Transcript Chronic Viral Hepatitis in the Pediatric Population

Chronic Viral Hepatitis B and C
in Pediatrics
Phyllis Losikoff, MD
Ezequiel Neimark, MD
Hasbro Children’s Hospital
Brown University Medical School
Divisions of Infectious Diseases and Pediatric Gastroenterology,
Hepatology and Nutrition
Disclosure Statement
Speakers: Phyllis Losikoff and
Ezequiel Neimark
Drs. Losikoff and Neimark have documented that
he has nothing to disclose.
Off Label Use Disclosure
Phyllis Losikoff and Ezequiel Neimark have
documented that their presentation will not
involve discussion of unapproved or off-label,
experimental or investigational use.
Chronic Viral Hepatitis B and C
in Pediatrics
Neimark
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Epidemiology
Transmission
Natural History
Treatment
Losikoff
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Prevention
RI screening and
prevention
Perinatal Hepatitis
Program
Hepatitis B Virus (HBV)
Epidemiology of Hepatitis B in
Pediatrics
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Prevalent in Asia, Africa, Southern
Europe and South America (2-20%)
Children adopted from Asia
Age of infection is important in
determining the outcome of the
disease.
Chronic Hepatitis B Infection
Risk Factors for Hepatitis B
40
Heterosexual
40
35
IV Drug
31
30
High Risk
behavior
Homosexual
25
20
15
14
15
10
5
0
1
1998
3
3
Health Care
Worker
Household
Unknown
Diagnostic Interpretations of
Hepatitis B markers
HBsAg
Non infectious component
of viral coat
Indicator of disease. If > 6
months: chronic HBV
Anti-HBs
Antibody response to HBsAg
Indicates recovery and/or
immunity
HBeAg
Antigen that correlates with
replication and infectivity
High level of infectivity and
replication
Anti-HBe
Antibody response to HBeAg
Decreasing level of
replication
Remission/resolution
Anti-HBc IgM
Non protective antibody to
the HBcAg
Recent HBV infection
Anti-HBc IgG
As above
Acute or remote exposure
to HBV
Replictative genetic
material of HBV; infectious
agent
Viral replication and
continues infection
HBV DNA
Diagnostic Interpretations of
Hepatitis B markers
HBsAg
Non infectious component
of viral coat
Indicator of disease. If > 6
months: chronic HBV
Anti-HBs
Antibody response to HBsAg
Indicates recovery and/or
immunity
HBeAg
Antigen that correlates with
replication and infectivity
High level of infectivity and
replication
Anti-HBe
Antibody response to HBeAg
Decreasing level of
replication
Remission/resolution
Anti-HBc IgM
Non protective antibody to
the HBcAg
Recent HBV infection
Anti-HBc IgG
As above
Acute or remote exposure
to HBV
Replictative genetic
material of HBV; infectious
agent
Viral replication and
continues infection
HBV DNA
Hepatitis B e Antigen
(HBeAg)
•Spontaneous clearance occurs gradually as
children ages
•Low before 3 years of age
•Increases 5%/year after 3 years of age
•Most common between 15-30 years old
Natural History of Chronic
Hepatitis B
Asymptomatic carrier
Chronic HBV infection
Chronic Hepatitis
Cirrhosis
Liver Failure
Hepatocellular carcinoma
Death
Chronic Hepatitis B
Infection in Pediatrics
•Mostly asymptomatic
•Normal growth
•Liver damage mild during childhood
•Cirrhosis, hepatocellular carcinoma at any age (rare)
Natural History of Chronic HBV
(Pediatrics)
•HBeAb seroconversion rate 55% in 12
years
•Lower seroconversion in vertical
transmitted (38.5%) Vs. horizontal
(74%)
•Loss of HBsAg seen in 5%
Zacharakis G. J Pediat Gastr Nutr; 44:84-91.2006
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
Who to treat?
Children with chronic HBV (HBsAg > 6 months)
Better
Response
to
treatment
High ALT
 Inflammation in biopsy
 Low HBV DNA
 Late acquisition of infection
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Mei-Hwei Chang. Pediatric Gastroint Dis. 2004
Goals of treatment in Pediatric
population
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Reducing the risk of HBV related
cirrhosis and HCC
Elimination of HBeAg may
considerable improve prognosis
How to treat?
Pediatrics
IFN-α
Lamivudine
How to treat?
Pediatrics
IFN-α
Entecavir
Lamivudine
Adefovir
INF-α
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Approx 58% of patient response
Pros:
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More durable response
Fixed duration of treatment
Lack of resistant mutants
Cons:
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Weekly SC administration
Very expensive
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Adverse reactions: Flu-like symptoms, depression,
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anorexia, bone marrow suppression
Lamivudine
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Virologic response in children, 23%
compared to 13% in placebo
Pros:
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Oral
Well tolerated
Cheap
Cons:
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Less durability of response
Increased risk of drug resistant , 70% by 5 years
Hepatitis C Virus (HCV)
Courtesy of the C. Everett Koop Institute at Dartmouth
Prevalence of Hepatitis C
•1.8% prevalence in US (NHANES III)
•150,000-200,000 US children with HCV
•10,000-60,000 newborn will be infected
worldwide yearly
El-Kamary SS. J Pediatr. 143:54-9, 2003.
Jonas MM. J Pediatr. 131:314-6, 1997.
Yeung LT. Hepatology. 34:223-9, 2001.
Aletr MJ. N Engl J Med. 341; 556-62. 1999
Prevalence of Hepatitis C
Genotype Distribution of
Hepatitis C
Mode of Transmission
of Hepatitis C
•Transfusion of blood or contaminated
products (prior to 1992)
•Use of intravenous drugs
•Sexual
•Vertical (most important among children)
Perinatal Transmission
of Hepatitis C
•3.7% of the infants acquired HCV.
•Infection rate in HIV positive mothers, 25%
•Multivariate analysis for infected mothers,
membrane rupture for >6 h and internal fetal
monitoring were associated with maternal
transmission of HCV
Mast EE. J Infect Dis. 192:1880-1889, 2005
Breast feeding and
transmission of Hepatitis C
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HCV detected in breast milk and colostrum
•
Rate of transmission identical to bottle-fed infants
•
Safety based on the absence of traumatized,
cracked or bleeding nipples
Yeung LT. Hepatology.34:223-9, 2001.
Risk Factors for Vertical
Transmission of Hepatitis C
Does not increase vertical transmission:
 Breast feeding
 Vaginal delivery
Mast EE. J Infect Dis. 192:1880-1889, 2005
Risk Factors for Vertical
Transmission of Hepatitis C
Does increase vertical transmission:
 Use of internal fetal monitoring devices
 High viral loads
 Prolonged rupture of membranes (>6 h)
 HIV co-infection
Mast EE. J Infect Dis. 192:1880-1889, 2005
Natural History of Hepatitis C
Exposure
<75%
Chronic
>20%
Acute
No infection
Spontaneous
clearance
(early)
•Cirrhosis
(20-40%)
•HCC
(1-4%/year)
Clinical Features of
Hepatitis C in Pediatrics
•Normal growth
•Mostly are asymptomatic
•Hepatomegaly 2-61%
•Elevated liver enzymes 44-93%
England K. J Pediatr. 147:227-32, 2005.
Diagnosis of Hepatitis C
HCV antibodies
(IgG)
Initial screening
Diagnosis
Confirmation of Diagnosis
HCV RNA PCR
(quantitative/qualitative)
(qualitative)
Pretreatment evaluation
Post treatment monitor
Antiviral Therapy for Hepatitis C
•Combined PEG interferon and Ribavarin
•45-62% sustained virological response
•Better response
Genotype 2, 3
Low pretreatment viral load
Younger age
Absence of cirrhosis
•Ribavirin Side effects
•Anemia/Thrombocytopenia
•Fetal malformations
Kelly DA. Hepatology; 34:680A. 2001
Wirth S. Hepatology; 36:1280-4. 2002
Davis GL. N Engl J Med; 339:1493-9.1998
McHutchinson JG. N Engl J Med; 339:1485-92.1998
Hepatitis B vs. Hepatitis C
Hepatitis B
Hepatitis C
Prevalence
Decreasing
Increasing
Transmission
Blood, Sexual
Blood, Sexual
Natural
History
Carrier, clearance,
cirrhosis, HCC
Similar but
unknown
Treatment
INF, Lamivudine,
Adefovir, Entecavir
INF/Ribavirin
Chronic Viral Hepatitis in
Pediatrics
Prevention
The Good News: Hepatitis B (HBV)
Vaccine
HBsAg recombinant DNA technology
90%-95% efficacy (anti-HBs titers > 10mIU/ml)
Long-term protection
Post Exposure Prophylaxis(PEP)
Hep B Immunoglobulin(HBIG) passively acquired anti-HBs
Infants born to HBsAg+ mothers
(HBIG & vaccine, efficacy 95% )
Advisory Committee on Immunization
Practices (ACIP) 1991
Comprehensive National Strategy to Eliminate
Transmission of HBV
Prevent perinatal HBV transmission
Universal infant vaccination
Catch-up vaccination of all children and
adolescents <19 years
Vaccination of adults in high risk groups
Well Conceived Public Health Strategy?
In Taiwan rates of HCC among children born after
routine immunization was started have declined >50%.
A Well Conceived Public Health Strategy
Reported Acute HBV Incidence by Age Group:
US, 1990-2004
12
Cases per 100,000
10
≥20 years
94% decline
8
6
71% decline
12-19 years
4
2
<12 years
0
1990
1992
1994
1996
1998
Year
2000
2002
2004
HBV: Despite Success Challenges Remain
Identified &Expected Births to HBsAg + Mothers; 1993-2003
80
60
40
Expected number
19,043
20000
48% 15000
Percent identified
41%
10000
5000
20
Source: National Immunization Program, CDC
03
20
02
20
01
00
20
Year
20
99
19
98
19
97
19
96
19
95
19
19
19
94
0
93
0
Expected Number
Percent Identified
100
23,827
HBV: Remaining Challenges
Percent of Infants
Proportion of Infants Receiving Birth Dose,
1999-2004
100
90
80
70
60
50
40
30
20
10
0
Hepatitis B Vaccine 0-2 Days from Birth
53.7%
1999
2000
46.0%
2001
Source: CDC, National Immunization Survey
2002
Year
2003
2004
HBV: Remaining Challenges
Medical Errors
Baby girl; DOB: 9/99
Died: 12/99; Cause - fulminant hepatitis B
Mother tested HBsAg-positive during pregnancy
Prenatal care provider
Made a transcription error and reported mother as “hepatitis
negative” to the hospital
Used prenatal record form from 1966
Did not report HBsAg-positive test (Michigan law)
Hospital staff
Relied on written record from prenatal provider
Did not have a copy of mother’s laboratory result
HBV: ACIP New Recommendations
December 2005
Improve prevention of perinatal and early
childhood HBV transmission
Improve hepatitis B vaccine coverage in
children/adolescents not previously
vaccinated
HBV: ACIP 2005 Recommendations
The Hospital is a SAFETY NET
1.
Universal verification of maternal HBsAg status in
the hospital
2.
Identification of infants born to HBsAg-positive
and HBsAg-unknown status women,
administration of PEP and initiation of case
management to monitor completion of vaccine
series and post vaccination testing
3.
Universal birth dose administration
HBV: ACIP 2005 Recommendations
Birth Dose
“For all medically stable infants weighing ≥2,000 grams
at birth and born to HBsAg negative mothers, the first
dose of vaccine should be administered before hospital
discharge.”
Exceptions on a case-by case basis and rare.
If birth dose delayed, medical record should document:
physician’s order not to administer birth dose
copy of original laboratory report indicating mother was
HBsAg-negative during this pregnancy
ACIP 2005
HBV Vaccination of Children and Adolescents
Not Previously Vaccinated
Immunization record reviews should be conducted for:
all children aged 11-12 years
all children and adolescents <19 years:
born in Asia, the Pacific Islands, Africa, or other countries
w/ HBsAg prevalence >2%
who have at least one parent who was born in these countries
Children not previously vaccinated or incompletely vaccinated
should complete the vaccine series
Prevention HBV Rhode Island
2004 Birth dose coverage 84%
97% infants born to HBsAg+ women received
PEP w/in 24o
Perinatal Hepatitis Prevention Program
Year
HBV exposed infants
2005
2006
67
46
Prevention HBV Rhode Island
Vaccinate Before you Graduate
Hepatitis B Vaccination provided to juveniles
at the Rhode Island Training School
Prevention
The Less Good News: Hepatitis C
There is NO effective vaccine
Spontaneous clearance of HCV can occur in
20-50% of acute infections
Immunity against persistent HCV can be acquired
Prevention HCV
Immune Correlates of Viral Clearance
Humoral Immunity
Neutralizing antibodies, in vitro, are not necessary for
resolution of HCV infection.
Cellular Immunity
Vigorous polyclonal CD4+ and CD8+ T-cell responses
Weak and narrowly in chronically infected
HCV
Cellular Immune Response in Acute
Infection
Bowen and Walker, Nature 2005
Prevention HCV
Acquired Immunity to HCV Infection
The majority of re-exposed individuals do not develop
chronic disease
Risk for chronic infection after re-exposure to HCV was 12fold lower among persons with prior HCV infection
Mehta 2002 Lancet
Resolution of HCV infection results in durable memory cells
Subjects who resolved an infection from a single
contaminated source had strong HCV-specific T-cell
immunity 18 years later
Takaki 2000 Nature Med
National HCV Prevention Strategy
Identifying and Screening At Risk Individuals
Increased screening and knowledge of HCV status
reduces HCV transmission
Kwiatkowski 2002 Addiction
Hagan 2001 Am J Pub Health
Treatment options (early therapy more efficacious)
Test for co-infection (HIV,HBV)
Education alcohol cessation, risk reduction
Hepatitis A and B vaccination
2/3 of people with chronic HCV are not
diagnosed
*No federal funding is available to support HCV counseling and
testing services.
HCV Prevention
Risk Based Screening
Ever injected illegal drugs
Blood transfusion or organ transplant before July
1992 or clotting factor before 1987 or ever on
long-term dialysis
Children born to HCV-positive women
No routine testing for pregnant women
HCV Prevention
Risk Based Screening
Sexual Transmission(2-6%) Tahan 2005 Am J Gastro
Magder 2005 Int J of Epi
Intranasal Drug Use *
Household contacts of HCV positive
Cosmetic procedures; tatooing, piercing*
Hand 2005 Am J Gastro
*Hwang 2006 Hepatology
10% of people with HCV infection have
no recognized source for their infection
Rhode Island HCV
At Risk Pediatric Populations
Rhode Island Training School; Risk based screening
1% (5/484) HCV positive
0.4% prevalence in the general adolescent population
12% reported intravenous or intranasal drug use
Losikoff 2004 NCCHC, New Orleans La.
Perinatal HCV Exposure
Estimated 150-200 infants born to HCV + mothers annually
Perinatal Hepatitis Program
Rhode Island Department of Health
2005 Rhode Island expanded the Perinatal Hepatitis
Prevention Program to include services for pregnant
women with HCV and case management of their
infants
Year
2005
2006
HCV+ mother/infant pairs
35
26
Department of Health: Pat Raymond RN, Susan Ferrara RN
W&I Center for Womens’ GI Disorders: Dr Silvia Degli-Esposti, Director
Pediatric Viral Hepatitis Clinic
Pediatric Viral Hepatitis Clinic
Resource for Providers and Families in
Rhode Island
444-6191
Ezequiel Neimark
Phyllis Losikoff