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Chronic Viral Hepatitis B and C in Pediatrics

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  • The hepatitis B virus is a member of the smallest known group of DNA viruses, called Hepadnaviridae. The HBV genome is a small, circular DNA molecule. The surface (S) gene encodes for the hepatitis B surface antigen. The C (core) gene encodes the protein of the hepatitis B core antigen. And the short Pre-C region encodes hepatitis B e antigen. The P gene encodes enzymes DNA polymerase.
  • Most patients with acute hepatitis B go undetected unless they present with obvious clinical signs and symptoms, such as jaundice, or undergo biochemical tests that disclose aminotransferase elevations. Diagnosis of a case of acute hepatitis is less likely the younger the individual. Infections acquired perinatally and in early childhood usually becomes chronic in 90% and 30% of cases, respectively.
  • Shifts have developed in the frequency of some risk factors between the 1980s and 1990s. High-risk heterosexual activity as a risk factor increased from 26% in 1989 to 40% in 1998, whereas cases involving injection drug use, health care employment, and unknown risk associations have decreased. Interestingly, cases associated with homosexual activity have increased from 8% in 1989 to about 15% in 1998. Over the past decade, the number of cases of acute hepatitis B reported annually has decreased by more than 75%. This lowered frequency of acute HBV probably reflects changes in behavior as a consequence of the AIDS epidemic as well as the impact of focused HBV vaccination programs. It is anticipated that emphasizing HBV immunization for infants, children, and adolescents will serve to limit the population at risk for acquiring HBV and should gradually result in disappearance of the disease in the United States. Breastfeeding is not contraindicated.
  • Spontaneous clearance of HBeAg occurs gradually as children ages. Low before 3 years of age, it increases 5% per year after 3 years of age.
  • Spontaneous clearance of HBeAg occurs gradually as children ages. Low before 3 years of age, it increases 5% per year after 3 years of age.
  • Chronic infection with hepatitis B virus (HBV) can result in the development of a chronic carrier state with little or no evidence of liver injury or progression to a chronic necroinflammatory condition. Chronic hepatitis may lead to hepatic failure over a relatively short time interval in the presence or absence of cirrhosis. Alternatively, cirrhosis may result, with subsequent development of hepatocellular carcinoma or hepatic failure. Progression to cirrhosis occurs at an annual rate of 2–6% in hepatitis B early antigen (HBeAg)-positive and 8–10% in HBeAg-negative patients with chronic hepatitis. The estimated 5-year progression from compensated cirrhosis to hepatocellular carcinoma is 6–15%.
  • Hematoxylin and eosin-stained photomicrograph of a regenerative nodule. This patient has cirrhosis due to hepatitis B virus (HBV) infection. Portal areas are expanded and infiltrated by a mixture of inflammatory cells. Some bile ductular proliferation is apparent.
  • Trichrome-stained preparation of the area corresponding to the previous slide. The portal area is expanded, and the regenerative nodule is encircled by collagen (stained blue).
  • Ground-glass hepatocytes represent cells with cytoplasm swollen by viral particles.
  • Viral particles can also be detected by immunohistochemistry. Immunoreactive hepatitis B surface antigen (HBsAg; stained red) is deposited in the cytoplasm, and some large HBsAg aggregates can be seen.
  • Two large studies done by the CDC and another multicenter don in Europe showed that in contrast to what it happens with HIV, HCV…
  • Only the CDC found that the use of internal monitoring devices increase the risk of maternal HCV transmission.
  • Hepatitis surveillance: report no. 56. Atlanta, GA: US Department of Health and Human Services, CDC; 1996 (on the basis of application of racial/ethnic-specific HBsAg prevalence estimates to U.S. Study in JAMA : Women without prenatal care The need for proper management of women without prenatal care, is underscored by the higher prevalence of HBsAg seropositivity among these women than among women who are screened prenatally ( 12 ).
  • In summary Rhode Island does a marvelous job – but residents who may be practicing in different regions of the country or world Effective prevention does exist, responsibility of the provider/(ob and peditrician) to insure HCC due to HBV historical – Rhode Island is one of the more successful states HOWEVER to date many unkown status and room for improvement Hope you appreciate the importance of 2005 recommendatons – administering birth dose and PEP as necessary and completing hep b vaccine for immigrants or adolescents who have not received.
  • Chimpanzees are the only animal model available and develop only mild clinical sequelae
  • Many important questions remain – before effective vaccine can be developed Further understanding of the conponents of successful immune rsponses make therapeutic vaccine closer to realization
  • Transcript

    • 1. 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
    • 2. Speakers: Phyllis Losikoff and Ezequiel Neimark Drs. Losikoff and Neimark have documented that he has nothing to disclose. Disclosure Statement
    • 3. Phyllis Losikoff and Ezequiel Neimark have documented that their presentation will not involve discussion of unapproved or off-label, experimental or investigational use. Off Label Use Disclosure
    • 4.
      • Neimark
      • Epidemiology
      • Transmission
      • Natural History
      • Treatment
      • Losikoff
      • Prevention
      • RI screening and prevention
      • Perinatal Hepatitis Program
      Chronic Viral Hepatitis B and C in Pediatrics
    • 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 Viral replication and continues infection Replictative genetic material of HBV; infectious agent HBV DNA Acute or remote exposure to HBV As above Anti-HBc IgG Recent HBV infection Non protective antibody to the HBcAg Anti-HBc IgM Decreasing level of replication Remission/resolution Antibody response to HBeAg Anti-HBe High level of infectivity and replication Antigen that correlates with replication and infectivity HBeAg Indicates recovery and/or immunity Antibody response to HBsAg Anti-HBs Indicator of disease. If > 6 months: chronic HBV Non infectious component of viral coat HBsAg
    • 10. Diagnostic Interpretations of Hepatitis B markers Viral replication and continues infection Replictative genetic material of HBV; infectious agent HBV DNA Acute or remote exposure to HBV As above Anti-HBc IgG Recent HBV infection Non protective antibody to the HBcAg Anti-HBc IgM Decreasing level of replication Remission/resolution Antibody response to HBeAg Anti-HBe High level of infectivity and replication Antigen that correlates with replication and infectivity HBeAg Indicates recovery and/or immunity Antibody response to HBsAg Anti-HBs Indicator of disease. If > 6 months: chronic HBV Non infectious component of viral coat HBsAg
    • 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. Zacharakis G. J Pediat Gastr Nutr; 44 :84-91.2006 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%
    • 15. Courtesy of Jerrold R. Turner, M.D., Ph.D. Hepatitis B Liver Biopsy
    • 16. Courtesy of Jerrold R. Turner, M.D., Ph.D. Hepatitis B Liver Biopsy
    • 17. Courtesy of Jerrold R. Turner, M.D., Ph.D. Hepatitis B Liver Biopsy
    • 18. Courtesy of Jerrold R. Turner, M.D., Ph.D. Hepatitis B Liver Biopsy
    • 19. Who to treat?
        • High ALT
        • Inflammation in biopsy
        • Low HBV DNA
        • Late acquisition of infection
      Better Response to treatment Mei-Hwei Chang. Pediatric Gastroint Dis. 2004 Children with chronic HBV (HBsAg > 6 months)
    • 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
      IFN- α Lamivudine
    • 22. How to treat?
      • Pediatrics
      IFN- α Lamivudine Adefovir Entecavir
    • 23. INF- α
      • 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. Courtesy of the C. Everett Koop Institute at Dartmouth Hepatitis C Virus (HCV)
    • 26. 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
      • 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
    • 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. Mast EE. J Infect Dis . 192:1880-1889, 2005 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
    • 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. 34 :223-9, 2001.
    • 32. Risk Factors for Vertical Transmission of Hepatitis C
      • Does not increase vertical transmission:
      • Breast feeding
      • Vaginal delivery
      Mast EE. J Infect Dis . 192:1880-1889, 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 (>6 h)
      • HIV co-infection
      Mast EE. J Infect Dis . 192:1880-1889, 2005
    • 34. Natural History of Hepatitis C Exposure No infection Acute Chronic Spontaneous clearance (early)
      • Cirrhosis (20-40%)
      • HCC (1-4%/year)
      <75% >20%
    • 35.  
    • 36.  
    • 37. England K. J Pediatr . 147 :227-32, 2005. Clinical Features of Hepatitis C in Pediatrics
      • Normal growth
      • Mostly are asymptomatic
      • Hepatomegaly 2-61%
      • Elevated liver enzymes 44-93%
    • 38. Diagnosis of Hepatitis C HCV antibodies (IgG) HCV RNA PCR (quantitative/qualitative) Initial screening Diagnosis Confirmation of Diagnosis (qualitative) Pretreatment evaluation Post treatment monitor
    • 39. 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 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
    • 40. Hepatitis B vs. Hepatitis C Similar but unknown Carrier, clearance, cirrhosis, HCC Natural History INF/Ribavirin INF, Lamivudine, Adefovir, Entecavir Treatment Blood, Sexual Blood, Sexual Transmission Increasing Decreasing Prevalence Hepatitis C Hepatitis B
    • 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 > 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) 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%.
    • 44. A Well Conceived Public Health Strategy Reported Acute HBV Incidence by Age Group: US, 1990-2004 ≥ 20 years 12-19 years <12 years 71% decline 94% decline Year Cases per 100,000
    • 45. HBV: Despite Success Challenges Remain Identified &Expected Births to HBsAg + Mothers; 1993-2003 Expected number Percent identified Source: National Immunization Program, CDC 48% 23,827 19,043 41%
    • 46. HBV: Remaining Challenges Proportion of Infants Receiving Birth Dose, 1999-2004 46.0% 53.7% Source: CDC, National Immunization Survey Hepatitis B Vaccine 0-2 Days from Birth
    • 47. 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
    • 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 Recommendations The 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:
        • physician’s order not to administer birth dose
        • copy of original laboratory report indicating mother was HBsAg-negative during this pregnancy
    • 51. 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
    • 52. Prevention HBV Rhode Island
      • 2004 Birth dose coverage 84%
      • 97% infants born to HBsAg+ women received PEP w/in 24 o
      • 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 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
    • 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 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.
    • 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 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 HCV+ mother/infant pairs
      • 2005 35
      • 2006 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
    • 63. Pediatric Viral Hepatitis Clinic
      • Resource for Providers and Families in Rhode Island
      • 444-6191
      • Ezequiel Neimark Phyllis Losikoff