The S ABC of Pediatric Viral Hepatitis Amy E. Warner, MPH Colorado Department of Public Health and Environment Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis A Hepatitis A • Picornavirus (RNA) • Incubation: 15-50 days (mean 28) • Transmission: – Oral-fecal (household, intimate, institutions) – Common Source (water, food, shellfish) – Parenteral (rare) Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Clinical Hepatitis A • Symptoms by Age – <6 years of age = 30% – >6 years of age = 70% or more • Flu like symptoms: fever, malaise, anorexia, nausea, abdominal pain, jaundice • Children less likely to be jaundiced • Peak period of being infectious – 2 weeks before symptoms • Complications: – Fulminant hepatic failure (1:10,000) – Relapsing hepatitis Risk of Acquiring Hepatitis A U.S. • Risk groups: – International travel, – Men who have sex with men – Users of Injection and Noninjection drugs – Person with Occupational Risk – Persons with ClottingFactor Disorders – Persons with chronic liver disease • Less Likely Risk Groups – – – – Food handlers Child care centers Health-care workers Persons with developmental disabilities – Schools – Workers exposed to sewage MMWR: May 19, 2006/Vol.55/No.RR-7 Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis A Risks Higher Risk Transmission High Risk of Severe Outcomes International Travel Persons with chronic liver Food workers disease Men who have sex with men Persons with clotting factor disorders Users of illicit injectable and non-injectable drugs Viral Hepatitis Program http://www.hepatitiscolorado.info Public Health Implications Healthcare workers Childcare centers Hepatitis A Worldwide • In developing countries, infection in the first decade of life is common • In developed countries, infection occurs at an older age Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Anti-HAV prevalence (%) Greece USA Sweden Hepatitis A Rates in Colorado, 1983-2009 30.0 Rate per 100,000 Hepatitis A vaccine available 880 cases 25.0 20.0 15.0 10.0 27 cases 5.0 0.0 1983 85 87 89 91 93 95 97 99 01 03 05 07 09 Report Year The hepatitis A vaccine is safe and effective. Since Colorado introduced it in 1996, hepatitis A has declined dramatically. Hepatitis A: Colorado Cases Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis A Prevention • The best way to prevent hepatitis A infection is to get the hepatitis A vaccine • Vaccine is recommended – Before international travel – For all children at age one – Others in high risk groups Hepatitis A Vaccine • Inactivated vaccine. • Very effective immunogenicity – 97-100% seroconversion at one month after vaccination • Approved for children 1 year and older • Duration of protection estimated 12-25 years • Contraindications – a history of severe allergic reaction to a previous dose or to a vaccine component (alum, phenoxyethanol) • Specific dosing guidelines are available in the Redbook and on the CDC guidelines Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Who to Vaccinate?? Occupational Risk Travelers to endemic regions Children 1 year of age or older Viral Hepatitis Program http://www.hepatitiscolorado.info High risk behaviors Transplant recipients Chronic liver disease ph: 303-692-2780 fax: 303-759-5257 Preventing Transmission – U.S. • Vaccination (preferred) – All those at risk – All children 1 year of age or older • Immunoglobulin – Short-term protection through passive transfer of anti-HAV – 85% effective if given ≤2 wks of exposure – protection conferred for up to 5 months – Given post-exposure to individuals < 1 year of age or >40 years of age Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis B Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis B • DNA virus from the heptadnavirus • Incubation: 60-15 days (mean 90 days) • Results in an acute or chronic infection CDC Pink Book 12th Edition Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis B:Transmission • • • • Vertical transmission Immigration from endemic areas Infection by HBsAg+ household contacts Chronic HBV infection develops in – 90% of infants infected as neonates – 25-50% of children aged 1-5 years of age • 5-10% of adults Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis B: Epidemiology Universal vaccination of infants Viral Hepatitis Program http://www.hepatitiscolorado.info Clinical Hepatitis B • At least 50% of infections are asymptomatic even more if you are < 5 years of age • The risk of chronic HBV infection decreases with age • An estimated 3,000 – 4,000 persons die of hepatitis B related cirrhosis each year in U.S. • 1,000-1,500 people die of HBV-related liver cancer annually in the U.S. Viral Hepatitis Program http://www.hepatitiscolorado.info Consequences of HBV infection Incident Hepatitis <1% FHF 80% Death 5% adults 30%- 50% for children 1-5 years 90% for children < 1 year Chronic infection 20% 30-70% Chronic Hepatitis 25% Hepatocellular Carcinoma Cirrhosis Asymptomatic Carrier Recovery 90-95% 25% Pediatric Infections in the U.S. • International adoptees • Children born in endemic countries even if records indicate HBV vaccination. • Children born to HBsAg+ mothers who did not receive prophylaxis Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Clinical Hepatitis B • Prodrome: serum sickness, rash, arthritis • Symptomatic phase: fatigue, fever, myalgia, nausea, vomiting, abdominal pain, jaundice, icterus (often anicteric in children) • Convalescence • Complications: FHF, membranous nephropathy, vasculitis, papular acrodermatitis Viral Hepatitis Program http://www.hepatitiscolorado.info Children to Screen for HCV: • Children born to HCV-infected mothers (IOM, CDC, NIH) • Children born in HBV endemic countries even if they received hepatitis B vaccine • Children born in the US to immigrant parents from endemic areas • Children living with an HBsAg+ individual • Children using illicit injection drugs even once in the distant past - especially if drugs, equipment, paraphernalia or rinse water were shared (IOM,CDC, NIH) IV (IOM, CDC) • Persons with HIV (IOM, CDC) Viral Hepatitis Program http://www.hepatitiscolorado.info Approach to patient • HBsAg test • If high suspicion and HBsAg negative, anti HBc IgM or retest HBsAg 2-3 weeks • Post exposure prophylaxis: HBIG, Hepatitis B vaccine Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Phases of Chronic Hepatitis B Infection Phase Labs and Histology Note Immune Tolerant DNA>20,000 IU/ml ALT normal HBsAg and HBeAg detectable Minimal liver inflammation and fibrosis  Antiviral Immune Active DNA levels decline ALT elevated HBsAg and HBeAg remain detectable Liver inflammation and fibrosis can develop  Most Inactive HBsAg Carrier DNA<2,000 IU/ml or undetectable ALT normalizes HBeAg undetectable, anti-HBe present No liver inflammation, fibrosis may regress  Age Reactivation DNA levels increase ALT normal or elevated HBeAg remains undetectable  therapies are generally ineffective  Risk of drug resistance if treated children still show no signs or symptoms of disease at serocoversion appears to be influenced by HBV genotype  Risk of developing cirrhosis and HCC declines   Occurs in 20-30 % of patients e-antigen-negative disease Usually due to a mutant virus Haber BA, et al., Pediatrics 2009;124:e1007-13 Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Recommended approach to monitoring children with chronic hepatitis B infection • ALT and WBC/Pit are generally part of a hepatitis function panel and CBC • Greater than the testing laboratory ULN, or >40 IU/L, whichever is lower • ALT and AFP q6-12 mos; HBeAg/Anti-Hbe and HBV DNA q12 mos; Also consider ultrasound q1-2yr, particularly with elevated ALT or AFP or family history of HCC Hepatitis B Foundation www.hepb.org Haber BA, et al., Pediatrics 2009;124:e1007-13 Hepatitis B: Treatment • The primary means of treatment of hepatitis B is prevention of acquisition. • Second goal is the treatment of HBV if the first goal is not achieved. Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 HBV Childhood Vaccination Recommendations • All infants at birth • Newborns of mothers with detected HBsAg+ or mothers with unknown HBsAg status. Vaccinate within 12 hours of birth, plus 1 dose of HBIG at separate sites • All children <19 years old who were not previously vaccinated Mast EE, et al, MMWR Recomm Rep. 2005;54(RR-16):1–31 [corrections in MMWR 2006;55(6):158 –159; MMWR 2007;56(48):1267] Haber BA, et al., Pediatrics 2009;124:e1007-13 Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Goals of treatment • • • • • • Eliminate HBV (unlikely) Decrease risk of chronic liver disease/HCC Decrease social stigma/isolation Decrease transmission Decrease HBV DNA to <2000 IU/ml or less Most children will not require treatment, however routine monitoring for progression of disease is essential Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Pediatric Treatment Challenges • Chronic HBV infection • selection of patients who may benefit • appropriate timing of treatment • choice of antiviral therapy • Limited therapeutic options for children and significant potential for development of viral resistance to nucleos(t)ide analogs Jonas, MM, et al. Hepatology. Published online ahead of print Oct 1, 2010 Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Recommended approach to selection of children for treatment a ALT ULN is the local testing lab ULN, or 40 IU/L, whichever is lower. For treatment consideration, ALT should be 1.5 x the lab ULN, or 60 IU/L (1.5 x 40 IU/L), whichever is lower, at least twice in 6 months for HBeAg-positive disease, and at least 3 times in 12 months for HBeAg-negative disease. Hepatitis B Foundation www.hepb.org Jonas, MM, et al. Hepatology. Published online ahead of print Oct 1, 2010 Treatment of Chronic HBV Infection • 7 drugs are currently approved for use in adults (2 IFNs, 5 nucleos(t)ide analogs) • 4 of these are labeled for use in children (<18 years old) (IFNα, 3 analogs) • 2 are available for young children under 3 years old (IFNα, 1 analog) – – – IFN response: 30-40% response in older children and adults. 60-80% response in younger children Jonas, MM, et al. Hepatology. Published online ahead of print Oct 1, 2010 Predictors of response to therapy Higher response rates • < 5 years • ALT >> normal • Low HBV DNA • Compensated liver disease • HBV genotype A and B • Low drug resistant mutant rates • HBeAg + hepatitis • Low HBsAg levels Viral Hepatitis Program http://www.hepatitiscolorado.info Lower response rates • • • • • • > 5 years Normal ALT High HBV DNA Liver failure HBV genotype C and D High drug resistance mutant rates • HBeAg negative hepatitis • HDV • High HBsAg levels ph: 303-692-2780 fax: 303-759-5257 Special Populations That Should Also Be Considered for HBV Treatment Regardless of HBV DNA & ALT Levels • Patients with rapid deterioration of liver function • Patients with compensated cirrhosis • If DNA > 2,000 IU/mL, regardless of ALT • Patients with decompensated cirrhosis (IFN contraindicated) • Recurrent HBV infection post liver transplantation • HBV carriers undergoing immunosuppressive or cytotoxic chemotherapy Lok A, et al. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. EASL HBV Guidelines. Journal of Hepatology. 2009;50:227–242. Sorrell MF, et al. Ann Intern Med. 2009;150:104-110. Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Summary: Screen, Monitor, and Refer Screen: Conduct HBsAg and anti-HBc tests on children at high risk for HBV, especially those born in endemic countries even if they received HBV vaccine in their country of origin Monitor Children with chronic HBV infections and routinely consult with a pediatric liver specialist. Refer to a pediatric liver specialist Any child with an elevated ALT and/or AFP level, and/or a positive family history for liver disease, especially liver cancer. Hepatitis C Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 PUB MED:24,641 articles, 1645 in children Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis C- Epidemiology 2.7 million HCV+ * HCV affects >170 million people worldwide Hepatitis C: Epidemiology CDC Website Features of Hepatitis C Virus Infection • Single stranded RNA flavivirus – Incubation 6-7 weeks ( range 2-26 weeks) • Chronic infection up to 85% • Case fatality rate is low Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Risk of Fatal Outcome in Persons Who Develop HCV Time 100 85% Chronic 85 15% Resolve 20% Cirrhosis 17 80% 15 Stable 68 Courtesy of Seeff, LB and Alter, HJ. 75% Stable 13 25% Mortality 4 Reported Risk Factors for Acute Hepatitis C, United States, 2001-2004 Injection drug use (39%) Occupation (4%) Sex with known anti-HCV (+) partner (10%) Transfusions (2%) No Identified Risk (33%) Sex with >2 partners in past 6 mos (6%) Household (3%) Aggregate Risk Factor (4%)* Source: Sentinel Counties Study of Acute Viral Hepatitis, CDC Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Recent Trends Children: CDC • Most infections in children are due to passage at birth, or risk taking behaviors in adolescents • The risk for perinatal HCV transmission is about 5% • If coinfected with HIV the risk for perinatal infection is about 19% Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Risk of vertical transmission of HCV? • If Mom is HIV negative, HCV PCR positive – 26 studies 1157 infant mother pairs: 6.48% – BMJ 23 studies: 6.2% (95% CI: 4.6-7.8%) • If Mom is HIV negative and HCV PCR negative (HCV antibody positive) – BMJ: 0% (95% CI: 0-0.4%) • If Mom is HIV positive and HCV antibody positive – BMJ: 15.8% (95% CI: 11.8-19.8%) BMJ 315:333, 1997 Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Hepatitis C – Perinatal Aquisition • Avoid use of fetal scalp monitors • Scheduled C-sections: ?slight decrease? In transmission compared to vaginal delivery • Hep C in colostrum and breast milk, however NO increased risk of transmission unless mastitis Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Strategies for child of HCV positive mother Mom HCV antibody/PCR positive Infant HCV PCR negative Infant anti-HCV/ PCR positive Refer to specialist for follow-up evaluation Negative NO HCV Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Long Term Outcome: Perinatal HCV • Generally uncertain • Benign Extreme: (Hepatology 39:90, 2005) – 35 year f/u of mini transfusions 31 at risk, 18 infected – 10% with ALT >1.5 times uln – No or minimal fibrosis in 82% • Severe Extreme: (Am J Gastro 98:660, 2003) – 77% of 112 children with HCV had hepatic fibrosis – Higher fibrosis score if > 10 years of infection – Rate of fibrosis would predict cirrhosis by ~40 years of age in the majority Outcome of Pediatric HCV • Most children have normal LFTs • LFTs do not correlate with histology • No long term outcome data from vertical infection available ModerateSevere Hepatitis Mild Non Specific Bortolotti JPGN 18:281, 1994 Treatment in Children • Augment spontaneous clearance • No consensus on – If we should treat children – Who to treat – When to treat Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Strategies for HCV Infected Children • No treatment prior to 2 years (high rate of clearance, SE) • Vaccinate for HBV, HAV, Counsel to avoid alcohol, or risk behaviors • Baseline Genotype, PCR • Twice a year LFT’s, CBC, Annual AFP, US ? • Liver biopsy if persistently abnormal LFTs or disease > 10 years • Treatment: – Strongly consider: Genotype 2 or 3 or aggressive liver biopsy – Individual option: Genotype 1 with minimal disease – Wait: Individuals with high risk of reexposure, psychiatric contraindications, thyroid disease, autoimmune disease Factors that may affect outcome/response to treatment • Viral load (lower is better) • Duration of disease (shorter is better) • Genotype 2 and 3 more responsive to interferon – >80% response – No apparent genotype dependent response to ribavirin • Abnormal transaminases • Low liver iron • Absence of cirrhosis • IL28b polymorphism (not studied in children) • Children almost always have 3/6 Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Factors for HCV Treatment Response HOST IFN γ production, immunotolerance, fibrosis, genes VIRUS Genotype(1,2,3 or 4), quasispecies, proteins inhibit t cell activation ENVIRONMENT Toxins, alcohol, iron overload Hepatitis C: Treatment • Interferon – Class II family of alpha-helical cytokines – Effects: direct antiviral, immunomodulatory, anti-proliferative, anti-angiogenic, anti-tumor, control of apoptosis – Pegylation of interferon decreases clearance and allows once a week dosing • PEG and ribavirin is current treatment of choice in adults where the response rate is ~40-50% genotype 1 and 80-90% for genotype 2 or 3 • Ribavirin – Guanosine-like nucleoside analogue – Mechanism: mutation in HCV virus leading to less replication and easier clearance? – Single agent: reduces ALT, but not viral load • When combined with IFN generally reduces relapse after treatment (↑SVR) Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 Interferon/Ribavirin Side Effects • • • • • • Flu like symptoms are uniform GI symptoms: 40% Neuropsychiatric/Behavioral symptoms: 70% Neutropenia requiring dose reduction: 35% Mean Hemoglobin decline of 2 gm/dl Mean weight loss of ~10%, regained after treatment • Severe side effects: suicide attempts, retinopathy Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257 THANKS!!! Shikha S. Sundaram, MD MSCI The Children’s Hospital Digestive Health Institute Alicia Cronquist, RN Communicable Disease Colorado Department of Public Health and Environment Candace Vonderwahl Viral Hepatitis Program Colorado Department of Public Health and Environment Viral Hepatitis Program http://www.hepatitiscolorado.info ph: 303-692-2780 fax: 303-759-5257