-related mortality was calculated in more than 140,000 individuals between the ages of 35 and 59.15Kim H.C. Nam C.M. Jee S.H. et al.Normal serum aminotransferase concentration and risk of mortality from liver diseases prospective cohort study.BMJ. 2004; 328: 983Crossref PubMed Google Scholar All had been tested for ALT values. In this study, the relative risk for liver-related mortality was 2.9 (95% confidence interval, 2.4–3.5) for men and 9.5 (95% confidence interval, 7.9–11.5) for women. Importantly, the best cut-off value for the prediction of liver disease in men was 30 IU/L (normal range, ≤40). Accordingly, members of the workshop determined there was good evidence to reject the statement. Eighty-five percent of the expert panel members voted to reject the statement, including 64% who rejected it completely. Only 2 panel members accepted the statement and neither did so completely. The responses of the AASLD membership were very discordant with nearly 60% accepting the statement and only 16% rejecting it completely (Table 5). The intent of this statement was to determine if knowledge of minimal hepatitis on liver biopsy examination would dissuade physicians from treatment even if all other criteria for therapy were met as indicated in the published guidelines. The workshop focused on what is known about the natural history of minimal hepatitis B and the implications for therapy. The members defined minimal hepatitis as grade 1 and stage 1 disease or less, roughly equivalent to the term chronic persistent hepatitis as expressed in the older literature. The annual spontaneous HBeAg seroconversion rate in patients with chronic persistent hepatitis has been shown to be lower than in patients with more extensive disease.16Liaw Y.F. Chu C.M. Huang M.J. et al.Determinants for hepatitis B e antigen clearance in chronic type B hepatitis.Liver. 1984; 4: 301-306Crossref PubMed Scopus (33) Google Scholar Both chronic persistent hepatitis and stage 1 hepatitis B have been documented to progress to stage 4 disease whenever HBV replication persists, although the interval required to reach this end point often is longer than in those with more advanced disease at baseline.17Aldershvile J. Dietrichson O. Skinhoj P. et al.Copenhagen Hepatitis Acuta Programme. Chronic persistent hepatitis: serological classification and meaning of the hepatitis B e system.Hepatology. 1982; 2: 243-246Crossref PubMed Scopus (34) Google Scholar, 18Moreno-Otero R. Garcia-Monzon C. Garcia-Sanchez A. et al.Development of cirrhosis after chronic type B hepatitis a clinicopathologic and follow-up study of 46 HBeAg-positive asymptomatic patients.Am J Gastroenterol. 1991; 86: 560-564PubMed Google Scholar, 19Ikeda K. Saitoh S. Suzuki Y. et al.Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis a prospective observation of 2215 patients.J Hepatol. 1998; 28: 930-938Abstract Full Text PDF PubMed Scopus (402) Google Scholar, 20Huo T.-L. Wu J.-C. Hwang S.-J. et al.Factors predictive of liver cirrhosis in patients with chronic hepatitis B a multivariate analysis in a longitudinal study.Eur J Gastroenterol Hepatol. 2000; 12: 687-693Crossref PubMed Scopus (68) Google Scholar, 21Fattovich G. Brollo L. Giustina G. et al.Natural history and prognostic factors for chronic hepatitis type B.Gut. 1991; 32: 294-298Crossref PubMed Scopus (370) Google Scholar Multivariate analyses using pooled phase III treatment data have shown that treatment responses occur significantly less frequently in patients with minimal disease activity; however, both virologic and histologic responses to antiviral therapy have been well documented.9Perrillo R.P. Lai C.L. Liaw Y.F. et al.Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.Hepatology. 2002; 36: 186-194Crossref PubMed Scopus (286) Google Scholar The workshop members uniformly agreed there was good evidence to support the statement if all other criteria outlined in the current guidelines had been met. Seventy-two percent of the expert panel accepted the statement, either completely or with some reservations only, and comparable responses were provided by the AASLD respondents (Table 5). Statement 5, the inverse of statement 4, was intended to determine if a decision to treat would require moderate to severe hepatitis as an absolute criterion for treatme
Referência(s)