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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 Epidemiology Transmission Natural History Treatment Losikoff Prevention RI screening and prevention Perinatal Hepatitis Program Hepatitis B Virus (HBV) 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. 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 Mei-Hwei Chang. Pediatric Gastroint Dis. 2004 Goals of treatment in Pediatric population 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 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 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 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 • 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