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Guideline Summary
Guideline Title
National Institutes of Health Consensus Development Conference statement: management of hepatitis B.
Bibliographic Source(s)
Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM, Kern ER, McHugh JA, Petersen GM, Rein MF, Strader DB, Trotter HT. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med. 2009 Jan 20;150(2):104-10. [1 reference] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Chronic hepatitis B

Guideline Category
Management
Prevention
Risk Assessment
Treatment
Clinical Specialty
Family Practice
Gastroenterology
Infectious Diseases
Internal Medicine
Preventive Medicine
Intended Users
Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Health Plans
Managed Care Organizations
Nurses
Patients
Physician Assistants
Physicians
Guideline Objective(s)

To help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services to patients with hepatitis B infection

Target Population

Patients with chronic hepatitis B

Interventions and Practices Considered

Risk Assessment/Prevention

  1. Hepatitis B immunoglobulin and hepatitis B vaccination for infants of hepatitis B surface antigen (HBsAg)-positive women
  2. Assessment of comorbid conditions

Management/Treatment

  1. Interferon-alfa and pegylated interferon-alfa
  2. Nucleoside and nucleotide analogues
  3. Monitoring of treatment response
Major Outcomes Considered
  • Incidence of hepatocellular carcinoma, liver failure and cirrhosis
  • Overall and liver-specific mortality
  • Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) clearance
  • Alanine transaminase (ALT) and aspartate transaminase (AST) levels
  • Change in hepatitis B e antigen (HBeAg) status
  • Hepatitis B surface antigen (HBsAg) conversion
  • Histologic outcomes (improvement in total, fibrosis, or necroinflammatory score)
  • Adverse events of antiviral drugs
  • Development of drug resistance

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Note from the National Guideline Clearinghouse (NGC): A systematic review of the literature was prepared by the Minnesota Evidence-based Practice Center (EPC) for the Agency for Healthcare Research and Quality (AHRQ) for use by the National Institutes of Health (NIH) (see the "Availability of Companion Documents" field).

Literature Search

The EPC staff searched MEDLINE® via PubMed®, the Cochrane library, Medwatch, and United Kingdom Current Problems in Pharmacovigilance. They used the European Public Assessment Report to find original epidemiologic studies of adults with chronic hepatitis B (CHB) published in English that reported mortality, incidence of hepatocellular carcinoma (HCC), or liver failure, prevalence and incidence of cirrhosis, hepatitis B e antigen (HBeAg) or hepatitis B surface antigen (HBsAg) presence or seroconversion, viral load of hepatic virus B deoxyribonucleic acid (HBV DNA), alanine aminotransferase (ALT) levels, histological necroinflammatory and fibrosis scores, and adverse events after antiviral drugs approved by the Food and Drug Administration (FDA) for CHB, including interferon alfa-2b, pegylated interferon alfa-2a, lamivudine, adefovir, entecavir, tenofovir, and telbivudine. The search strategies for the four research questions are described in Appendix A of the Evidence Report (see the "Availability of Companion Documents" field). Excluded references are shown in Appendix B (see the "Availability of Companion Documents" field). All work was conducted under the guidance of a Technical Expert Panel (TEP), whose members are identified in Appendix C of the Evidence Report.

Eligibility

Three investigators independently decided on the eligibility of the studies according to recommendations from the Cochrane manual for systematic reviews. The algorithm to define eligibility of the studies was developed for each research question (refer to Appendix D of the Evidence Report [see the "Availability of Companion Documents" field]). The EPC staff reviewed abstracts to exclude secondary data analysis, reviews, letters, comments, case reports, and clinical trials of healthy populations to prevent hepatitis B. They confirmed eligible target populations of adults with chronic hepatitis B. The full texts of the original epidemiologic studies published in English after 1989 were examined to include studies with adult patients diagnosed with CHB. Eligible outcomes were defined as overall and liver-specific mortality, incidence of hepatocellular carcinoma or liver failure, prevalence and incidence of cirrhosis, surrogate measures of HBeAg or HBsAg presence or seroconversion, viral load of hepatic virus B HBV DNA, aspartate aminotransferase (AST) and ALT levels, and histological necroinflammatory and fibrosis scores.

For question 1 (Which persons with hepatitis B should be treated?), the EPC staff included studies if they: (1) were original research articles; (2) reported at least one of the following: hepatocellular carcinoma, liver failure, cirrhosis, liver-related death, and all-cause mortality; (3) had at least 1 year of either prospective or retrospective follow-up between the measurement of predictive factors and at least one of the outcomes of interest; or (4) reported results for a hepatitis B only population. Since the focus of this report is to provide evidence most relevant for a U.S. population, all studies meeting the previous criteria were included if the study reported results from a U.S. population. Only large studies (at least 1,000 participants) of populations outside of the United States were included. For questions 2-4 randomized controlled clinical trials (RCTs) of the drugs approved by the FDA for CHB, including interferon alfa-2b, pegylated interferon alfa-2a, lamivudine, adefovir, entecavir, tenofovir, and telbivudine were eligible. The EPC staff included publications from the multinational HBV 99-01 Study Group of pegylated interferon alfa-2b that has been intensively examined in patients with CHB but not yet approved in the United States. Observational studies of more than 50 treated adults with more than 1 year follow-up that examined surrogate predictors of clinical outcomes were eligible for question 4 (What measures are appropriate to monitor therapy and assess outcomes?).

Exclusion criteria included the following:

  • Studies with target population as children and adolescents, healthy adults, adults with HCC, human immunodeficiency virus (HIV), undergoing transplantation or chemotherapy, pregnant women, CHB populations mixed with other hepatitis patients (e.g., hepatitis C, CHB carriers, pregnant women with CHB, or individuals undergoing chemotherapy, if results were not separately provided for designated eligible cohort of CHB adults).
  • Interventions of drugs not approved in the United States as of June 2008.
  • Studies that reported not eligible outcomes including intra-hepatic concentrations of HBV DNA, acute pharmacokinetics measures, cardiovascular markers, or visual evoked potentials.
  • Studies that evaluated cost effectiveness of different treatment options.
  • Case series with small numbers of cases and no control comparison.
  • Clinical trials of reverse transcriptase inhibitor that included less than 50 patients or examined active treatments for less than 24 weeks. Trials evaluating interferon for at least 12 weeks were eligible.
  • Secondary data analysis with multiple reporting of the same outcomes.
  • Data from randomized clinical trials that were reported ignoring randomization.
Number of Source Documents

Key Question (KQ) 1: What is the natural history of hepatitis B? = 41

For KQ 2-4, 101 articles were abstracted:

KQ 2: What are the benefits and risks of the current therapeutic options for hepatitis B with defined or continuous courses of treatment? = 16

KQ 3: Which persons with hepatitis B should be treated? = 15

KQ 4: What measures are appropriate to monitor therapy and assess outcomes? = 7

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Level of Evidence as Defined by the U.S. Preventive Services Task Force

Level I: Evidence obtained from at least one properly designed randomized controlled trial.

Level II-1: Evidence obtained from well-designed controlled trials without randomization.

Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials.

Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Methods Used to Analyze the Evidence
Meta-Analysis of Randomized Controlled Trials
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Note from the National Guideline Clearinghouse (NGC): A systematic review of the literature was prepared by the Minnesota Evidence-based Practice Center (EPC) for the Agency for Healthcare Research and Quality (AHRQ) for use by the National Institutes of Health (NIH) (see the "Availability of Companion Documents" field).

Quality Assessment and Rating the Body of Evidence

The EPC staff analyzed study quality using the following criteria: subject selection, length and loss of follow-up, adjustment for confounding factors in observational studies and intention to treat principle in clinical trials, masking the treatment status, randomization scheme and adequacy, allocation concealment, and justification of sample sizes in randomized controlled trials (RCTs). The level of evidence for all studies was estimated using a subset of the U.S. Preventive Services Task Force criteria.

For all questions, evidence tables were developed identifying the purpose of the study, sample, design, independent and dependent variables, and findings (refer to Appendix E of the Evidence Report [see the "Availability of Companion Documents" field]). Baseline data were compared in different studies to test differences in the target population and unusual patterns in the data. Standard deviations, regression coefficients, and 95 percent confidence intervals (CI) were calculated from reported event rates, means, standard errors, and sample size. The protocol for the meta-analyses was created according to recommendations for meta-analysis of randomized controlled trials. The level of evidence was assessed based on GRADE Working Group criteria. The EPC staff determined low level of evidence and confidence when data were from small RCTs or observational studies or from RCTs/observational studies with serious flaws in design/analysis and from post hoc subgroup analysis, moderate level of evidence, and confidence when a single large multinational study or several small RCTs/observational studies reported consistent effect of the same drugs or associations with factors and outcomes, and high level of evidence from multiple high quality studies in applicable patients reporting consistent sustained effects (post therapy at least 6 months).

Applicability of the population was estimated by evaluating the selection of the subjects in observational studies and clinical trials. Large observational cohorts based on nationally representative samples had high applicability. Applicability of the intervention duration was high for studies with follow-up 1 year or more and acceptable for studies with follow-up of 6 to 12 months. Baseline patient characteristics were evaluated including age, gender, HBeAg status, previous treatment, and the presence of cirrhosis for generalizability.

EPC staff assumed the presence of publication bias and did not use statistical tests for bias defined as the tendency to publish positive results and to predict association when all conducted (published and unpublished) studies are analyzed. Several strategies were used to reduce bias, including a comprehensive literature search of published and unpublished evidence in several databases, reference lists of systematic reviews, contacts with experts for additional references they might provide, and agreement on the eligibility status by several investigators.

Data Extraction

Evaluations of the studies and data extraction were performed independently by five researchers. The data abstraction forms are shown in Appendix F of the Evidence Report (see the "Availability of Companion Documents" field). Errors in data extractions were assessed by a comparison with the established ranges for each variable and the data charts with the original articles. Any discrepancies were detected and discussed.

The EPC staff abstracted the number of events among treatment groups to calculate rates, relative risk, odds ratios, and absolute risk differences (ARD). They abstracted the number randomized to each treatment group as the denominator to calculate estimates applying intention to treat principle. Means and standard deviations of continuous variables were abstracted to calculate mean differences with a 95 percent CI. Staff abstracted the time when the outcomes were assessed as weeks from randomization and the time of follow-up post treatments. Sustained response was defined as 6 months or more post therapy. Author reported adjustments for patient age, race, gender, and comorbidities were extracted. The EPC staff prioritized clinical outcomes in the assessment of treatment benefits and harms. Sustained resolved hepatitis B was considered the next most relevant outcome.

Data Synthesis

For questions 2 and 3 the results of individual studies were summarized in evidence tables to analyze differences in the outcomes among treatment groups.

For question 3 the results from subgroup analyses were synthesized when the authors reported outcomes among patients according to age, gender, body mass index (BMI), baseline ALT, viral load, HBeAg status, pretreatment history, or histological activity. The evidence of effect measure modification was synthesized when authors compared the effects of baseline patient characteristics on the effects of the drug therapies. The effects of the same drugs on different patient populations were compared across the RCTs that included patients with only positive or negative HBeAg status.

Pooling criteria included the same operational definitions of outcomes and the same risk factors or clinical interventions. Meta-analysis was used to assess the consistency of the association between treatments and outcomes with random effects models. The EPC staff conducted analyses separately for clinical, biochemical, virological, and histological outcomes and for relative risk and absolute risk differences. Assumptions underlying meta-analysis included valid measurements of the outcomes and similarity in study and target populations.

The EPC staff tested consistency in the results comparing the direction and strength of the association. Chi squared tests were used to assess heterogeneity. Significant heterogeneity means the effects of interventions on the outcomes were not consistent in the studies. Heterogeneity was explored with meta-regression and sensitivity analysis and reported the results from random effects models. The EPC staff analyzed whether duration of treatments or follow-up, doses of the drugs, proportion of the patients with HBeAg-positive baseline status, proportion of the patients with baseline cirrhosis, or control rates of the outcomes could explain heterogeneity between studies. Calculations were performed using STATA software at the 95 percent confidence level. The number needed to treat and the number of the events attributable to the treatments per 1,000 treated were calculated.

Methods Used to Formulate the Recommendations
Expert Consensus (Consensus Development Conference)
Description of Methods Used to Formulate the Recommendations

National Institutes of Health (NIH) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ); 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session; 3) questions and statements from conference attendees during open discussion periods that are part of the public session; and 4) closed deliberations by the panel during the remainder of the second day and morning of the third.

The NIH Consensus Development Conference was held on 20–22 October 2008 at the National Institutes of Health, Bethesda, Maryland.

The Evidence-based Practice Center EPC staff were charged with answering the following critical questions:

  • What is the current burden of hepatitis B?
  • What is the natural history of hepatitis B?
  • What are the benefits and risks of the current therapeutic options for hepatitis B?
  • Which persons with hepatitis B should be treated?
  • What measures are appropriate to monitor therapy and assess outcomes?
  • What are the greatest needs and opportunities for future research on hepatitis B?

At the conference, invited experts presented information relevant to these questions and a systematic literature review, prepared under contract with the Agency for Healthcare Research and Quality (AHRQ), was summarized. The evidence report, available at www.ahrq.gov/clinic/tp/hepbtp.htm External Web Site Policy (see also the "Availability of Companion Documents" field), emphasizes randomized controlled trials with health outcomes as their end points. Conference attendees also provided oral and written comments in response to the conference questions, and all of this evidence was considered when preparing the consensus statement.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

The guideline developers reviewed published cost analyses.

Method of Guideline Validation
Not stated
Description of Method of Guideline Validation

Not applicable

Recommendations

Major Recommendations

The most important predictors of cirrhosis or hepatocellular carcinoma in persons who have chronic hepatitis B virus (HBV) are persistently elevated HBV deoxyribonucleic acid (DNA) and alanine aminotransferase (ALT) levels in blood. Other risk factors include HBV genotype C infection, male sex, older age, family history of hepatocellular carcinoma, and co-infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV).

The major goals of anti-HBV therapy are to prevent the development of progressive disease, specifically cirrhosis and liver failure, as well as hepatocellular carcinoma development and subsequent death. To date, no randomized controlled trials (RCTs) of anti-HBV therapies have demonstrated a beneficial impact on overall mortality, liver-specific mortality, or development of hepatocellular carcinoma.

Most published reports of hepatitis therapy use changes in short-term virologic, biochemical, and histologic parameters to infer likelihood of long-term benefit. Approved therapies are associated with improvements in intermediate biomarkers, including HBV DNA, hepatitis B e antigen (HBeAg) loss or seroconversion, decreases in ALT levels, and improvement in liver histology (see Table below).

Although various monitoring practices have been recommended, no clear evidence exists for an optimal approach.

The most important research needs include representative prospective cohort studies to define the natural history of the disease and large RCTs of monotherapy and combined therapies, including placebo-controlled trials that measure the effects on clinical health outcomes.

The guideline developers recommend routine screening for hepatitis B of newly arrived immigrants to the United States from countries where the HBV prevalence rate is greater than 2%. Screening will facilitate the provision of medical and public health services for infected patients and their families and provide public health data on the burden of disease in immigrant populations. The screening test should not be used to prohibit immigration.

Table. Criteria Useful in Determining for Whom Therapy Is Indicated
Patients for whom therapy is indicated:
  • Patients who have acute liver failure, cirrhosis and clinical complications, cirrhosis or advanced fibrosis and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) in serum, or reactivation of chronic HBV after chemotherapy or immunosuppression
  •  Infants born to women who are hepatitis B surface antigen (HBsAg)-positive (immunoglobulin and vaccination)
Patients for whom therapy may be indicated:
  • Patients in the immune-active phase who do not have advanced fibrosis or cirrhosis
Patients for whom immediate therapy is not routinely indicated:
  • Patients with chronic hepatitis B in the immune-tolerant phase (with high levels of serum HBV DNA but normal serum alanine transaminase [ALT] levels or little activity on liver biopsy)
  • Patients in the inactive carrier or low replicative phase (with low levels of or no detectable HBV DNA in serum and normal serum ALT levels)
  • Patients who have latent HBV infection (HBV DNA without HBsAg)
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is not specifically stated for each recommendation.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate management of chronic hepatitis B to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma

Potential Harms

Adverse Effects of Medications

  • The use of interferon is associated with systemic side effects, such as headache, nausea, flu-like symptoms, depression, and some hematologic abnormalities.
  • Nucleoside and nucleotide analogues, if prematurely discontinued, are associated with resurgence of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels or reactivation of hepatitis. In addition, long-term use of these drugs is compromised by the development of resistance. Several of the nucleoside and nucleotide analogues are associated with renal toxicity, myopathy (muscle weakness or pain), and mitochondrial toxicity.

Contraindications

Contraindications

Interferon-alfa and pegylated interferon-alfa therapies are contraindicated in patients with rapid deterioration of liver function and with decompensated cirrhosis because of the risk for hepatic failure.

Qualifying Statements

Qualifying Statements
  • This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the U.S. government. The statement reflects the panel's assessment of medical knowledge available at the time the statement was written. Thus, it provides a "snapshot in time" of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research.
  • The evidence available at this time does not permit concrete recommendations regarding selection of a particular therapeutic course. Health care providers should discuss the risks and benefits of treatment options with patients to arrive at the best possible decisions.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM, Kern ER, McHugh JA, Petersen GM, Rein MF, Strader DB, Trotter HT. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med. 2009 Jan 20;150(2):104-10. [1 reference] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2009 Jan 20
Guideline Developer(s)
National Institutes of Health Consensus Development Conference - Independent Expert Panel
Source(s) of Funding

United States Government

Guideline Committee

National Institutes of Health (NIH) Consensus Development Panel

Composition of Group That Authored the Guideline

Primary Authors: Michael F. Sorrell, MD; Edward A. Belongia, MD; Jose Costa, MD; Ilana F. Gareen, PhD; Jean L. Grem, MD; John M. Inadomi, MD; Earl R. Kern, PhD; James A. McHugh, MD; Gloria M. Petersen, PhD; Michael F. Rein, MD; Doris B. Strader, MD; and Hartwell T. Trotter, MS

Panel Members: Michael F. Sorrell, MD (Panel and Conference Chairperson), Section of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, Nebraska; Edward A. Belongia, MD, Epidemiology Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin; Jose Costa, MD, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Ilana F. Gareen, PhD, Department of Community Health, Center for Statistical Sciences, Brown University, Providence, Rhode Island; Jean L. Grem, MD, Department of Internal Medicine, Section of Oncology and Hematology, University of Nebraska Medical Center, Omaha, Nebraska; John M. Inadomi, MD, Policy and Economics (HOPE) Research Program, University of California, San Francisco, and Clinical Gastroenterology, San Francisco General Hospital, San Francisco, California; Earl R. Kern, PhD, Department of Pediatrics, The University of Alabama School of Medicine, Birmingham, Alabama; James A. McHugh, MD, Department of Family Medicine, University of Washington School of Medicine, and Family Medicine, Swedish Medical Center, Swedish Physicians—Central Seattle Clinic, Seattle, Washington; Gloria M. Petersen, PhD, College of Medicine, Mayo Clinic, Rochester, Minnesota; Michael F. Rein, MD, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia; Doris B. Strader, MD, Division of Gastroenterology/Hepatology, Fletcher Allen Health Care, University of Vermont College of Medicine, Burlington, Vermont; H. Thomas Trotter, MS, U.S. Navy (Ret.), American Melanoma Foundation, San Diego, California

Financial Disclosures/Conflicts of Interest

Panel members signed a confirmation that they have no financial or other conflicts of interest pertaining to the topic.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available from the National Institutes of Health (NIH) Consensus Development Conference Program Web site External Web Site Policy.

Print copies: Available from the NIH Consensus Development Program Information Center, PO Box 2577, Kensington, MD 20891; Toll free phone (in U.S.), 1-888-NIH-CONSENSUS (1-888-644-2667); autofax (in U.S.), 1-888-NIH-CONSENSUS (1-888-644-2667); e-mail: consensus_statements@mail.nih.gov.

Availability of Companion Documents

The following are available:

Patient Resources

None available

NGC Status

This summary was completed by ECRI Institute on January 28, 2010. The information was verified by the developer on February 16, 2010.

Copyright Statement

No copyright restrictions apply.

Disclaimer

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The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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