Article gastroenterology

Chronic Viral Hepatitis:

Always Be Current!
Jay A. Hochman, MD,*
Objectives After completing this article, readers should be able to:
William F. Balistreri, MD†
1. Define the natural history of hepatitis B and hepatitis C infections.
2. Identify clinical manifestations and complications of hepatitis B and hepatitis C
infections.
3. Discuss strategies for treatment and prevention of chronic viral hepatitis.

Introduction
Rapid progress in understanding viral hepatitis during the past 15 years has led to direct
improvements in prevention, detection, and treatment. This expansion of knowledge has
immediate implications for bedside management, including the use of new molecular-
based assays for diagnosis and management of chronic viral hepatitis and potent therapeu-
tic antiviral drugs (Table 1).
Primary acute viral infection of the liver in the United States is caused most commonly
by one of three hepatotropic viruses: hepatitis A (HAV), hepatitis B (HBV), and hepatitis
C (HCV). In 1992, a Centers for Disease Control and Prevention survey showed that
HBV accounted for 41% of the cases, HAV for 33%, and HCV for 26%. Besides these
hepatotropic viruses, many other infectious agents and noninfectious diseases can cause
hepatitis, including Epstein-Barr virus, cytomegalovirus, alpha-1-antitrypsin deficiency,
autoimmune hepatitis, Wilson disease, drug/toxin-associated hepatitis, steatohepatitis,
ischemic hepatitis, and a wide range of disorders in newborns. All morbidity and mortality
due to HAV can be prevented with widespread use of HAV immunization. In this review,
the two infections responsible for chronic viral hepatitis, HBV and HCV, are discussed.

Hepatitis B
Epidemiology
HBV is a 42-nm double-stranded DNA virus from the hepadnavirus family that has
multiple genotypes and serotypes capable of causing chronic
disease. HBV has infected approximately 2 billion people
worldwide or one third of the world’s population. Of the
Abbreviations 350 million persons who live with chronic HBV, 15% to 25%
AAP: American Academy of Pediatrics risk dying due to HBV-related chronic liver disease, includ-
ACIP: American Council on Immunization Practices ing chronic hepatitis, cirrhosis, and hepatocellular carcinoma
ALT: alanine aminotransferase (HCC). Approximately 1 million deaths annually are due to
HAV: hepatitis A virus HBV. In the United States, 1.25 million people have chronic
HBIG: hepatitis B immune globulin HBV infection that results in more than 5,000 deaths each
HBV: hepatitis B virus year.
HCC: hepatocellular carcinoma Most HBV infections occur after exposure resulting from
HCV: hepatitis C virus sexual activity, injection drug use, occupational exposure, or
HIV: human immunodeficiency virus via maternal-fetal transmission (Table 2). Less frequent
IFN: interferon sources include household contact, hemodialysis, and receipt
PCR: polymerase chain reaction of blood products. HBV transmission occurs most efficiently
PEG-IFN: pegylated-interferon through direct percutaneous exposure to blood from chronic
carriers where HBV is present in large quantities (108 to 1010

*Children’s Center for Digestive Healthcare, Associate Clinical Professor of Pediatrics, Emory University School of Medicine,
Atlanta, GA.
†
Dorothy Kersten Professor of Pediatric Gastroenterology and Nutrition; Director, Pediatric Gastroenterology, Nutrition, and
Hepatology, Children’s Hospital Medical Center, University of Cincinnati Medical School, Cincinnati, OH.

Pediatrics in Review Vol.24 No.12 December 2003 399

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gastroenterology chronic viral hepatitis
Table 1. Advances in Viral Hepatitis
Advance
Hepatitis A recognized
Hepatitis B strains and hepatitis A virus
isolated
Fecal excretion of hepatitis A documented
Hepatitis D (delta) identified
Vaccine for hepatitis B licensed
Hepatitis C virus identified
Hepatitis E virus identified
Vaccine for hepatitis A licensed
Ribavirin/Interferon treatment for hepatitis C
Hepatitis G recognized
Pegylated interferon treatment for hepatitis C
virions per milliliter), although improved screening tech-
niques have lowered the risk of contracting HBV from a
single blood transfusion to less than 1 in 60,000. Lower
concentrations of HBV are found in all body fluids,
including saliva, semen, cervical secretions, and human
milk. HBV is not present in stool.
Clinical Aspects and Pathogenesis
Symptomatic HBV infection presents with a prodrome
of malaise, fatigue, anorexia, nausea, and low-grade fever
after an incubation period of 45 to 160 days (Fig. 1).
Subsequently, jaundice develops in association with ele-
vated serum aminotransferase levels. Less common clin-
ical features include papular acrodermatitis (Gianotti-
Crosti syndrome) and glomerulonephritis. HBV also
Children and Adolescents at
Table 2.
High Risk for Chronic Hepatitis
Risk Groups HBV
Infants born to infected mothers ⴙⴙⴙ
Children from endemic areas ⴙⴙⴙ
Adolescents involved in sexual contact* ⴙⴙ
Adolescents involved in parenteral drug ⴙⴙ
abuse
Institutionalized children ⴙⴙ
Classroom contacts of developmentally ⴙ ⴚ
disabled carriers
Recipients of hemodialysis ⴙ ⴙ
Recipients of blood product transfusion ⴞ†
before 1992
*All homosexual sexual encounters and nonmonogamous heterosexual
activity are considered high-risk.
†
Pediatric population at low risk due to routine screening of blood
products for HBV prior to 1992.
400 Pediatrics in Review Vol.24 No.12 December 2003
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may cause fulminant hepatic failure. In these cases, jaun-
dice persists and encephalopathy and coagulopathy de-
Year velop.
Diagnosing HBV relies on serology (Tables 3 and 4).
1947
1967 The presence of HBsAg indicates acute or chronic infec-
tion. Usually antibodies to the core antigen (anti-HBc)
1973 of the immunoglobulin M class are present during acute
1977 HBV infection. The persistence of HBsAg for more than
1982
6 months has been the “gold” standard to diagnose
1989
1990 chronic HBV infection. The presence of HBeAg indi-
1996 cates active viral replication in both acute and chronic
1996 infection. Currently, the ability to detect HBV DNA by
1996 polymerase chain reaction (PCR) also serves as a marker
2000
of both infection and viral replication. Furthermore,
quantitation of HBV DNA helps to predict the response
to antiviral therapy. Immunity to HBV is indicated by the
development of anti-HBs, which usually appears 3 to 4
months after the clearance of HBsAg. Not all acutely
infected individuals clear HBsAg; many patients become
chronic carriers or have chronic hepatitis B (Fig. 2).
The host immune attack triggered by HBV causes
liver injury in the immunocompetent host. This attack is
mediated by a complex cellular response to HBV pro-
teins, especially HBcAg, on the surface of the hepatocyte.
For most patients who have competent immune systems,
the virus is effectively eradicated. When HBV is not
cleared, insufficient recognition and activation occurs
between the HBV antigens presented by the host major
histocompatibility complex molecules and the specific
T-cell receptor repertoire of the host. Therefore, the host
response cannot destroy all infected cells completely.
Among individuals incapable of clearing HBV, there
are two clinical patterns of chronic HBV infection:
1) chronic liver disease, with elevated aminotransferase
levels and abnormal hepatic histology, and 2) an asymp-
tomatic carrier state that is characterized by no biochem-
HCV ical (normal aminotransferase values) or clinical features
of infection.
ⴙ
In the perinatal period, symptomatic HBV infection is
ⴞ
ⴙⴙ rare. If exposure occurs, usually through vertical trans-
ⴙⴙ mission, 95% of the neonates develop chronic infections
in the absence of HBV prophylaxis. Most affected indi-
ⴚ viduals are asymptomatic carriers. After the neonatal
period and before approximately 6 years of age, the risk
of chronic HBV is approximately 30% after contracting
ⴙⴙⴙ HBV. Most older children and adults clear the virus; the
risk of chronic HBV is 3% to 5% (Fig. 2).
Although most neonates have asymptomatic infec-
tion, the age at time of acquisition of primary HBV
infection may be a key factor in carcinogenesis; liver
cancer prevalence in areas of HBV endemicity is highest
 gastroenterology chronic viral hepatitis

of this review; additional informa-

tion can be found in the Suggested
Reading.

Immunoprophylaxis and
Treatment
An effective vaccine for HBV has
been available since 1982. How-
ever, the initial vaccination pro-
gram that targeted high-risk groups
made little progress in eradicating
this common infection. Addition-
ally, primary prophylactic measures,
including the promotion of con-
doms and efforts to eliminate con-
taminated needles, were not effec-
tive in reducing the incidence of
HBV. Subsequently, in 1991, the
practice of vaccinating all newborns
with the current vaccine, a recom-
binant DNA-produced HBsAg,
Figure 1. Typical course of HBV Infection. The earliest marker of HBV infection following
was proposed by the American
exposure is a rise in HBsAg. Increases in HBV DNA and HBeAg follow. Clearance of the
infection is indicated by the presence of anti-HBs, although anti-HBc IgM may be the only
Council on Immunization Prac-
marker of HBV infection after clearance of HBsAg. This antibody, anti-HBc, is not a tices (ACIP) and approved by the
neutralizing antibody despite indicating a host response to HBV. American Academy of Pediatrics
(AAP). A similar strategy reduced
the incidence of HBsAg positivity
among those infected with HBV in early life. Further- as well as the incidence of HCC in children after a
more, routine vaccination in these endemic regions re- 10-year nationwide campaign in Taiwan, which has a
duces the incidence of HCC. In the absence of high endemic rate of HBV infection. More recently,
prevention/treatment of HBV, HCC occurs in 20% to mortality in Taiwan from fulminant hepatitis in infants, a
50% by age 72 years. complication of HBV infection, has been reduced as a
consequence of HBV vaccination.
HBV Mutants Immunoprophylaxis also relies on use of hepatitis B
The application of molecular tech-
niques has shown that the HBV Table 3. Serologic Markers of Hepatitis B Infection
genome has a significant mutation
rate. The rate of mutation is related Tests for HBV Description Presence Indicates
to the viral replication cycle, which
HBsAg Surface antigen of HBV Acute or chronic infection
involves a reverse transcriptase Anti-HBs Antibody to surface antigen Immunity due to viral clearance or
mechanism that is similar, but not immunization
identical, to that of retroviruses. HBeAg e antigen Active viral replication and
The biologic consequences of HBV increased infectivity
Anti-HBe Antibody to HBeAg Low risk of transmitting virus;
genome mutations include not pro-
asymptomatic carrier in those
ducing HBsAg or HBeAg despite who have HBsAg
detectable viral DNA. “Vaccine es- IgM Anti-HBc IgM antibody to HBV core Acute HBV infection
cape” mutants, also rare mutations, antigen
allow for HBV to develop in indi- Anti-HBc Total antibody to HBV core Present or past HBV infection
antigen (IgG and IgM)
viduals who have been vaccinated.
HBV DNA Quantitates HBV viremia Active replication of HBV
A full discussion of these rare HBV level by PCR
mutant strains is beyond the scope

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gastroenterology chronic viral hepatitis

Table 4. Summary for Viral Hepatitis tion due to the presence of thimer-
osal (mercury-based preservative)
Type of Hepatitis Hepatitis Serology/PCR* Indications for Referral in the vaccine. Despite the availabil-
ity of thimerosal-free vaccine 2
Acute Hepatitis† HAV: IgM anti-HAV –Altered liver synthetic function
HBV: HBsAg, IgM anti-HBc –Underlying disease months later, investigators have
HCV: anti-HCV (EIA) –Newborn confirmed a decrease in immuniza-
–Diagnosis uncertain tion rates among newborns in
Chronic Hepatitis HBV: HBsAg, anti-HBs, –All confirmed cases hospital nurseries. This interrup-
HBeAg, HBV DNA
tion in HBV vaccination has re-
HCV: anti-HCV (EIA), HCV
RNA sulted in at least one case of ful-
minant HBV in an infant. In
*PCR assays usually are not necessary to establish infection. Primarily, these assays are useful to predict
response to treatment or when serology is not reliable, such as during the newborn period. addition, in a recent survey, 24%
†
Assumes exclusion of toxic (eg, acetaminophen), metabolic, or systemic disease of hospitals did not have policies
to vaccinate infants whose moth-
ers’ HBsAg status was unknown;
6% did not have immunopro-
immune globulin (HBIG), which provides temporary phylaxis policies for infants born to HBsAg-positive
immunity. HBIG is indicated in conjunction with the mothers.
vaccine in all cases of possible perinatal exposure, in Despite these setbacks, the overall trend has been a
accidental percutaneous/permucosal exposure, and in decline in acute HBV among children younger than 15
household contacts who have been exposed to blood. years of age as a result of immunization from an esti-
Transmission of perinatal HBV can be prevented in 95% mated 0.66 per 100,000 in 1990 to 0.16 per 100,000 in
of infants born to HBsAg-positive mothers by early 1998. Vaccine coverage surveys demonstrate that 88% of
administration of HBIG (within 12 hours of birth) along 19- to 36-month-old children and 48% of adolescents
with vaccination. Therefore, it is
imperative that all pregnant moth-
ers be screened for HBV. These
mothers can breastfeed as long as
the susceptible neonates have
started vaccination and HBIG.
Despite the importance and suc-
cess of immunoprophylaxis, con-
troversy and obstacles remain. In
1998, French authorities sus-
pended HBV vaccination in school-
age children due to concerns re-
garding multiple sclerosis resulting
from HBV vaccine. Subsequent
studies have demonstrated no cor-
relation between multiple sclerosis
and HBV vaccination. In fact, the
Institute of Medicine stated em-
phatically, “no causal relationship
between vaccination and multiple
sclerosis” exists, and there has been
no evidence to link any other dis-
Figure 2. Clinical sequelae of HBV infection. The sequelae of HBV are age-related. Among
eases (eg, autism) to HBV vaccina- neonates born to HbsAgⴙ mothers who do not receive HBV prophylaxis, approximately
tion. 5% clear HBV and recover completely. Most develop a persistent infection. Between 1 and
In 1999, the AAP and the 5 years of age, only 30% of affected children recover completely. After age 5 years,
United States Public Health Service approximately 95% of affected children clear acute HBV and recover without sequelae. In
recommended delays in immuniza- all age groups, a small percentage develop fulminant hepatic failure.

402 Pediatrics in Review Vol.24 No.12 December 2003

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have been immunized. Immunizing adolescents, al-
though difficult, is important because of the chance of
acquisition during unprotected sexual activity. HBV re-
mains the leading vaccine-preventable sexually transmit-
ted disease.
The discovery that a two-dose (10-mcg) vaccination
regimen is as effective as a three-dose regimen may
facilitate immunization in this population. This advance-
ment was shown in a study involving 1,026 adolescents
randomized to five treatment groups. With all of the
regimens, anti-HBs was induced in more than 95% of
vaccinees. Ultimately, the dosing regimen will assume a
lesser importance when the cohort of vaccinated infants
reaches adolescence, but even then, immunization of
older patients at risk will remain a priority.
Although progress in preventing HBV through im-
munization has been slow in the United States, it is
essential because progress in treating this infection has
been difficult. Currently, the mainstay of treatment is
interferon (IFN), which was approved by the United
Immunizing adolescents is
important . . . . HBV remains the leading
vaccine-preventable sexually transmitted
disease.
States Food and Drug Administration in 1992. The
rationale for IFN treatment is that it would allow for
exogenous IFN activity in patients who have deficient
endogenous IFN responses to HBV. Administration of
recombinant IFN may lead to both immunomodulatory
and antiviral effects by promoting viral lysis by CD8⫹
cytotoxic lymphocytes and by directly inhibiting viral
protein synthesis. Among adults and children, treatment
with IFN in selected study patients resulted in a 30% to
45% remission rate after 4 months of therapy. Results are
less favorable in perinatally infected Asian children, who
often have high circulating HBV DNA levels and low
levels of inflammatory activity, both biochemically (low
aminotransferase concentrations) and histologically on
liver biopsy.
Criteria for a favorable response to IFN in adults and
in children include elevated aminotransferase levels, the
presence of HBV DNA (at a level of less than 200 pg/
mL), and a liver biopsy indicating moderate or severe
inflammatory activity. Typical dosing in adults has been
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gastroenterology chronic viral hepatitis
5 million units (MU) administered subcutaneously each
day or 10 MU administered three times per week for
16 weeks. In pediatric studies, IFN doses are frequently
5 to 6 MU/m2 three times a week. Due to the expense,
pain of injections, extensive adverse effect profile, and
suboptimal response rate, the decision to treat with IFN
must be considered carefully. Although IFN has been
described as well tolerated in pediatric studies, large
randomized studies have not been performed. In addi-
tion, the treatment responses have evaluated primarily
surrogate markers, such as loss of HBeAg and HBsAg,
because cirrhosis and HCC may not develop for many
years. Therefore, the precise risk/benefit ratio of IFN is
difficult to assess. Among asymptomatic children who
have HBV and normal aminotransferase concentrations,
cumulative data have not shown a clear benefit for anti-
viral therapy. Furthermore, a recent study has suggested
that IFN may accelerate the clearance of HBeAg in
predisposed pediatric patients but not necessarily alter
the natural history. After 5 years, among 107 patients
who had participated in two con-
trolled trials, the conversion rate
to HBeAg-negative was the same
when treated children were com-
pared with controls.
Fortunately, additional treat-
ments are emerging for HBV.
Lamivudine, a nucleoside analog,
inhibits both human immunode-
ficiency virus (HIV) and HBV
replication. In nearly 100% of pa-
tients treated with lamivudine, HBV DNA levels become
undetectable and liver histology improves, although sus-
tained remissions when the drug is withdrawn are seen in
fewer than 30% of patients, and escape mutants develop
with prolonged therapy.
Pediatric data with lamivudine include a double-
blind, placebo-controlled study of 286 children. Among
the inclusion criteria were elevated alanine aminotrans-
ferase (ALT) levels (⬎1.3 times upper limit of normal).
After 52 weeks of treatment, 26% of lamivudine-treated
patients had loss of HBeAg compared with 15% of con-
trol patients. Sustained normalization of ALT occurred
in 55% of treated patients (13% of controls), and loss of
HBV DNA occurred in 61% (16% of controls). Better
results were noted when the data were analyzed with
respect to patients whose baseline ALT levels were more
than twice normal. In this subgroup, a complete viro-
logic response (loss of HbeAg and HBV DNA) was
noted in 34% of treated patients and 16% of the placebo-
control children. The development of YMDD mutant
Pediatrics in Review Vol.24 No.12 December 2003 403
gastroenterology chronic viral hepatitis
HBV strains was detected in 18% of treated patients.
Based on these data, lamivudine recently was approved
by the FDA for use in pediatric patients 2 years of age and
older who have chronic HBV infection.
The pediatric and adult data make it clear that lami-
vudine has a role in select patient populations, including
liver transplant recipients. In other patients who require
treatment due to symptomatic or progressive HBV dis-
ease and intolerance to IFN, lamivudine is likely to be an
important therapy that may be maintained indefinitely
due to its minimal adverse effects.
Other antiviral agents are being evaluated for use in
HBV treatment. The most promising is adefovir dipi-
voxil. Adefovir is an analog of adenosine monophos-
phate that inhibits HBV DNA polymerase at levels
much lower than those needed to inhibit human DNA
polymerases. In a multicenter double-blind, placebo-
controlled trial involving adults infected with HBV,
adefovir dipivoxil resulted in histologic improvement
in 53% to 61% of patients with-
out the emergence of adefovir-
resistant HBV polymerase muta-
tions. The overall adverse profile
was similar to that of placebo,
although higher doses may affect
renal function. Studies in chil-
Transmission
can be prevented in 95% of infants born to
dren have not been published. HBsAg-positive mothers by early
In addition to new antivirals, administration of HBIG, within 12 hours of
an improved IFN, pegylated-
interferon (PEG-IFN), is available. birth, along with vaccination.
Its use has been studied for HCV
and is discussed in the HCV treat-
ment section. Recommendations/approval for the use of
PEG-IFN in children and in all patients who have HBV
are not available at this time.
Other aspects of care for children who have chronic
liver disease include monitoring for complications and
providing immunizations. Almost all children who have
chronic liver diseases benefit from additional immuniza-
tions to protect against HAV, varicella, influenza, and
pneumococcal infections. Monitoring for HCC with ul-
trasonography and serum alpha-fetoprotein levels in in-
dividuals who have chronic HBV should begin in child-
hood. Although HCC is considered an “adult disease,”
with a peak incidence in the fifth decade, it has been
documented as early as 9 months of age in association
with HBV. The frequency and effectiveness of screening
remain controversial; many pediatric gastroenterologists
recommend screening every 6 to 12 months with these
tools despite the lack of data showing that screening is
capable of detecting curable HCC.
404 Pediatrics in Review Vol.24 No.12 December 2003
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When complications such as fulminant liver failure,
cirrhosis, or HCC develop, liver transplantation is a
treatment option for both HBV and HCV. Clearly,
disease recurrence and graft survival emerge as promi-
nent issues. A full discussion of these topics is beyond the
scope of this review.
Hepatitis C
The discovery of HCV presents important issues for the
pediatric population. It has become clear that HCV is a
common disease among children that is underdiagnosed.
With widespread publicity about the spread of HCV,
many “silent” cases are coming to the attention of the
pediatric clinician. There are few data, however, regard-
ing the outcome of infants and children who are infected
with HCV. Furthermore, the efficacy of various treat-
ments has not been studied carefully, which has led to an
inability to develop definitive recommendations for man-
agement.
of perinatal HBV
Virology
In 1989, HCV was discovered and diagnostic assays
developed. Results of epidemiologic studies soon made it
clear that HCV was the major cause of posttransfusion
“non-A, non-B hepatitis.” This, in turn, led to wide-
spread screening of donated blood, which resulted in a
remarkable decrease in the incidence of posttransfusion
hepatitis.
HCV is an RNA virus of the flavivirus family. There
are nine known genotypes; the prevalence of each varies
geographically. The most common genotype in the
United States is type 1. The presence of HCV genotypes
and the genetic heterogeneity has important implications
for diagnosis, pathogenesis, treatment, and vaccine de-
velopment. For example, the rapid mutation rate of
HCV in defiance of the host immune response makes it
difficult to eliminate the virus. This leads to chronic
infection (Fig. 3). A unique HCV host-virus interaction
allows a continuous cycle. The initial host immune re-
 gastroenterology chronic viral hepatitis

anti-HCV antibody was present in

approximately 1.8% of 20,000 indi-
viduals, which extrapolates to al-
most 4 million individuals infected
in the United States. The preva-
lence was greatest among individu-
als in the 30- to 49-year age range
(Fig. 4). Of those who had anti-
HCV antibody, 74% had viremia
(HCV RNA-positive). In the pedi-
atric age range, the prevalence was
approximately 0.2% among 6- to
11-year-old children and approxi-
mately 0.4% in 12- to 19-year-olds.
The major risk factor for acqui-
sition of HCV is direct percutane-
ous exposure to the virus. Prior to
the initiation of universal blood
bank screening in the early 1990s,
this was due to receipt of blood or
blood products. With refinements
Figure 3. Clinical sequelae of HCV. Acute HCV infection is generally benign; only 20% of
affected patients have symptomatic infection, and fulminant hepatic failure is exceed-
in screening, the risk of HCV infec-
ingly rare. However, approximately 60% to 80% develop persistent infection that results tion from a single blood transfusion
in chronic hepatitis in most affected patients. Serious sequelae, including cirrhosis and is less than 1 in 100,000. At
hepatocellular carcinoma (HCC), may develop over many years in about 20% of infected present, major risk factors include
patients. The time course for these changes varies. Typically, cirrhosis is seen 20 years (or parenteral drug abuse, high-risk
more) following acquisition of HCV; the time course is even longer in patients who have sexual behavior, and tattooing (Ta-
normal aminotransferase levels. For this reason, the incidence of cirrhosis among pediatric ble 2). HCV transmission by sexual
patients is less than 5%. Cirrhosis most often precedes HCC by several years. or close physical contact is possible

sponse to HCV is effective tempo-

rarily, but the virus then mutates to
escape the immune response.
Therefore, within an individual
host, HCV exists as the heteroge-
neous mixture of closely related vi-
ruses called “quasi-species.” This
cycle allows perpetuation of vire-
mia, continuation of the inflamma-
tory process, and the emergence of
resistant strains. This feature also
makes vaccine development diffi-
cult.

Epidemiology
HCV infection occurs worldwide;
the overall prevalence is approxi-
mately 2% in adults, although this
varies widely. In a study of HCV Figure 4. HCV infection affects all age groups, with the lowest prevalence in children 6 to
prevalence in the United States, 11 years of age (0.2%) and a peak at ages 30 to 49 (3.9%).

Pediatrics in Review Vol.24 No.12 December 2003 405

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gastroenterology chronic viral hepatitis

but uncommon; HCV is not spread

efficiently by this route.
With widespread blood screen-
ing, the major route of HCV trans-
mission in the pediatric population
is via maternal-infant transmission.
Of infants born to anti-HCV-
positive women, approximately 5%
(range, 0 to 25%) acquire HCV. Of
infants born to women coinfected
with HCV and HIV, the rate of
perinatal infection is 14% (range,
5% to 36%). The difference is attrib-
utable to the higher titers of HCV
RNA in coinfected women. Recent
studies have attempted to deter-
mine maternal factors associated
with the risk of transmission. It ap-
pears that both internal fetal moni- Figure 5. Typical course of posttransfusion HCV infection. Approximately 2 to 12 weeks
toring devices and prolonged rup- following a blood transfusion, a slow rise in alanine aminotransferase levels indicates the
ture of membranes raise the risk of onset of hepatitis. HCV RNA can be detected at this time. Anti-HCV may be positive
transmission of HCV from an in- within 1 to 3 months of HCV infection. Most patients do not develop jaundice. Serum
fected mother to her child. Among levels of aminotransferases tend to fluctuate during the acute and chronic infected state.
infants delivered by elective cesar- Chronic infection develops in most patients; often, this results in only modest elevation
ean section, the risk of transmission of aminotransferase levels.
is low. Therefore, although routine
screening of all pregnant women for HCV is not recom- screening is not recommended by the AAP. The decision
mended, the data regarding additional perinatal risk fac- to test should be individualized.
tors suggest a value for maternal screening.
At present, it is recommended that all infants born to Outcome of Infection
HCV-infected women be screened for HCV. The ques- The natural history of HCV infection is variable; the
tions are when and how screening should be done. The most remarkable feature is the high rate of chronic infec-
length of time that passively acquired maternal antibody tion, which occurs in 60% to 80% of individuals following
persists is not known, but it is unlikely to be greater than acute HCV infection (Fig. 3). The typical course of acute
HCV infection is characterized by a mild systemic illness
12 months. Therefore, testing for anti-HCV should be
in most patients (Fig. 5). Early treatment offers the best
performed after 12 months of age.
chance for eradicating the infection among patients in
Another frequently asked question relates to the role
whom HCV is identified during the acute infection
of breastfeeding in the transmission of HCV. Acquisition
stage. In a study of 44 adults, the administration of IFN
of HCV from human milk has not been documented,
monotherapy eliminated HCV RNA in 42 of 43 patients.
and the overall rate of HCV transmission among breast- Among these patients, 9 contracted the infection due to
fed infants is the same as that among bottle-fed infants. It intravenous drug usage, 14 following needle-stick injury,
appears that maternal HCV infection is not a contraindica- 7 after a medical procedure, 10 due to sexual transmis-
tion to breastfeeding, although these observations are based sion, and 4 due to unknown causes. The most remarkable
on a small cohort of infants. Therefore, HCV-infected feature of this study was the rapid initiation of treatment,
mothers who wish to breastfeed should be counseled that which occurred an average of 89 days following HCV
although there appears to be no increased risk of transmis- infection and only about 1 month following initial symp-
sion, the data are limited, and the decision should be tomatology. Although this study did not involve children
individualized. who had acute HCV, urgent referral in this circumstance
At present, national and international adoptees are to a pediatric hepatologist is prudent so that potential
not at increased risk of HCV infection. Thus, routine treatment can be considered.

406 Pediatrics in Review Vol.24 No.12 December 2003

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Figure 6. Histologic stages of HCV infection. In panel A, a core
biopsy specimen from an adult patient who has chronic HCV
infection shows dense portal lymphocytic infiltrates (arrow)
and architectural changes (arrowhead) (hematoxylin and eo-
sin, x10). The lymphocytes are not limited to the portal tract,
but also extend into the lobules (arrowheads in panel B)
(hematoxylin and eosin, x100). Panel C shows normal liver
architecture with scant fibrous tissue (arrows) limited to the
portal tracts (trichrome stain, x20). During the progressive
course of infection, the fibrotic areas expand, and bridging
fibrosis develops (arrows in panel D) (trichrome stain, x20).
The final stage of cirrhosis (panel E) is characterized by marked
fibrosis and regenerative nodules (RN) (trichrome stain, x20).
Once cirrhosis has become established, hepatocellular carci-
noma (panel F) is a feared complication (hematoxylin and
eosin, x20). Reprinted with permission from Lauer GM, Walker
BD. Medical progress: hepatitis C virus infection. N Engl
J Med. 2001;345:41–52. Copyright © 2001 Massachusetts
Medical Society.
The outcome of posttransfusion HCV infection has
been studied in pediatric patients. Approximately 460
children who underwent cardiac surgery before 1991,
when blood donor screening was introduced, were stud-
ied. Approximately 15% became anti-HCV-positive ver-
sus fewer than 1% of control subjects. More than 20 years
following surgery, 55% of the anti-HCV-positive cohort
were HCV RNA-positive; the infection had cleared in
the other 45%. Only one HCV RNA-positive patient had
increased levels of liver enzymes. Liver biopsies were
obtained in 17 persistently infected patients, and only 3
had histologic evidence of liver disease. Therefore, the
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gastroenterology chronic viral hepatitis
Interpretation of HCV Test
Table 5.
Results
Interpretation of Diagnostic
Anti-HCV HCV RNA Tests
Negative Negative No infection
Positive Positive Acute or chronic infection
Negative Positive Early infection or chronic
infection in an
immunosuppressed host
Positive Negative Resolved infection or chronic
infection or false-positive
antibody test
children who received blood transfusions before the im-
plementation of screening were at high risk of acquiring
HCV infection, but 20 years later, the virus had cleared
spontaneously in many patients, and the clinical course of
those who still were infected was benign.
The outcome of perinatal infection is not well-stud-
ied; recovery seems unlikely, although patients are stated
to be asymptomatic despite the presence of chronic hep-
atitis on biopsies.
The histology of patients who have chronic HCV is
variable (Fig. 6) and may be related to the mode and age
of acquisition of HCV infection. In addition, cofactors
that increase or decrease the risk of fibrosis have not been
taken into consideration. Although increased amino-
transferase levels are predictive of progressive disease, the
absolute level of these enzymes does not correlate well
with the level of fibrosis induced by HCV. Ultimately,
most children have mild fibrosis, only a few develop
chronic hepatitis, and the incidence of cirrhosis due to
HCV is less than 5%.
Diagnostic Tests
Two major types of tests are currently available for the
laboratory diagnosis of HCV infection: 1) antibody as-
says for anti-HCV and 2) detection and quantitation of
HCV ribonucleic acid (Tables 4 and 5). For the evalua-
tion of a patient in whom HCV is suspected, the anti-
HCV enzyme immunoassay should serve as the initial
test. PCR detection of HCV RNA is applicable for con-
firmation of acute infection and to distinguish resolved
from persistent HCV. Quantitation of the amount of
virus is useful in planning and following treatment.
Management
As mentioned, there are few data regarding the manage-
ment of children who have HCV infection. Limited
Pediatrics in Review Vol.24 No.12 December 2003 407
gastroenterology chronic viral hepatitis
Figure 7. Effectiveness of HCV treatments. Combination
treatment with pegylated interferon/ribavirin (PEG/R) is su-
perior to interferon/ribavirin (IFN/R), which is superior to
interferon monotherapy (IFN) with both 6-month and 12-
month treatment courses. However, the additional 6 months
of treatment is a benefit only to patients who have HCV
genotype 1, which is responsible for approximately 70% of
HCV infections in the United States. For patients who have
genotypes 2 and 3, combination treatment courses of 6
months and 12 months are equally effective.
guidelines are provided by the AAP and ACIP. As with
chronic HBV, two major issues are avoidance of addi-
tional hepatotoxins and follow-up. HAV vaccine should
be administered to avoid further insult to the liver.
Hepatotoxins, especially alcohol, should be avoided, as
should hepatotoxic medications, including excessive
acetaminophen.
Exclusion of a child infected with HCV from a child
care center is not justified. Infected adolescents should
be informed of the possible risk of transmission to their
sexual partners. Follow-up at regular intervals is the
current standard of practice; the goal is to assess the
degree of hepatic inflammation via serum aminotransfer-
ase levels and perhaps to screen for HCC with alpha-
fetoprotein levels and ultrasonography. The data are very
limited regarding the value of these procedures.
Treatment
The general goals in the treatment of HCV infection are
to eradicate the virus, thereby inducing a remission in
liver injury and reducing the risk of transmission. In
addition, treatment should relieve symptoms, if any, and
prevent progression to end-stage liver disease. However,
attainment of these goals has been difficult. The current
strategy used in adults is combination therapy with long-
acting forms of IFN. The current formulation of choice is
PEG-IFN, which is a form of IFN conjugated to a
polyethylene glycol molecule. This formulation allows
408 Pediatrics in Review Vol.24 No.12 December 2003
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slow release of the drug and delivers a consistent dose
that increases the biologic half-life of IFN. Thus, the
drug can be administered once per week instead of the
previously used schedule of three times per week.
The best success, according to published data, is de-
rived when IFN is combined with ribavirin (Fig. 7).
Overall, the sustained viral response rate with this com-
bination is approximately 54%. Furthermore, this com-
bined treatment is capable of reversing fibrosis and cir-
rhosis. Combination treatment with PEG-IFN/ribavirin
was examined in a large study of adults infected with
HCV. Among a subgroup of 153 patients who had
baseline cirrhosis, 75 (49%) had reversal of cirrhosis.
Factors that were associated with the absence of signifi-
cant fibrosis at the conclusion of the study included
sustained viral response, low viral load (⬍3.5 million
copies per milliliter), age younger than 40 years, minimal
baseline inflammation and fibrosis, and a body mass
index of less than 27 kg/m2. However, these drugs are
not approved for children younger than 18 years of age.
In addition, ribavirin is teratogenic, which is another
impediment to its use in children and teenagers.
Uncontrolled trials of IFN monotherapy in children
who have chronic HCV mirror the experience in adults.
A recent analysis of these studies included 366 treated
patients who were compared with 105 untreated pa-
tients. Overall, a sustained response was attained in 36%
of the treated group compared with only 5% of the
control group. Among children who had genotype 1, the
response was 27%. However, there are no large-scale,
multicenter, prospective, placebo-controlled, random-
ized pediatric studies of HCV treatment. Moreover,
there are significant adverse effects of IFN and ribavirin
therapy. These factors preclude definitive recommenda-
tions on the treatment of HCV in children.
Our strategy is to make the patient aware of the
limitations of the currently used treatments and the
potential for a relapse or a nonresponse following exten-
sive antiviral therapy. In select patients, treatments with
combination PEG-IFN and ribavirin are being offered
despite the limited data in children. We also emphasize
the hope for the future development of alternative meth-
ods to treat HCV infection, such as protease inhibitors,
antisense oligonucleotides, or ribozymes.
Conclusion
With the continuing rapid pace of research in viral hep-
atitis, additional treatments and controversies will
emerge. In the case of HBV, adherence to universal HBV
vaccination of infants and adolescents is crucial. For
HCV, we cannot create immunologic barriers at this

time. Therefore, explanation of the hazards of high-risk
activity (eg, intravenous drug use) remains the only
protection. With both HBV and HCV, additional insults
to the liver can be minimized by completing a full set of
immunizations, including HAV, as well as avoiding hep-
atotoxic medications and alcohol.
Vaccination strategies against HCV must be devel-
oped. Future vaccine development also may need to
target HBV escape mutants by incorporating additional
sequences and epitopes into vaccines. Because the num-
ber of individuals worldwide who have chronic viral
hepatitis is enormous, future research must continue to
find novel methods of treating these infections as well as
their complications. Specifically, the advances in treat-
ment must “leave no child behind.” While awaiting
further advances, education of medical care workers and
the public about the significant advancements in our
understanding of viral hepatitis is essential to realize the
benefits of available control measures, immunoprophy-
laxis, and treatments.
This manuscript was accepted for publication initially on
December 12, 2001. Due to delays in publication, a revision
was undertaken and submitted on February 4, 2003.
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Pediatrics in Review Vol.24 No.12 December 2003 409
gastroenterology chronic viral hepatitis

PIR Quiz
Quiz also available online at www.pedsinreview.org.

1. You are reviewing a mother’s prenatal care record while completing the admission examination of a child
born 8 hours ago. The mother has been screened for HBV and is HbsAg-positive. The most appropriate
course of action is to administer:
A. Hepatitis B immune globulin (HBIG) in the first 12 hours after birth and hepatitis B vaccine at the 2-
week health supervision visit.
B. Hepatitis B vaccine in the first 12 hours after birth.
C. Hepatitis B vaccine and HBIG in the first 12 hours after birth.
D. Hepatitis B vaccine in the first 12 hours after birth and HBIG at the 2-week health supervision visit.
E. No treatment.

2. A 16-year-old woman is seen in the clinic for routine care. She has never been vaccinated for hepatitis and
is reluctant to do so now. Accurate arguments for hepatitis B vaccination include that HBV infection:
A. Has no long-term adverse effects.
B. Is a sexually transmitted disease.
C. Is not transmitted perinatally.
D. Is transmitted in blood, but in no other body fluids.
E. Is treated successfully with acyclovir.

3. Hepatitis C is the most common cause of “non-A, non-B” hepatitis. Management of hepatitis C infection
could be improved with the following change in clinical practice:
A. Advise infected adolescents of the possible transmission of hepatitis C to their sexual partners.
B. Exclude hepatitis C-infected children from child care.
C. Prohibit breastfeeding by hepatitis C-infected mothers.
D. Screen all pregnant women for hepatitis C.
E. Screen international adoptees for hepatitis C.

4. A Vietnamese family brings their unvaccinated 9-year-old daughter to the clinic, requesting that she be
evaluated for hepatitis. The father is hepatitis B-positive, and the mother’s hepatitis B status is unknown. If
the child had been exposed to HBV and developed either an asymptomatic carrier status or chronic
infection, the best screening laboratory test to define the daughter’s immunity status is:
A. Anti-HBe.
B. Anti-HBs.
C. HBeAg.
D. HBsAg.
E. IgM anti-HBc.

410 Pediatrics in Review Vol.24 No.12 December 2003

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 Chronic Viral Hepatitis: Always Be Current!
Jay A. Hochman and William F. Balistreri
Pediatrics in Review 2003;24;399
DOI: 10.1542/pir.24-12-399

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 Chronic Viral Hepatitis: Always Be Current!
Jay A. Hochman and William F. Balistreri
Pediatrics in Review 2003;24;399
DOI: 10.1542/pir.24-12-399

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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