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Wilt TJ, Shamliyan T, Shaukat A, et al. Management of Chronic Hepatitis B. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Oct. (Evidence Reports/Technology Assessments, No. 174.)
This publication is provided for historical reference only and the information may be out of date.
Appendix D contains details on analytical framework of the report: algorithm to define eligibility of the studies, definitions, hypotheses, and statistical models
Management of Chronic Hepatitis B:
Article Screening Form
Author (first): ____________________________________________________
Journal: _____________________________________________________
Year of publication: ________________________________________________
Article Call Number (MEDLINE ID): _________________________________
Data Abstractor: ______________________________________________
VERIFICATION / SELECTION OF STUDY ELIGIBILITY
| Subjects randomly assigned | Yes | No | Unclear |
| Subjects age ≥18 years | Yes | No | Unclear |
| Addresses treatments for chronic HVB | Yes | No | Unclear |
| Surrogate outcomes of interest | Yes | No | Unclear |
| (ALT/AST levels; HBV viral load, etc.) | |||
| Clinical outcomes of interest | Yes | No | Unclear |
| (Cirrhosis, liver failure, death, etc.) | |||
| Or | |||
| Is a systematic review/meta-analysis based on above | Yes | No | Unclear |
CHECK ONE
___YES / Unclear, pull article for further review
___NO, exclude article:
Reason(s) ____________________________________
Conceptual definitions
Hepatitis B - Inflammation of the liver in humans caused by a member of the orthohepadnavirus genus, hepatitis B virus. It is primarily transmitted by parenteral exposure, such as transfusion of contaminated blood or blood products, but can also be transmitted via sexual or intimate personal contact.1
Chronic hepatitis B - Inflammation of the liver in humans caused by a member of the orthohepadnavirus genus, hepatitis B virus lasting six months or more.1
Definitions of the American Association for the Study of Liver Diseases2
Chronic necroinflammatory disease of the liver caused by persistent infection with hepatitis B virus. Chronic hepatitis B can be subdivided into HBeAg positive and HBeAg negative chronic hepatitis B.
Inactive HBsAg carrier state: Persistent HBV infection of the liver without significant, ongoing necroinflammatory disease
Resolved hepatitis B: Previous HBV infection without further virologic, biochemical or histological evidence of active virus infection or disease
Acute exacerbation or flare of hepatitis B: Intermittent elevations of aminotransferase activity to more than 10 times the upper limit of normal and more than twice the baseline value
Reactivation of hepatitis B: Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B
HBeAg clearance: Loss of HBeAg in a person who was previously HBeAg positive
HBeAg seroconversion: Loss of HBeAg and detection of anti-HBe in a person who was previously HBeAg positive and anti-HBe negative. For analytical purpose we may define HBeAg clearance as HBeAg seroconversion considering the same immunological response to achieve the outcome
HBeAg reversion: Reappearance of HBeAg in a person who was previously HBeAg negative, anti-HBe positive
Diagnostic criteria (one of several diagnostic criteria that may be utilized)
Chronic hepatitis B
- 1.
HBsAg + >6 months
- 2.
Serum HBV DNA >20,000 IU/ml (105 degree copies/ml), lower values 2,000–20,000 IU/ml (104 degree-105 degree copies/ml) are often seen in HBeAg-negative chronic hepatitis B. For analytical purpose we will abstract the viral load as reported and further categorize it according to cut off of >20,000 IU/ml
- 3.
Persistent or intermittent elevation in ALT/AST levels
- 4.
Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation For analytical purpose we define moderate as 2 or higher according to grade (1–5) (Knodell, Metavir, Ishak, HAI)
Inactive HBsAg carrier state
- 1.
HBsAg+ >6 months
- 2.
HBeAg-, anti-Hbe+
- 3.
Serum HBV DNA <2,000 IU/ml
- 4.
Persistently normal ALT/AST levels
- 5.
Liver biopsy confirms absence of significant hepatitis
Resolved hepatitis B
- 1.
Previous known history of acute or chronic hepatitis B or the presence of anti-HBe ± anti-HBs
- 2.
HBsAg-
- 3.
Undetectable serum HBV DNA
- 4.
Normal ALT levels
Table D1Operational definitions of treatment options for hepatitis B1, 3
| Agent | Definition |
|---|---|
| Interferon Alfa-2b
Pegylated interferon alfa-2a | A recombinant alfa interferon consisting of 165
amino acid residues with arginine in position 23 and histidine
in position 34. It is used extensively as an antiviral and
antineoplastic agent
interferon alfa-2A chemically modified by the covalent attachment of a polyethylene glycol |
| Lamivudine | A reverse transcriptase inhibitor and ZALCITABINE
analog in which a sulfur atom replaces the 3′ carbon of the
pentose ring.
Active Ingredient: ABACAVIR SULFATE; LAMIVUDINE Dosage Form;Route: TABLET; ORAL Proprietary Name: EPZICOM Active Ingredient: ABACAVIR SULFATE; LAMIVUDINE; ZIDOVUDINE Dosage Form; Route: TABLET; ORAL Proprietary Name: TRIZIVIR Active Ingredient: LAMIVUDINE Dosage Form; Route: SOLUTION; ORAL Proprietary Name: EPIVIR Active Ingredient: LAMIVUDINE Dosage Form; Route: SOLUTION; ORAL Proprietary Name: EPIVIR-HBV Active Ingredient: LAMIVUDINE; ZIDOVUDINE Dosage Form; Route: TABLET; ORAL Proprietary Name: COMBIVIR |
| Adefovir dipivoxil | A reverse transcriptase inhibitor.
Active Ingredient: ADEFOVIR DIPIVOXIL Dosage Form; Route: TABLET; ORAL Proprietary Name: HEPSERA |
| Entecavir | Guanine/analogs and derivatives
Active Ingredient: ENTECAVIR Dosage Form; Route: TABLET; ORAL Proprietary Name: BARACLUDE |
| Telbivudine | Nucleosides
Active Ingredient: TELBIVUDINE Dosage Form; Route: TABLET; ORAL Proprietary Name: TYZEKA |
Definition of Response to Antiviral Chronic Hepatitis B
Category of response
Biochemical (BR): Decrease in serum ALT to within the normal range
Virologic (VR): Decrease in serum HBV DNA to undetectable levels by PCR assays, and loss of HBeAg in patients who were initially HBeAg positive. Primary nonresponse (not applicable to interferon therapy): Decrease in serum HBV DNA by <2 log10 IU/ml after at least 24 weeks of therapy
Virologic relapse: Increase in serum HBV DNA of 1 log10 IU/ml after discontinuation of treatment in at least two determinations more than 4 weeks apart
Histologic (HR): Decrease in histology activity index by at least 2 points and no worsening of fibrosis score compared to pre-treatment liver biopsy
Complete (CR): Fulfill criteria of biochemical and virological response and loss of HBsAg
Time of assessment
On-therapy: During therapy
Maintained: Persist throughout the course of treatment
End-of-treatment: At the end of a defined course of therapy
Off-therapy: After discontinuation of therapy
Sustained (SR-6): 6 months after discontinuation of therapy
Sustained (SR-12): 12 months after discontinuation of therapy
Definition of Terms Relating to Antiviral Resistance to Nucleoside Analogue (NA) Treatment
Virologic breakthrough: Increase in serum HBV DNA by >1 log10 (10-fold) above nadir after achieving virologic response, during continued treatment
Viral rebound: Increase in serum HBV DNA to >20,000 IU/ml or above pretreatment level after achieving virologic response, during continued treatment
Biochemical breakthrough: Increase in ALT above upper limit of normal after achieving normalization, during continued treatment
Genotypic resistance: Detection of mutations that have been shown in vitro studies to confer resistance to the NA that is being administered
Phenotypic resistance: In vitro confirmation that the mutation detected decreases susceptibility (as demonstrated by increase in inhibitory concentrations) to the NA administered.
Definitions of the studies' design characteristics to estimate the level of evidence 4
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.
Algorithms of meta-analysis 5
Pooled estimate as a weighted average:
Weights are inverse of variance (standard error):
Standard error of pooled estimate:
Heterogeneity (between-study variability) measured by:
Assumptions for random effects model: true effect sizes qi have a normal distribution with mean q and variance t2; t2 is the between-study variance
Between study variance:
Where:
wi are the weights from the fixed effect inverse-variance method
Q is the heterogeneity test statistic from before (either from inverse-variance method or Mantel-Haenszel method)
k is the number of studies, and
t2 is set to zero if Q<k-1
Random effect pooled estimate is weighted average:
Weights used for the pooled estimate are similar to the inverse-variance, but now incorporate a component for between-study variation:
Standard error of pooled estimate:
Meta regression with random effects was obtained using aggregate level data.
Additive component of variance tau2 was estimated:
y[i] = a + B*x[i] + u[i] + e[i],
where u[i] is a normal error (standard deviations that may vary across units), e[i] is a normal error with variance tau2 to be estimated, assumed equal across units.
t-distribution was used calculating p-values and confidence intervals6, 7
Number needed to treat to prevent one event of incontinence was calculated as reciprocal to absolute risk differences in rates of outcomes events in the active and control groups:8, 9
NNT =1/(control group event rate - treatment group event rate).
The number of avoided or excess events (respectively) per 1000 population is the difference between the two event rates multiplied by 1000:
(control group event rate - treatment group event rate)*1000
References
- 1.
- National Library of Medicine (U.S.), National Center for Biotechnology Information (U.S.), National Institutes of Health (U.S.). PubMed central: an archive of life science journals. NCBI U.S. National Library of Medicine NIH Dept. of Health and Human Services [Digital archive searchable database]. Available at: http://www
.pubmedcentral.nih.gov/ - 2.
- Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507–39. [PubMed: 17256718]
- 3.
- U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER): Center for Drug Evaluation and Research (CDER).
- 4.
- Hamer S, Collinson G. Achieving evidence-based practice : a handbook for practitioners. 2nd ed. Edinburgh; New York: Baillìere Tindall Elsevier; 2005.
- 5.
- DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986 Sep;7(3):177–88. [PubMed: 3802833]
- 6.
- Knapp G, Biggerstaff BJ, Hartung J. Assessing the amount of heterogeneity in random-effects meta-analysis. Biom J. 2006 Apr;48(2):271–85. [PubMed: 16708778]
- 7.
- Knapp G, Hartung J. Improved tests for a random effects meta-regression with a single covariate. Stat Med. 2003 Sep 15;22(17):2693–710. [PubMed: 12939780]
- 8.
- Egger M, Smith GD, Altman DG. Systematic Reviews in Health Care. London: NetLibrary, Inc. BMJ Books; 2001.
- 9.
- Ebrahim S. The use of numbers needed to treat derived from systematic reviews and meta-analysis. Caveats and pitfalls. Eval Health Prof. 2001 Jun;24(2):152–64. [PubMed: 11523384]
- Conceptual definitions
- Definitions of the American Association for the Study of Liver Diseases
- Diagnostic criteria (one of several diagnostic criteria that may be utilized)
- Definition of Response to Antiviral Chronic Hepatitis B
- Definition of Terms Relating to Antiviral Resistance to Nucleoside Analogue (NA) Treatment
- Appendix D. Analytic Framework - Management of Chronic Hepatitis BAppendix D. Analytic Framework - Management of Chronic Hepatitis B
- Appendix E Tables and Figures - Management of Chronic Hepatitis BAppendix E Tables and Figures - Management of Chronic Hepatitis B
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