Chronic Viral Hepatitis B and C in Pediatrics

1
Chronic Viral Hepatitis B and C in Pediatrics

• Phyllis Losikoff, MD
• Ezequiel Neimark, MD
• Hasbro Childrens Hospital
• Brown University Medical School
• Divisions of Infectious Diseases and Pediatric
  Gastroenterology, Hepatology and Nutrition

2
Disclosure Statement
Speakers Phyllis Losikoff and Ezequiel Neimark
Drs. Losikoff and Neimark have documented that
he has nothing to disclose.
3
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.
4
Chronic Viral Hepatitis B and C in Pediatrics

• Neimark
• Epidemiology
• Transmission
• Natural History
• Treatment

• Losikoff
• Prevention
• RI screening and prevention
• Perinatal Hepatitis Program

5
Hepatitis B Virus (HBV)
6
Epidemiology of Hepatitis B in Pediatrics

• 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.

7
Chronic Hepatitis B Infection
8
Risk Factors for Hepatitis B
9
Diagnostic Interpretations of Hepatitis B markers
10
Diagnostic Interpretations of Hepatitis B markers
11
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

12
Natural History of Chronic Hepatitis B
13
Chronic Hepatitis B Infection in Pediatrics

• Mostly asymptomatic
• Normal growth
• Liver damage mild during childhood
• Cirrhosis, hepatocellular carcinoma at any age
  (rare)

14
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 4484-91.2006
15
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
16
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
17
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
18
Hepatitis B Liver Biopsy
Courtesy of Jerrold R. Turner, M.D., Ph.D.
19
Who to treat?
Children with chronic HBV (HBsAg gt 6 months)
Better Response to treatment

• High ALT
• Inflammation in biopsy
• Low HBV DNA
• Late acquisition of infection

Mei-Hwei Chang. Pediatric Gastroint Dis. 2004
20
Goals of treatment in Pediatric population

• Reducing the risk of HBV related cirrhosis and
  HCC
• Elimination of HBeAg may considerable improve
  prognosis

21
How to treat?

• Pediatrics

Lamivudine
IFN-a
22
How to treat?

• Pediatrics

Lamivudine
IFN-a
Adefovir
Entecavir
23
INF-a

• Approx 58 of patient response
• Pros
• More durable response
• Fixed duration of treatment
• Lack of resistant mutants
• Cons
• Weekly SC administration
• Very expensive
• Adverse reactions Flu-like symptoms, depression,
  anorexia, bone marrow suppression

24
Lamivudine

• Virologic response in children, 23 compared to
  13 in placebo
• Pros
• Oral
• Well tolerated
• Cheap
• Cons
• Less durability of response
• Increased risk of drug resistant , 70 by 5 years

25
Hepatitis C Virus (HCV)
Courtesy of the C. Everett Koop Institute at
Dartmouth
26
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. 14354-9, 2003. Jonas
MM. J Pediatr. 131314-6, 1997. Yeung LT.
Hepatology. 34223-9, 2001. Aletr MJ. N Engl J
Med. 341 556-62. 1999
27
Prevalence of Hepatitis C
28
Genotype Distribution of Hepatitis C
29
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)

30
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 gt6 h and internal fetal
  monitoring were associated with maternal
  transmission of HCV

Mast EE. J Infect Dis. 1921880-1889, 2005
31
Breast feeding and transmission of Hepatitis C

• 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.34223-9, 2001.
32
Risk Factors for Vertical Transmission of
Hepatitis C

• Does not increase vertical transmission
• Breast feeding
• Vaginal delivery

Mast EE. J Infect Dis. 1921880-1889, 2005
33
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 (gt6 h)
• HIV co-infection

Mast EE. J Infect Dis. 1921880-1889, 2005
34
Natural History of Hepatitis C
lt75
Exposure
Chronic
gt20
Acute
No infection
Spontaneous clearance (early)

• Cirrhosis (20-40)
• HCC (1-4/year)

35
(No Transcript)
36
(No Transcript)
37
Clinical Features of Hepatitis C in Pediatrics

• Normal growth
• Mostly are asymptomatic
• Hepatomegaly 2-61
• Elevated liver enzymes 44-93

England K. J Pediatr. 147227-32, 2005.
38
Diagnosis of Hepatitis C
Initial screening

• HCV antibodies (IgG)
• HCV RNA PCR (quantitative/qualitative)

Diagnosis
Confirmation of Diagnosis (qualitative)
Pretreatment evaluation
Post treatment monitor
39
Antiviral Therapy for Hepatitis C

• Combined PEG interferon and Ribavarin
• 45-62 sustained virological response
• Better response
• Ribavirin Side effects
• Anemia/Thrombocytopenia
• Fetal malformations

Genotype 2, 3
Low pretreatment viral load
Younger age
Absence of cirrhosis
Kelly DA. Hepatology 34680A. 2001 Wirth S.
Hepatology 361280-4. 2002 Davis GL. N Engl J
Med 3391493-9.1998 McHutchinson JG. N Engl J
Med 3391485-92.1998
40
Hepatitis B vs. Hepatitis C
41
Chronic Viral Hepatitis in Pediatrics

• Prevention

42
The Good News Hepatitis B (HBV)

• Vaccine
• HBsAg recombinant DNA technology
• 90-95 efficacy (anti-HBs titers gt
  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 )

43
Advisory Committee on Immunization Practices
(ACIP) 1991Comprehensive National Strategy to
Eliminate Transmission of HBV

• Prevent perinatal HBV transmission
• Universal infant vaccination
• Catch-up vaccination of all children and
  adolescents lt19 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
  gt50.

44
A Well Conceived Public Health StrategyReported
Acute HBV Incidence by Age Group US, 1990-2004
20 years
71 decline
94 decline
12-19 years
Cases per 100,000
lt12 years
Year
45
HBV Despite Success Challenges
RemainIdentified Expected Births to HBsAg
Mothers 1993-2003
23,827
Expected number
19,043
48
Percent identified
41
Source National Immunization Program, CDC
46
HBV Remaining ChallengesProportion of Infants
Receiving Birth Dose, 1999-2004
Hepatitis B Vaccine 0-2 Days from Birth
53.7
46.0
Source CDC, National Immunization Survey
47
HBV Remaining ChallengesMedical 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 mothers laboratory result

48
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

49
HBV ACIP 2005 RecommendationsThe Hospital is a
SAFETY NET

• Universal verification of maternal HBsAg status
  in the hospital
• 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
• Universal birth dose administration

50
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
• physicians order not to administer birth dose
• copy of original laboratory report indicating
  mother was HBsAg-negative during this
  pregnancy

51
ACIP 2005HBV 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 lt19 years
• born in Asia, the Pacific Islands, Africa, or
  other countries
• w/ HBsAg prevalence gt2
• who have at least one parent who was born in
  these countries
• Children not previously vaccinated or
  incompletely vaccinated should complete the
  vaccine series

52
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 67
• 2006 46

53
Prevention HBV Rhode Island

• Vaccinate Before you Graduate
• Hepatitis B Vaccination provided to juveniles at
  the Rhode Island Training School

54
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

55
Prevention HCVImmune 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

56
HCV Cellular Immune Response in Acute Infection
Bowen and Walker, Nature 2005
57
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 12-fold 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

58
National HCV Prevention StrategyIdentifying 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.

59
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

60
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

61
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

62
Perinatal Hepatitis ProgramRhode 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 HCV mother/infant pairs
• 2005 35
• 2006 26
• Department of Health Pat Raymond RN, Susan
  Ferrara RN
• WI Center for Womens GI Disorders Dr Silvia
  Degli-Esposti, Director
• Pediatric Viral Hepatitis Clinic

63
Pediatric Viral Hepatitis Clinic

• Resource for Providers and Families in Rhode
  Island
• 444-6191
• Ezequiel Neimark Phyllis Losikoff