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Hepatitis C in Children

Hepatitis C in Children. Prevalence of Anti-HCV by Age (U.S.). Alter MJ, NEJM, 1999:341:556. Proportion of Anti-HCV Seropositive Subjects in Pediatric Age Groups (U.S.). Alter MJ, NEJM, 1999:341:556. Children at Risk for HCV Infection. Recurrent blood or blood product transfusion

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Hepatitis C in Children

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  1. Hepatitis C in Children

  2. Prevalence of Anti-HCV by Age (U.S.) Alter MJ, NEJM, 1999:341:556

  3. Proportion of Anti-HCV Seropositive Subjects in Pediatric Age Groups (U.S.) Alter MJ, NEJM, 1999:341:556

  4. Children at Risk for HCV Infection • Recurrent blood or blood product transfusion • hemophilia (80-95%), thalassemia (60-75%) • Blood or blood product transfusion prior to 1992 • ALL (4-9%), cardiac surgery (4-5%), orthopedic surgery, NICU care • Adolescents with “high-risk” behaviors • Children born to HCV-infected women

  5. Low Seroprevalence of Anti-HCV in Urban Adolescents • 869 subjects from Adolescent Clinic or a high-school based clinic • 3.2% (22/669) repeatedly anti-HBc seropositive • 1 (0.1%) anti-HCV seropositive Jonas MM, J Pediatr 1997;131:314

  6. Frequency of Perinatal HCV Transmission

  7. Perinatal HCV Transmission 266 infants born to HCV RNA + women (all infants anti-HCV +) Birth (cord blood) HCV RNA + HCV RNA - 18 248 Age 4 months HCV RNA - HCV RNA + HCV RNA - 16 2+6 = 8* 242 * remained infected at 18 months Conte D, Hepatology 2000;31:751

  8. Risk Factors for Perinatal HCV Transmission • HIV coinfection • associated with increased HCV viremia • not necessarily with HIV co-transmission • Prolonged rupture of membranes • > 6 hours [Mast E; Antiviral Therapy 2000; 5 (Suppl): 54] • Internal fetal monitoring [Mast E] • Mode of delivery not a demonstrable risk in most studies

  9. Perinatal HCV Transmission fromHIV Coinfected Women

  10. Perinatal HCV TransmissionOccurs Peripartum • 441 mother-child pairs in the UK and Ireland • Overall perinatal transmission rate 6.7% • 3.8 times higher transmission from HIV coinfected women (no concurrent HIV transmission) • Negative PCR common in infected newborns • Mode of Delivery • Vaginal 7.7% • Emergency C/S 5.9% • Elective C/S 0% adjusted OR 0 (0-0.87) Early rupture of membranes Gibb DM, Lancet 2000;356:904

  11. Current Recommendations regarding Perinatal HCV Transmission • Universal testing of pregnant women is not indicated (yet) - targeted testing is recommended • Elective C/S to prevent HCV transmission is not recommended - avoid internal fetal monitoring or prolonged ROM? • Breast feeding is not contraindicated • Testing infants of HCV infected women after 15 months of age for anti-HCV is recommended

  12. Clinical Features of HCV Infectionin Children • Acute infection is rarely symptomatic • Chronic infection is rarely symptomatic • chronic fatigue may be difficult to assess • extrahepatic manifestations are much less common than in adults

  13. Natural History of HCV Infectionin Children - Critical Issues • What is the rate of progression of liver disease? • Does fibrosis progress linearly? • What are the risk factors for progression during childhood? • What is the role of underlying disease? Mode of acquisition? • Most natural history studies thus far are cross-sectional cohort studies; prospective studies go out only a few years - is this enough?

  14. Natural History of Transfusion-Acquired HCV in Children

  15. HCV Infection Among Survivors of Childhood Cancer 1456 transfused/deceased 1521 transfused/survivors 12/346 (3.5%)HCV infected 77 (6.6%) 1 death from liver failure 35 have undergone liver bx (9 years after rx) 2 deaths from HCC 80% chronic hepatitis (25 and 27 years after rx) 71% fibrosis 9% cirrhosis (9.6, 20, 27 yr after rx) Strickland DK, Blood 2000;95:3065

  16. Natural History of Perinatally Acquired HCV in Children Palomba, 1996: 7 HCV-infected infants born of HCV/HIV coinfected women  all remained infected after 26-90 months Sasaki, 1997: 3/15 at risk infants HCV RNA positive in first month  only 1/15 infected at 16 months Bortolotti, 1997: 10 HCV-infected infants followed for 12-48 months  8/10 remained infected Zuccotti, 2000: 11 HCV-infected infants followed for 42-144 months   10/11 remained infected: Anecdotes: 2 perinatally-infected children developed cirrhosis by age 11, 13 years 3 perinatally-infected children with decompensated cirrhosis at 4, 6, 11 years - 2 born to HCV/HIV coinfected women

  17. Comparison of Histopathologic Features of HCV Infection - Adults and Children

  18. Histopathologic Features of HCV Infection in Children • The features are generally the same as seen in adults - suggesting the same disease and pathogenesis • There is an association between extent of fibrosis and age and duration of infection

  19. Natural History of HCV Infection in Children - Summary • May be different in children infected by transfusion vs those infected perinatally • May be different according to underlying disease for which transfusion was indicated • Benign in the first 20 - 25 years in most instances; a few have aggressive disease • Not known in the 3rd decade and beyond

  20. HCV in ChildhoodGoals of Therapy • Sustained normalization of ALT • Sustained virologic response • Improvement in hepatic histology • Decrease risk of cirrhosis • Decrease risk of HCC

  21. Treatment of HCV Infection in ChildrenInterferon Monotherapy • No large, randomized, controlled trials • Heterogeneous patient groups • Different dosages and types of interferon • Different lengths of treatment

  22. Interferon Monotherapy Trialsin Children * includes some of the same patients

  23. Interferon Monotherapy in ChildrenA Meta-analysis • 11 manuscripts and 3 abstracts • 270 treated children, 37 controls • One of the controls cleared HCV RNA • SVR in treated subjects 35% (0-73%) • 26% in genotype 1 • 70% in genotype non-1 • Few controls, heterogeneous rx, publication bias Jacobson KR, JPGN 2000;S123

  24. Interferon MonotherapyGreater Efficacy in Children? • Younger age • Earlier stage of liver disease • Different modes of acquisition • Higher relative interferon dose • Lack of co-morbid factors • Artifact

  25. IFN Side Effects in Children • Flu-like illness • Neutropenia • Weight loss / failure to gain weight • Irritability, poor school performance, behavior disturbance • Seizures, lower seizure threshold • Spastic diplegia (infants) • Long-term?

  26. Ribavirin Toxicity • Hemolytic anemia • most common in the first weeks • stabilizes thereafter • usually < 2 g drop in hemoglobin • reversible, dose dependent • Teratogenic, male and female • Mutagenic in animal models

  27. Rebetron Pediatric ClinicalTrials • Phase I Dose Finding Study (Complete) • 48 weeks treatment, 24 weeks follow up • Intron A 3 MIU/m2 TIW & Rebetol 8,12,15 mg/kg/day • Dose of 15mg/kg/day selected for phase III • 61 children age 5 to 16 enrolled • 57 naïve/4 relapse • Phase III Open Label Study (Ongoing) • 48 weeks treatment, 24 weeks follow up • Intron A 3 MIU/m2 TIW & Rebetol 15 mg/kg/day • 105 children age 3 to 16 enrolled • naïve only

  28. Combination Therapy for Childhood HCV - Safety (Phase 1) • Types of AEs observed similar to those seen in adults • 2 of the 61 patients (3%) discontinued due to AEs • 7 of the 61 patients (11%) required dose modification due to AEs

  29. Phase I Clinical TrialSustained Virologic Response Interferon-alfa 2b 3 MU/m2 thrice weekly plus *1 nonresponder GT4

  30. HCV in ChildhoodTherapeutic Considerations • The long-term natural history is still not completely known - benign in most? Aggressive in some. • Which children should be treated? • Use same criteria as for adults • None - no DBRCT’s • All - short duration, mild liver disease, more likely to respond?

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