ISSUES IN HBV
From Viral Hepatits Summit, sponsored by the Cleveland Clinic
| EPIDEMIOLOGY AND GLOBAL BURDEN OF VIRAL HEPATITIS B—Brian J. McMahon, MD, Scientific and Medical
Director, Liver Disease and Viral Hepatitis Program, Alaska Native Medical Center, and Guest Researcher, Arctic Investigations
Laboratory, Centers for Disease Control and Prevention, Anchorage, AK
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| Incidence: 1 in 3 people in world exposed to hepatitis B virus (HBV); 350 to 400 million chronically infected and at risk for
complications (hepatocellular carcinoma [HCC] and cirrhosis); worldwide, 1.4 million deaths annually; in United
States—Third National Health and Nutrition Examination Survey (NHANES III) found prevalence of HBV 0.4%; survey
consisted primarily of whites, Hispanics, and blacks; Asian Pacific Islanders underrepresented; American Indians and Alaskan
natives not represented; other high-risk groups (institutional residents, homeless, and incarcerated) also not represented
(NHANES IV correcting for this); of people with HBV worldwide, 75% Asians; overall incidence in United States 1 in 200
(1 in 10 in Asian-Americans); chronic HBV infection in Asians associated with significant morbidity and mortality;
survey—by Centers for Disease Control and Prevention (CDC) in New York City; screened 925 Asians and Pacific Islanders;
prevalence ≈15%; of those in United States 10 yr, 12% hepatitis B surface antigen (HBsAg)-positive; higher percentage
in those in United States <10 yr; necessary to screen first-generation Asian-Americans for HBV markers, vaccinate negatives,
and evaluate positives for complications
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| Who should be screened: immigrants and adoptees from areas where HBV endemic; test subsequent generations if first-
generation found HBsAg-positive; CDC recommends screening individuals with abnormal liver function tests (LFTs) and
those with hepatitis C or HIV, and vaccinating all found seronegative; other high-risk groups include health care workers,
household and sexual contacts of HBsAg-positive persons (HbsAg marker for active infection), and hemodialysis patients
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| Modes of transmission by age group: perinatal—mother HBsAg-positive and usually hepatitis B e antigen
(HBeAg)-positive (marker for high infectivity); if nothing done, risk for chronic carriage 90%; early childhood—birth to
5 yr of age; inapparent parenteral transmission through open cuts and scratches and shedding virus on surfaces; unsafe injections
play role; late childhood, adolescence, and adulthood—unsafe injections, sexual contact, and injection drug use;
unlike HIV and hepatitis C, HBV hardy and can survive outside body ≤7 days; infected person can have 1010 copies/mL and
can shed billions of viruses from open cuts, scratches, and insect bites (horizontal transmission); risk of developing
chronic HBV infection—depends on when person infected; if infected at birth, risk 90%, unless vaccine and HBV immune
globulin (HBIG) given; if infected after birth but before first 5 yr of life, risk 25% to 30%; if >5 yr of age, risk 6%
to 10%; more cases of HCC from HBV than from cirrhosis (opposite of hepatitis C); ≈3000 per 100,000 per year (significant
problem in older people infected from birth)
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| HBV genotypes: 8 identified (A to H); based on 8% divergence in complete sequence of HBV genome; DNA in subgenotypes
differs by 4% to 8%; genotypes B and C predominant in Asia; B divided into several subtypes; genotype A
found in Northern Europe and South Africa; genotype A1 associated with high rates of HCC in young adults (not associated
with cirrhosis); genotype A2 associated with liver disease in older people; genotype D found in Southern Europe,
Asia, and India and associated with anti-HBe-positive chronic HBV infection after seroconversion; genotypes F and H
found in Americas (New World genotypes); in United States, genotypes A, B, C, and D present, distribution depends on
ethnicity distribution (west coast has predominantly B and C; east coast and south have predominantly A and D);
HBeAg-positive patients more likely to transmit during pregnancy; speaker believes genotype (not ethnicity) determines
transmission of HBV, eg, genotype C associated with perinatal transmission, while others associated with horizontal
transmission
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| Global prevention: Global Alliance for Vaccines and Immunization (GAVI)—partnership between public and private
organizations committed to improving immunization worldwide; provides technical and financial support to introduce
vaccines to countries and ensure that vaccines given in sterile manner; HBV included; in United States—dramatic
drop in HBV in all age groups due to routine childhood immunization, Occupational Safety and Health Administration
(OSHA) rules for health care workers, and adolescent immunization; when newborn immunization introduced, carrier
rate decreased immediately in children 10 yr of age; China study—showed decreased HBV incidence in children 10 yr
after start of routine childhood immunization; HBV vaccine first one to prevent cancer; immunizing population changes
natural history of disease
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| NATURAL HISTORY OF VIRAL HEPATITIS B—Eugene R. Schiff, MD, Leonard Miller Professor of Medicine, Chief,
Division of Hepatology, and Director, Center for Liver Disease, University of Miami Miller School of Medicine, Miami,
FL
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| Natural history of HBV: must be interrupted; once malignant transformation occurs, “the die is cast,” ie, some patients
develop liver cancer even if made HBV DNA-negative; HBeAg-negative patients do worse than HBeAg-positive ones;
many develop active disease because of core-promoter mutations, or precore mutations (natural history of disease acquired
at birth); in beginning, patients immunotolerant (do not clear HbsAg), but they become less tolerant to virus as
they get older, leading to enzyme elevation and histologic injury; some seroconvert into asymptomatic carriers or develop
active chronic hepatitis when HBeAg-negative
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| Categories of HBV patients: HBeAg-positive—younger, have higher viral levels, more infectious, and may or may
not have active disease (but likely to); HBeAg-negative asymptomatic carriers—classically, have undetectable or
low HBV DNA, HBsAg-positive, and have normal aminotransferases; people who remain asymptomatic carriers
throughout lives do relatively well, although still at risk for HCC; HBeAg-negative with active viral replication—
have chronic hepatitis
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| Natural history of HBV: can never eradicate virus (residual component of covalently closed circular DNA [cccDNA] in
nuclei of hepatocytes, and virus integrated into genome); patient who gets acute HBV as adult highly unlikely to develop
chronic disease (<1%); infection early in life, particularly through perinatal transmission, most likely to lead to chronic
disease; once chronic hepatitis established, ≈30% expected to get cirrhosis (salvaged with antiviral therapy and liver
transplantation); reinfection of transplanted liver prevented in majority of cases by use of antivirals and HBIG (not possible
with hepatitis C); risk for HCC always present and increases with severity of underlying disease
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| Differentiating HBeAg-negative chronic disease from asymptomatic carrier state: particularly difficult when
aminotransferases normal; negative viral level favors carrier state; if viral level low, difficult to differentiate; must follow
these patients
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| HBeAg seroconversion to anti-HBe in Asian patients: more complications in HBeAg-negative group (older);
among HBeAg-negative patients in Mediterranean, >90% have precore mutations; in Asia, 40% to 70% have core promoter
and 45% to 56% have precore mutations; in study of 79 Chinese patients with cirrhosis-related complications, 67%
anti-HBe-positive; of those, 25% had <104 copies/mL; in another study of 165 Chinese patients, 45% of those HBeAg-
negative had active disease and had <105 copies/mL; not possible to define cutoffs for HBV DNA values for HBeAg-
negative patients with active and inactive disease
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| Adverse outcomes in chronic HBV: some patients with chronic HBV develop cirrhosis (2%-6% for HBeAg-positive;
8%-10% for HBeAg-negative); with compensated cirrhosis, 3% to 5% decompensate and die or undergo liver transplantation;
increasing rates of HCC seen along continuum from carrier to death
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| HBV disease progression: acute HBV infection more likely to spontaneously seroconvert, but morbidity decreased by
treatment; factors that affect progression—coinfection with HIV; chemotherapy (causes reactivation in asymptomatic
carriers, leading to reconstituted host immune response with large viral load, and fulminant hepatitis in some cases);
antivirals
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| HBV disease burden in United States: the higher the level of viremia, the more likely development of HCC or
chronic liver disease; problem of determining who will develop HCC and when to start treatment; many patients who
progress with complications have subtle elevations of alanine transaminase (ALT; 1-2 times upper limit of normal
[ULN]); those with much higher levels more likely to seroconvert, and those with below-normal levels more likely asymptomatic
carriers
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| HBV TREATMENT IN CHILDREN —Maureen M. Jonas, MD, Associate Professor of Pediatrics, Harvard Medical
School, and Associate in Gastroenterology, Children’s Hospital Boston, MA
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| Monitoring of children with chronic hepatitis B: measure ALT every 6 mo; check HbeAg status annually; consider
alpha-fetoprotein (AFP) levels; HCC described in children; liver ultrasonography (US; but no data as to when to begin);
in pediatric lamivudine trial, large percentage of children (2 to 17 yr of age) had no or mild fibrosis at time of entrance,
but large percentage already had moderate to severe fibrosis (before therapy); disease not linear, eg, in some patients, fibrosis
early phenomenon
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| Algorithm for chronic HBV infection: not evidence-based; patient must be ≥2 yr of age (medications not tested or approved
for children <2 yr of age); must have active viral replication (most children HBeAg-positive); if patient HBeAg-
positive with measurable HBV DNA, ALT should be checked on several occasions to ensure consistently abnormal; if
ALT persistently normal, benefit of treatment not clearly established and therapies not clearly effective (monitor frequently);
if ALT persistently abnormal (1.5-2 times ULN), consider liver biopsy and continue to monitor patient (speaker
would treat)
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| Medications: only interferon-α (IFN-α not pegylated IFN) and lamivudine approved for pediatric use in United States;
meta-analysis—found loss of HBV DNA and HBeAg and normalization of ALT in children treated with standard
IFN vs placebo; study—all participants had abnormal ALT values, with mean of at least twice ULN; 35% of treated
group vs 11% of control group had HBeAg seroconversion within 1 yr and some had HbsAg conversion within observation
period
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 | IFN-α: for children ≥2 yr of age; dose 6 MIU/m2 for 6 mo; families advised that seroconversion can occur during treatment or
within year after; side effects include weight loss, failure to gain weight, depression, and suicide; also irritability, behavioral
disturbance, and possibly cognitive dysfunction
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| Lamivudine: trial—288 children; found loss of HBeAg in 23%, compared to 13% with placebo; 35% if baseline ALT at
least twice ULN (comparable to IFN); excellent safety and tolerability; resistance encountered; when lamivudine extended
for 2 yr in patients who had not seroconverted, continued virologic response present, as long as no resistance
developed; dosage 3 mg/kg up to 100 mg; recommended only for children with active liver inflammation; 1 yr of treatment
minimum; no data about how long to treat nonresponders; up to 3 yr safe if no resistance
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| Lamivudine and IFN: Turkish study of 3 groups of children with abnormal ALTs; different combinations of lamivudine
and IFN; found no significant difference in virologic response; study—21 children with normal ALTs and mildly abnormal
liver biopsies; lamivudine given first for 8 wk, then combination lamivudine and IFN for 10 mo; results showed
HBeAg seroconversion rate 22% and loss of HBsAg 17%, with no lamivudine resistance
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| Challenges in pediatric HBV infection: deletion of term “carrier” (implies benign prognosis); detection of children
with active liver disease (may be candidates for therapy); cultural issues; identification of best treatment; use of genotype
in selecting treatment; clarification of best cancer surveillance program; earlier access to new therapies; emergence of
HBeAg-negative hepatitis B
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| ROLE OF INTERFERONS IN HBV TREATMENT —Mitchell L. Shiffman, MD, Professor of Medicine, Virginia Commonwealth
University Medical Center, Richmond, VA
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| IFN and immune response to HBV infection: in HbeAg-positive patient, IFN mimics process of spontaneous seroconversion
(ie, interferon given for fixed period; HBV DNA becomes undetectable; HBeAg becomes undetectable; flare
in liver transaminases; anti-HBe becomes positive; liver transaminases normalize); IFN stimulates immune system (reason
for caution when using IFN in cirrhosis); long-term effects excellent; data—10-yr follow-up of original National Institutes
of Health (NIH) cohort using standard IFN to treat hepatitis B; 5 MIU daily for 16 wk; 33% seroconversion rate;
over 10 yr, 85% lost HBsAg, with appearance of anti-HBs, indicating complete seroconversion and eradication of HBV;
predictors of response to IFN—recent acquisition of disease; elevated ALT or low DNA at start of treatment; non-
Asian ethnicity; HBV genotype; prednisone priming—thought that priming and withdrawal of prednisone would
cause flare in liver transaminases, creating more favorable environment for seroconversion; multicenter randomized controlled
trial found no benefit (seroconversion rate same [≈33%])
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| Goals of IFN therapy: in HBeAg-positive group, goal loss of HbeAg, seroconversion to anti-Hbe; associated with normalization
of transaminases, loss of detectable HBV DNA, and improvement in liver histology; theoretically reduces risk
for HCC and eventually causes loss of HBsAg; HBeAg-negative patients with active hepatitis B unable to seroconvert;
therefore, goal simply to normalize liver enzymes and reduce HBV DNA level, leading to histologic improvement (unknown
whether reduction of risk for liver cancer and loss of HBsAg occurs)
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| Peginterferon: at time of study of peginterferon alfa-2a 180 µg once weekly vs placebo, lamivudine approved, so unethical
to have no-treatment group; middle group had IFN plus lamivudine; all groups treated 48 wk; results showed
peginterferon significantly better than lamivudine in normalizing ALT, lowering HBV DNA to undetectable range, and
rate of seroconversion increasing; adding lamivudine to peginterferon did not enhance process; predictors of
seroconversion—same as in original IFN studies; include level of HBV DNA (lower the level, higher the rate of seroconversion)
and liver transaminases (higher rate associated with slightly higher seroconversion rate); most important factor
genotype; genotype A particularly susceptible to IFN therapy (slightly >50% of patients achieve seroconversion);
accounts for 40% of genotypes in United States (non-Asians); dose and duration of therapy—original phase 2 study
compared standard IFN to various doses of peginterferon for 24 wk; results showed almost identical rates of seroconversion
(90 µg/wk equivalent to 180 µg/wk); original IFN studies did not look at HBeAg-negative status (thought that IFN
would push HBeAg-positive patients to seroconversion); side effects from IFN significantly less in hepatitis B patients
than hepatitis C; advantages of IFN—for HBeAg-positive patients, include finite treatment (24 or 48 wk) and absolute
response; long term, leads to HBsAg loss and anti-HBs; treatment better tolerated; one caveat risk for decompensation;
for HBeAg-negative patients, treatment duration not well defined; in some, response maintained for months or years after
treatment; may require periodic retreatment or maintenance IFN therapy; consider if resistance to antiviral agents present
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Suggested Readings
Bonino F et al: Peginterferon Alfa-2a HBeAg-Negative Chroni. Hepatitis B Study Group. Predicting response to peginterferon
alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 56:699, 2007; Chen CJ et
al: REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus
DNA level. JAMA 295:65, 2006; Chun S et al: Combination therapy for chronic hepatitis B: a one-two knockout punch, or
a swing and a miss? Gastroenterology 130:613, 2006; Hoofnagle JH: Hepatitis B--preventable and now treatable. N
Engl J Med 354:1074, 2006; Huo TI et al: Do baseline ALT levels predict complications of chronic hepatitis B? Gut
55:745; Ikeda K et al: Long-term outcome of HBV carriers with negative HBe antigen and normal aminotransferase. Am J
Med 119:977, 2006; Kripke C: Hepatitis B vaccine for infants of HBsAg-positive mothers. Am Fam Physician 75:49,
2007; Kumar M et al: Differentiating acute hepatitis B from the first episode of symptomatic exacerbation of chronic hepatitis
B. Dig Dis Sci 51:594, 2006; Livingston SE et al: Hepatitis B virus genotypes in Alaska Native people with hepatocellular
carcinoma: preponderance of genotype F. J Infect Dis 195:5, 2007; Rugge JB et al: What is the best surveillance
for hepatocellular carcinoma in chronic carriers of hepatitis B? J Fam Pract 55:155, 2006; Tanaka Y et al: Genetic diversity
of hepatitis B virus as an important factor associated with differences in clinical outcomes. J Infect Dis 195:1, 2007;
Weitzman G et al: Cost-effectiveness in hepatitis B. Ann Intern Med 143:757, 2005
Educational Objectives
| The goal of this program is to improve the management of hepatitis B virus (HBV) infection. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Determine which individuals should be screened for HBV.
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| 2. Review which HBV genotypes predominate in the United States and different parts of the world.
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| 3. Differentiate the various categories of HBV patients and their prognoses.
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| 4. Discuss the algorithm for treating HBV infection in children.
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| 5. Explain the factors associated with seroconversion.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the following has been disclosed: Dr. McMahon reports that his spouse owns shares of
GlaxoSmithKline. Dr. Jonas reports that he is an investigator for Gilead Sciences, Inc. and Schering-Plough Research Institute
and a consultant for Bristol-Myers Squibb. Dr. Schiff reports that he is consultant for Abbott, Achillion Pharmaceutical,
Bayer, Bristol-Myers Squibb, Cadence Pharmaceuticals, Gilead, GlobeImmune, Inc., Idenix, Maxim, Ortho-Biotech, Pharmasset,
Inc., Pfizer, PowerMed Limited, Prometheus, Roche Molecular, Salix Pharmaceuticals, Inc., Schering-Plough, and
SciClone Pharmaceuticals, receives grant or research support from Abbott, Bayer, Bristol-Myers Squibb, Coley, Gilead,
GlaxoSmithKline, Idenix, Ortho-Biotech, Prometheus, Roche Diagnostics, Roche Molecular, Roche Pharmaceutical, Schering-Plough,
SciClone Pharmaceuticals, and Vertex Pharmaceuticals, and is on the Speakers’ Bureaus of Abbott, Bristol-Myers
Squibb, Gilead, GlaxoSmithKline, Idenix, Maxim, and Schering-Plough. Dr. Shiffman reports that he is a consultant for
Roche and Gilead, is an investigator for Schering-Plough, Gilead, and Bristol-Myers Squibb, and is on the Speakers’ Bureaus
of Roche, Gilead, and Bristol-Myers Squibb.
Acknowledgements
Drs. McMahon, Schiff, Jonas, and Shiffman were recorded at Viral Hepatitis Summit, held August 24-26, 2006, in Cleveland,
OH, and sponsored by the Cleveland Clinic. The Audio-Digest Foundation thanks the speakers and Cleveland Clinic
for their cooperation in the production of this program.
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