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Recommendations for Screening, Monitoring, and Referral of Pediatric Chronic

Hepatitis B
Barbara A. Haber, Joan M. Block, Maureen M. Jonas, Saul J. Karpen, W. Thomas
London, Brian J. McMahon, Karen F. Murray, Michael R. Narkewicz, Philip
Rosenthal and Kathleen B. Schwarz
Pediatrics published online Oct 5, 2009;
DOI: 10.1542/peds.2009-0567

The online version of this article, along with updated information and services, is
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


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rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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SPECIAL ARTICLES

Recommendations for Screening, Monitoring, and


Referral of Pediatric Chronic Hepatitis B
AUTHORS: Barbara A. Haber, MD,a Joan M. Block, RN,
BSN,b Maureen M. Jonas, MD,c Saul J. Karpen, MD, PhD,d abstract
W. Thomas London, MD,e Brian J. McMahon, MD,f Karen F.
Murray, MD,g Michael R. Narkewicz, MD,h Philip
Most children with chronic hepatitis B virus infection (persistent hep-
Rosenthal, MD,i and Kathleen B. Schwarz, MDj atitis B surface antigen–positive for ⬎6 months) are asymptomatic
aDivision of Gastroenterology, Hepatology, and Nutrition, and do not generally require treatment. These children are, however,
Department of Pediatrics, Children’s Hospital of Philadelphia, at increased risk for severe complications later in life, including ad-
Philadelphia, Pennsylvania; bHepatitis B Foundation, Doylestown, vanced liver disease and liver cancer. On November 11, 2008, the Hep-
Pennsylvania; cDivision of Gastroenterology, Children’s Hospital
Boston, Boston, Massachusetts; dDepartment of Pediatrics/
atitis B Foundation, a nonprofit research and disease advocacy orga-
Gastroenterology, Hepatology, and Nutrition, Baylor College of nization, convened a panel of nationally recognized North American
Medicine, Houston, Texas; eFox Chase Cancer Center, pediatric liver specialists to consider and recommend an approach for
Philadelphia, Pennsylvania; fLiver Disease and Hepatitis
Program, Alaska Native Medical Center, Alaska Native Tribal
the screening, monitoring, initial management, and referral of children
Health Consortium, Anchorage, Alaska; gDivision of with chronic hepatitis B. The panel developed recommendations to
Gastroenterology, Hepatology, and Nutrition, Seattle Children’s provide guidance to practitioners on determining what additional tests
and University of Washington School of Medicine, Seattle,
Washington; hDepartment of Pediatrics, Section of Pediatric
to conduct, how often to monitor on the basis of test results, and when
Gastroenterology, Hepatology, and Nutrition and Pediatric Liver to refer to a pediatric liver specialist to build a partnership between
Center, University of Colorado Denver School of Medicine and the practitioner and liver specialist to enhance the success of manage-
Children’s Hospital, Aurora, Colorado; iPediatric Hepatology,
ment of children with this lifelong infection. Pediatrics 2009;124:e000
University of California, San Francisco, California; and jPediatric
Liver Center, Division of Pediatric Gastroenterology and
Nutrition, Department of Pediatrics, Johns Hopkins University
School of Medicine, Baltimore, Maryland The majority of children with chronic hepatitis B virus (HBV) infection
KEY WORDS have no signs or symptoms of chronic disease. It is for that reason that
hepatitis B, chronic, pediatrics, screening, disease management, identification requires a heightened awareness on the part of physi-
liver
cians. Once identified, the next steps for a child with hepatitis B are
ABBREVIATIONS often not clear. There are relatively few pediatric liver specialists who
HBV— hepatitis B virus
HCC— hepatocellular carcinoma focus on hepatitis B in North America, and management guidelines
HBsAg— hepatitis B surface antigen specific for pediatric hepatitis B are lacking. Although most children
anti-HBs—antibody to hepatitis B surface antigen with chronic HBV are asymptomatic and do not generally require treat-
ALT—alanine aminotransferase
HBeAg— hepatitis B e-antigen ment, these children can have progressive disease and are at in-
anti-HBe—antibody to hepatitis B e antigen creased risk for severe complications later in life, with some children
ULN— upper limit(s) of normal going on to develop advanced liver disease and even liver cancer be-
CDC—Centers for Disease Control and Prevention
AFP—␣-fetoprotein
fore their third decade. HBV infection acquired via maternal-fetal
www.pediatrics.org/cgi/doi/10.1542/peds.2009-0567
transmission is associated with the highest risk of hepatocellular car-
cinoma (HCC).1 Although HCC is uncommon in the pediatric time frame,
doi:10.1542/peds.2009-0567
these facts compel us to be vigilant. Lifelong monitoring for progres-
Accepted for publication Aug 7, 2009
sion of disease is critical. It is important for practitioners to under-
Address correspondence to Barbara A. Haber, MD, Children’s
Hospital of Philadelphia, 3400 Civic Center Boulevard,
stand and use appropriate surveillance, monitoring, and timely refer-
Philadelphia, PA 19104. E-mail: haber@email.chop.edu ral. Our understanding of hepatitis B disease and the armamentarium
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). of available therapies has grown substantially in recent years, calling
Copyright © 2009 by the American Academy of Pediatrics for a fresh look at clinical practices and approaches. On November 11,
FINANCIAL DISCLOSURE: Dr Haber has received research 2008, the Hepatitis B Foundation, a nonprofit research and disease
support from Bristol-Myers Squibb, Gilead, and Roche; Dr Jonas advocacy organization, convened a panel of nationally recognized
has received research support from Bristol-Myers Squibb and
Gilead and has a consulting agreement with Gilead,
North American pediatric liver specialists from around the country to
(Continued on last page)
begin to discuss approaches to diagnosis, initial management, and
referral of children with chronic hepatitis B infection. This article was
designed to provide guidance to primary care practitioners on which

PEDIATRICS Volume 124, Number 5, November 2009 e1


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children to screen for HBV and on the Among adults who acquired chronic mothers within 12 hours of birth
initial management of chronic HBV, hepatitis B infection as an infant or rather than begin the series at a
specifically, additional tests that child, ⬃15% to 25% overall die a pre- subsequent appointment. Completion
should be considered, plans for moni- mature liver-related death.4–7 Chronic of the 3-dose hepatitis B vaccination
toring, and indications for referral of HBV is especially common in certain series by 6 months of age is recom-
HBV-infected children to a pediatric populations in the United States, in- mended for all infants, and postvac-
liver specialist. The overall goal was to cluding Asian Americans. Identification cination testing of infants born to
develop a strategy for primary practi- of infection and delivery of appropriate HBsAg-positive mothers for protective
tioners and pediatric liver specialists care and counseling have been ham- antibody response (antibody to hepati-
to partner in the long-term care of chil- pered by low health literacy.8,9 tis B surface antigen [anti-HBs]) and
dren with chronic HBV. (In this article, HBsAg is recommended at between 9
children are defined as persons VACCINATION AND PREVENTION and 18 months of age to determine if
through 17 years of age.) Hepatitis B vaccination is the most ef- infection has been prevented. The
fective approach to preventing HBV in- United States has yet to achieve 100%
EPIDEMIOLOGY fection. Over the past 2 decades, rec- compliance with the universal vaccina-
Despite the introduction of universal ommendations have evolved into a tion recommendation, however. It is
infant vaccination in 1991 in the United comprehensive strategy to eradicate estimated that 92% of the infants with
States, hepatitis B infection has not HBV infection. The US Advisory Commit- potential HBV exposure are receiving
been eradicated. Much of the world’s tee on Immunization Practices (ACIP) the appropriate immunization and
population lives in areas where the recommends that all infants be vacci- prophylaxis in a timely fashion. This
lifetime risk of contracting hepatitis B nated against HBV beginning at birth, number does not reflect regional vari-
exceeds 60%.2 In the United States, the and all children ⬍19 years of age who ations. States such as Louisiana, for
incidence of acute cases of hepatitis B have not been vaccinated previously example, are in the range of 78% to
have declined significantly, especially should also be vaccinated.10 Because 82% compliance.15 It has also been
in children, but chronic hepatitis B re- of the successful implementation of shown that infants born to women of
mains a substantial problem for a HBV vaccination in the United States, unknown HBsAg status are less likely
number of reasons including vertical the incidence of acute hepatitis B infec- to receive appropriate preventive im-
transmission, immigration to the tion in children ⬍15 years of age de- munization at the time of delivery.16
United States from areas of endemic- clined by 98% between 1990 and
ity, and infection from hepatitis B sur- 2006.11–13 Currently, the majority of PATHOPHYSIOLOGY
face antigen (HBsAg)–positive house- new cases of HBV in children in the Chronic HBV infection, defined as de-
hold contacts. Infants and young United States are those who were not tectable HBsAg for at least 6 months, is
children are at particular risk for de- fully vaccinated, in many cases home- marked by 4 phases of disease that are
veloping chronic hepatitis B infection less children, international adoptees, important in determining responsive-
after exposure to the virus. Ninety per- children born outside the United ness to therapy and risk of disease
cent of infants infected as a neonate States (even if the child supposedly re- progression. Most pediatric patients,
and 25% to 50% of children between ceived hepatitis B vaccine in their birth especially younger children, are in
the ages of 1 and 5 years who are country), or those who were born to the immune-tolerant phase, which is
acutely infected with HBV will progress HBsAg-positive mothers and did not re- marked by DNA levels that well exceed
to develop chronic infection, whereas ceive immunoprophylaxis or the birth 20 000 IU/mL (1 million copies per mL),
⬍5% of symptomatic and only 5% to dose of vaccine in a timely fashion. Un- a normal serum alanine aminotrans-
10% of asymptomatic infected adults fortunately, breakthrough infection ferase (ALT) level, and minimal liver in-
and teenagers will develop chronic occurs in ⬃5% of infants born to flammation and fibrosis. HBsAg and
hepatitis B. In the United States, the to- HBV-infected mothers even after ap- hepatitis B e-antigen (HBeAg) are de-
tal number of persons with chronic propriate immunoprophylaxis and tectable in serum during this phase. In
hepatitis B is thought to be almost 2 vaccination.14 For issues of compli- the immune-tolerant phase, currently
million,3 with many infected adults hav- ance, and to prevent perinatal trans- available antiviral therapies are gen-
ing acquired their infection during in- mission, the ACIP recommends admin- erally ineffective at maintaining sup-
fancy or childhood. Chronic infection is istration of 1 dose of hepatitis B pression of HBV, and there is a risk of
not only a public health concern but immunoglobulin and the first dose of HBV resistance occurring over time;
also a concern for the individual. vaccine to newborns of HBsAg-positive therefore, children in this phase of in-

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SPECIAL ARTICLES

fection are not treated. During the going into an inactive HBsAg-carrier ment at early time points, and lifetime
immune-active phase, serum viral DNA phase. It is important to recognize this monitoring are essential for success-
levels decline, there is elevation of the phase of infection, because the viral ful management of chronic HBV infec-
ALT level, and inflammation and fibro- variant is more virulent and may re- tion in children.
sis can develop in the liver. HBsAg and quire antiviral therapy to prevent liver
HBeAg remain detectable in serum. damage from occurring over time. SCREENING AND REFERRAL
Most children are still without signs or Recent findings regarding the patho- The panel collectively endorses the up-
symptoms of disease, yet the longer a physiology of HBV liver infection are dated (2008) Centers for Disease Con-
person remains in the immune-active particularly noteworthy for the practi- trol and Prevention (CDC) guidelines
phase, the more likely he or she will tioner. In a study of Asian subjects, for HBV testing and recommendations
develop chronic liver damage, cirrho- 20% to 25% of individuals with chronic for evaluation and management for
sis, and HCC. Most children will eventu- chronically infected people.11 A notable
hepatitis B developed severe hepatic
ally have undetectable HBeAg and de- change in the recent update is the rec-
fibrosis before the age of 25 years.19
velop antibody to the HBeAg (anti-HBe) ommendation to screen all individuals
These individuals most likely acquired
during childhood or early adulthood, born in geographic regions with an
their disease in childhood and may
except for those children infected with HBsAg prevalence of ⱖ2%, revised
have experienced a prolonged period
HBV genotype C, the genotype com- from ⱖ8% in the earlier guidelines.
in the immune-active phase. The Risk
monly found in Asia. There is increas-
Evaluation of Viral Load Elevation and This CDC update aimed to improve
ing evidence that what was previously
Associated Liver Disease/Cancer- identification of immigrants who ac-
attributed to ethnic differences is
Hepatitis B Virus (REVEAL-HBV) study quired HBV in their country of origin.
most likely influenced by genotype. A
suggested that during the immune- Previously, international adoptees
recent study by Livingston et al17 of a
active phase, high HBV DNA levels and were commonly screened for HBV, but
cohort of 1158 people found that the
elevated ALT levels are associated with children who immigrated with their in-
mean age of HBeAg clearance was 47.8
greater risk of cirrhosis and HCC.20–22 tact families were not. The CDC also
years for genotype C, whereas for ge-
In this study of adults whose average recommends that children born in the
notypes A, B, D, and F, the mean age of
age was mid-40s, serum ALT levels as United States to immigrant parents
HBeAg clearance occurred before 20
low as twice the upper limit of normal from endemic areas be screened, and
years. Furthermore, genotype C is
(ULN) were associated with progres- all children born to HBsAg-positive
more likely to revert to an HBeAg-
sion to cirrhosis and HCC. These find- mothers should be tested (generally at
positive state and more likely to be
ings have prompted a new, more ag- 1 year of age). In addition, children
transmitted vertically. When HBeAg be-
gressive approach to the treatment who live in a household with a known
comes undetectable and anti-HBe is
of adults during the immune-active HBsAg-positive person(s) should be
present, most persons move into the
phase of chronic hepatitis B. The new screened. Even those who received
inactive HBsAg-carrier phase, in which
guidelines for chronically infected vaccine but were not ever tested for
the viral DNA level is low (usually
⬍2000 IU/mL [10 000 copies per mL]) adults have led to a heightened aware- HBV infection should be tested in case
or undetectable, the ALT level normal- ness among pediatric liver specialists they were infected before vaccination
izes, liver histology is without inflam- that treatment during a prolonged or did not develop an adequate re-
mation, hepatic fibrosis may regress, immune-active phase is important for sponse to the vaccination (Table 1).
and the risk of cirrhosis and HCC de- decreasing an infected child’s risk of Serum HBsAg, along with anti-HBs, is
clines. Another phase is the reactiva- developing cirrhosis and/or cancer the most effective screening tool for
tion phase, which occurs in 20% to 30% later in life. In addition, a strict linkage HBV infection. HBsAg is detectable in
of patients.18 In this phase, viral DNA of ALT level with progression of liver virtually all individuals with chronic in-
levels increase, whereas HBeAg re- disease is not always apparent, espe- fection, even when HBV DNA levels are
mains undetectable. The ALT level cially in children.23 Practitioners need undetectable. A lack of anti-HBs identi-
may be either normal or elevated. This to rigorously monitor HBV-infected pa- fies susceptible children who need
is also termed e-antigen–negative tients at regular intervals (every 6 to vaccination. Children found to be
chronic hepatitis B and is usually 12 months) and refer to a pediatric HBsAg-positive should be retested 6
caused by infection with a mutant vi- liver specialist any patient who has el- months later to document chronic in-
rus. In addition, some persons may evated ALT and HBV DNA levels. Vacci- fection. As noted above, serum ALT lev-
move directly into this phase without nation, screening, referral for treat- els are not elevated in children in the

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TABLE 1 Children Who Should Be Screened
for Chronic HBV Infection11
Children born in a country endemic for HBV, even
if they received hepatitis B vaccine in their
country of origin, including
All of Asia
All of Africa
South- and mid-Pacific Islands
Europe (Eastern and Mediterranean
countries), Greenland, and Russia
Middle East
South America: Amazon Basin
Caribbean
Indigenous populations from the Arctic,
Australia, and New Zealand
Children born in the United States to
immigrant parents from endemic areas
Infants born to HBsAg-positive mothers
Children living in a household with an HBsAg-
positive individual, including those children
who received hepatitis B vaccine after birth
who were not screened before vaccination

immune-tolerant phase; therefore,


measurement of ALT is not an appro-
priate screening method for detecting
HBV infection.
Once a child is identified as having
chronic hepatitis B infection, the panel
recommends collection of a set of
baseline data and an initial consulta- FIGURE 1
Recommended approach to monitoring children with chronic hepatitis B (persistent HBsAg-positive)
tion with a pediatric liver specialist. infection. Any child who has an elevated ALT or AFP level, has a positive family history of HCC, or is
Figure 1 illustrates the recommended HBeAg-negative but has an HBV DNA level of ⬎2000 IU/mL should be referred to a pediatric liver
approach to monitoring children with specialist. a ALT level and white blood cell/platelet (WBC/Plt) count are generally included in the
baseline evaluation as part of a hepatic function panel and complete blood count, respectively. b The
chronic HBV infection. Specifically, the ALT level should be considered elevated if greater than the testing laboratory ULN or ⬎40 IU/L,
panel recommends that the following whichever is lower. c Measure ALT and AFP levels every 6 to 12 months and HBeAg/Anti-HBe and HBV
DNA levels every 12 months. Many pediatric specialists also consider ultrasound every 1 to 2 years
be included in the initial evaluation: appropriate (particularly with a family history of HCC or if the ALT or AFP level is elevated).
ALT level (usually measured as part of
a hepatic function panel); white blood
cell and platelet counts, because low positive, with normal ALT and AFP lev- ios, the pediatric liver specialist may
values are surrogate markers for ad- els, should be reevaluated every 6 to 12 be particularly valuable for outlining a
vanced liver fibrosis (usually mea- months, as described in Fig 1, along treatment plan and assessing extent of
sured as part of a complete blood with continued monitoring of HBeAg/ liver disease.
count); hepatitis B serology, specifi- anti-HBe status. In this immune- In the past 5 years the definition of ALT
cally serology for HBeAg and anti-HBe, tolerant phase, there is little risk of elevation has been scrutinized and re-
and quantitative HBV DNA, used in con- disease progression or HCC, and cur- vised with the new ULN being recom-
junction with the ALT level to determine rent therapies are ineffective. How- mended for adults. For adult men, the
the phase of disease; baseline liver ul- ever, if the ALT level is elevated, the ULN is 30 IU/L and for adult women, 19
trasound, used for crude assessment child is at risk for progression of liver IU/L.24 However, the ULN for children
of liver texture and nodularity as well disease and also may be a candidate have not been established. Therefore,
as spleen size; ␣-fetoprotein (AFP) lev- for treatment. If HBeAg is undetectable it is recommended that adult guide-
els, used to stratify risk of HCC; and yet the HBV DNA is detectable, then e- lines be applied to the older teenager.
family history of liver cancer or liver antigen–negative chronic hepatitis B For younger children, the ULN for ALT
disease. Children who are HBeAg- has developed. In these latter 2 scenar- can vary according to laboratory and

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SPECIAL ARTICLES

age. In the absence of guidelines for levels of children with detectable in the immune-active phase and being
children, the panel recommends that HBeAg and normal ALT levels. During considered for treatment and for
the ALT level be considered elevated if the immune-tolerant phase, when the those in the inactive HBsAg-carrier
it is greater than the testing laboratory child is not a candidate for treatment, phase to detect reactivation.
ULN or ⬎40 IU/L, whichever is lower. DNA levels may exceed 20 000 IU/mL The panel did not reach a consensus
Children with a family history that and are thought to have little predic- regarding the frequency of ultrasound
is suspicious for hepatitis B–related tive value regarding the risk of cancer after a baseline examination. For the
cirrhosis or liver cancer should be or cirrhosis. Likewise, children in the majority of infants and toddlers, can-
considered to be at high risk, and a inactive HBsAg-carrier phase (anti- cer and cirrhosis are unlikely events.
pediatric liver specialist should be HBe–positive and normal ALT level) do Even for young school-aged children
consulted concerning the frequency of not need monitoring of HBV DNA levels
the risk is minimal. Given the infre-
appropriate monitoring, taking into unless the ALT level becomes elevated,
quency of these events before young
consideration the age of the patient which may signify reactivation of HBV.
adulthood, there is no evidence-based
and the specifics of the family history. However, children in the inactive
guidance for ultrasound monitoring.
AFP is a marker of risk of HCC, but for HBsAg-carrier phase do need to have
For adolescents, many pediatric liver
children as well as adults, an elevated their ALT levels monitored every 6 to 12
specialists adopt the same guide-
AFP level alone often does not indicate months for the rest of their lives, and if
lines used by adult hepatologists and
whether HCC is present. AFP elevations the ALT level rises above normal, then
perform ultrasound every 6 months
commonly occur with active liver in- the HBV DNA level should be assessed.
for those with cirrhosis or an ele-
flammation and during pregnancy. It is important to remember that, as a
vated AFP level and/or a family his-
Therefore, the AFP level is best used result of the obesity epidemic in chil-
tory of HCC.
to stratify risk categories. In a dren, elevated ALT levels may be re-
lated to nonalcoholic fatty liver dis- In summary, adult treatment guide-
population-based study of children
ease (NAFLD), an increasingly common lines are rapidly evolving as an in-
and adults, AFP level was useful in
identifying most children who devel- finding in children with metabolic creasing range of therapies become
oped HCC at a treatable stage, and a syndrome. Thus, some children with available, as multidrug regimens are
normal AFP level had a high negative HBV infection in the inactive HBsAg- studied, and as interest in developing
predictive value for HCC.25 In the ab- carrier phase may have elevated ALT treatments for individuals with normal
sence of pediatric-specific studies on levels resulting from NAFLD or other ALT levels grows. At this time, however,
the usefulness of AFP levels, the panel causes, but as expected in this many of these newer therapies and
endorses periodic AFP testing. Increas- phase, the HBV DNA level will not be strategies have not been adequately
ing serum AFP levels correspond to in- elevated above 2000 IU/mL (10 000 evaluated in children. The panel rec-
creasing HCC risk, and an AFP level of copies per mL). ommends that any child with an ele-
⬎10 ng/mL merits ultrasound evalua- During the immune-active phase, the vated ALT and/or AFP level and/or a
tion for nodules and referral to a pedi- HBV DNA level can be helpful in design- positive family history for liver dis-
atric liver specialist for further evalu- ing a treatment plan (eg, HBV DNA lev- ease, especially liver cancer, be re-
ation and guidance. Although HCC els may predict the likelihood of re- ferred to a pediatric liver specialist
associated with HBV is a rare event in sponse to some treatment regimens, who will advise on opportunities to
childhood, it is important to remem- but it might only be measured if treat- treat and/or the need for further eval-
ber that some children develop HCC ment is being considered). During the uation. The specialist will also recom-
without cirrhosis and can do so be- inactive HBsAg-carrier phase, DNA lev- mend a strategy for long-term moni-
fore reaching adulthood.26,27 Further- els are undetectable, and it is during toring. In more urban areas, a local
more, children with documented cir- this phase that monitoring DNA levels pediatric liver specialist often as-
rhosis, a family history of HCC, and can be useful to identify reactivation; sumes responsibility for monitoring,
an elevated AFP level should be reg- thus, HBV DNA may be measured annu- whereas in more rural areas in which
ularly screened for HCC at 6-month ally. The panel concluded that there a specialist may not be geographically
intervals with liver ultrasound and was little value in routine monitoring accessible, it may be primary care
AFP-level measurement. of HBV DNA levels for those children practitioners who continue to monitor
In general, the panel did not recom- with normal ALT levels, but routine and treat in consultation with the
mend routine monitoring of HBV DNA monitoring is useful for those who are specialist.

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TREATMENT AND LIFELONG incidence of resistance observed with phase to the immune-clearance phase).
MONITORING this treatment and the concern that it For children who are HBeAg-positive
Response of children to therapy is, so will affect future treatment options. with elevated ALT levels and compen-
far, similar to that of adults, but the Adefovir is a less potent antiviral drug sated liver disease, an observation pe-
number of approved therapies for chil- against HBV, and increasing resis- riod of 6 to 12 months should be con-
tance to adefovir occurs over time.29 sidered to determine if spontaneous
dren has been limited. For adults,
Practice is rapidly evolving, and these HBeAg seroconversion occurs. There
there are 7 antiviral drugs that are
once-recommended medications are are many unanswered questions that
currently approved by the US Food and
now the least favored options among play into the decision to initiate treat-
Drug Administration for use as initial
adult hepatologists. Development of ment with antiviral therapy, not least
therapy for chronic hepatitis B: 2
resistance to interferon has not been of which are the potential efficacy, du-
forms of interferon (interferon alfa-2b
observed, and although efficacy in ration of therapy, and risk of drug re-
and peginterferon alfa-2a) and 5 nu-
adults is variable, young children (ⱕ5
cleos(t)ide analogs (lamivudine, ade- sistance in view of the limited thera-
years old) may have an enhanced re-
fovir dipivoxil, entecavir, telbivudine, peutic options for children.
sponse to this drug, but adverse ef-
and tenofovir disoproxil fumarate). For Again, a successful partnership be-
fects remain a concern.30,31 In addition
children, 4 of these therapies are cur- to the clinical impact drug resistance tween the primary practitioner and pe-
rently available: adefovir is labeled for has on the patient’s prognosis (de- diatric liver specialist can enhance the
ages 12 and older; entecavir is labeled creased seroconversion, increased success of screening, initial manage-
for ages 16 years and older; interferon rate of disease progression) and the ment, and monitoring of children with
alfa-2b is approved for use in children lifelong treatment challenges that face this lifelong infection.
as young as 12 months of age; and a child who harbors a resistant virus,
lamivudine may be used starting at 3 there are public-health ramifications ACKNOWLEDGMENTS
years of age. including the transmission of drug-
The workshop was convened and
Despite 4 possible therapies, only 2 are resistant strains to others. As such,
children who receive nucleos(t)ide an- funded by the Hepatitis B Foundation
approved for younger children. The de-
cision to initiate treatment is still com- tiviral therapy, alone or in combina- (www.hepb.org), which is supported
plicated and evolving. Lamivudine and tion, should be monitored for the de- primarily by federal, state, and private
adefovir are among the less potent op- velopment of resistance by periodic foundation grants as well as individual
tions, but their use is not without risk. assessment of HBV DNA and ALT levels, charitable donations, with small unre-
For lamivudine, the development of as suggested by several published stricted educational grants from
drug resistance is a significant con- adult guidelines.32,33 Bristol-Myers Squibb, Gilead Sciences,
cern. A study by Sokal et al28 showed a Antiviral therapy is generally reserved Idenix, Merck, and Novartis.
resistance rate of 64% in children who for those who have active liver disease, Medical writing services were pro-
received lamivudine for 36 months. If as indicated by monitoring tests such vided by Theresa M. Wizemann, PhD,
possible, lamivudine monotherapy as ALT levels (generally those who under contract with the Hepatitis B
should be avoided because of the high have moved from the immune-tolerant Foundation.
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(Continued from first page)


Novartis, and Roche; Dr Murray has received research funding from Gilead and Roche; Dr Rosenthal has received research support from Bristol-Myers Squibb
and Roche and serves on the speakers bureau with GlaxoSmithKline and Merck; and Dr Schwarz has received research support from Bristol-Myers Squibb,
Gilead, and Roche and has a consulting agreement with Novartis. The other authors have no financial relationships relevant to this article to disclose.

PEDIATRICS Volume 124, Number 5, November 2009 e7


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Recommendations for Screening, Monitoring, and Referral of Pediatric Chronic
Hepatitis B
Barbara A. Haber, Joan M. Block, Maureen M. Jonas, Saul J. Karpen, W. Thomas
London, Brian J. McMahon, Karen F. Murray, Michael R. Narkewicz, Philip
Rosenthal and Kathleen B. Schwarz
Pediatrics published online Oct 5, 2009;
DOI: 10.1542/peds.2009-0567
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