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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.)

Appendix D. Analytic Framework

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: ______________________________________________


Subjects randomly assignedYesNoUnclear
Subjects age ≥18 yearsYesNoUnclear
Addresses treatments for chronic HVBYesNoUnclear
Surrogate outcomes of interestYesNoUnclear
(ALT/AST levels; HBV viral load, etc.)
Clinical outcomes of interestYesNoUnclear
(Cirrhosis, liver failure, death, etc.)
Is a systematic review/meta-analysis based on aboveYesNoUnclear


___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


HBsAg + >6 months


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


Persistent or intermittent elevation in ALT/AST levels


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


HBsAg+ >6 months


HBeAg-, anti-Hbe+


Serum HBV DNA <2,000 IU/ml


Persistently normal ALT/AST levels


Liver biopsy confirms absence of significant hepatitis

Resolved hepatitis B


Previous known history of acute or chronic hepatitis B or the presence of anti-HBe ± anti-HBs




Undetectable serum HBV DNA


Normal ALT levels

Table D1Operational definitions of treatment options for hepatitis B1, 3

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
LamivudineA reverse transcriptase inhibitor and ZALCITABINE analog in which a sulfur atom replaces the 3′ carbon of the pentose ring.
Dosage Form;Route: TABLET; ORAL
Proprietary Name: EPZICOM
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
Dosage Form; Route: TABLET; ORAL
Proprietary Name: COMBIVIR
Adefovir dipivoxilA reverse transcriptase inhibitor.
Dosage Form; Route: TABLET; ORAL
Proprietary Name: HEPSERA
EntecavirGuanine/analogs and derivatives
Active Ingredient: ENTECAVIR
Dosage Form; Route: TABLET; ORAL
Proprietary Name: BARACLUDE
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:

Image er-chronichepeq1.jpg

Weights are inverse of variance (standard error):

Image er-chronichepeq2.jpg

Standard error of pooled estimate:

Image er-chronichepeq3.jpg

Heterogeneity (between-study variability) measured by:

Image er-chronichepeq4.jpg

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:

Image er-chronichepeq5.jpg


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:

Image er-chronichepeq6.jpg

Weights used for the pooled estimate are similar to the inverse-variance, but now incorporate a component for between-study variation:

Image er-chronichepeq7.jpg

Standard error of pooled estimate:

Image er-chronichepeq8.jpg

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


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​
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Cover of Management of Chronic Hepatitis B
Management of Chronic Hepatitis B.
Evidence Reports/Technology Assessments, No. 174.
Wilt TJ, Shamliyan T, Shaukat A, et al.

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