Disclosure. HBV Background

Transcription

1 Disclosure I have the following financial relationships with the manufacturers of any commercial product(s) and/or provider of commercial services discussed in this CME activity: Research Support from: Roche, BMS, Gilead, NIH Consultant for: Ikaria, Roche, Gilead I do not intend to discuss an unapproved/ investigative use of a commercial product/device in my presentation Chronic Hepatitis B Virus (HBV) Infection HBV Background Chronic HBV infection remains a serious health concern for those who are not vaccinated exposed prior to being vaccinated A challenge facing pediatricians is the lack of clear screening, monitoring and treatment guidelines In November 2008, the Hepatitis B Foundation charged an expert panel with developing recommendations for pediatric practitioners regarding screening children for HBV and managing those diagnosed with chronic HBV infection, including: Which children should be screened for HBV markers (HBsAg and anti-hbs) What additional tests to conduct in children who screen positive for HBV How often to monitor on the basis of test results When to refer to a pediatric liver specialist Goal: to enhance the success of management of children with this lifelong infection Persistent Hepatitis B Surface Antigen (HBsAg) Positive for >6 months Children: Are most commonly asymptomatic Do not generally require treatment Are at increased risk for severe complications later in life advanced liver disease (incl. cirrhosis) liver cancer (hepatocellular carcinoma, HCC) 1

2 Epidemiology In much of the world, the lifetime risk of contracting HBV is >60% In the US, universal infant vaccination was instituted in 1991 The incidence of acute hepatitis B has declined significantly Chronic hepatitis B remains a substantial problem due to: Vertical transmission Immigration from areas of endemicity Infection by HBsAg+ household contacts Chronic HBV infection develops in 90% of infants infected as neonates 25-50% of children aged 1-5 years who are acutely infected Vaccination ACIP recommendations for HBV vaccination All infants at birth, completion of 3-dose series by age 6 months Newborns of HBsAg+ mothers within 12 hours of birth, plus 1 dose HBIG All children <19 years old who were not previously vaccinated In the US, most new cases of childhood HBV are those who were not fully vaccinated Homeless children International adoptees Children born outside the US (incl. those supposedly vaccinated at birth) Newborns of HBsAg+ mothers who did not receive HBIG or the birth dose of vaccine in a timely fashion Phases of Chronic Hepatitis B Infection Phase Labs and Histology Note Immune Tolerant Immune Active Inactive HBsAg Carrier DNA>20,000 IU/ml ALT normal HBsAg and HBeAg detectable Minimal liver inflammation and fibrosis DNA levels decline ALT elevated HBsAg and HBeAg remain detectable Liver inflammation and fibrosis can develop DNA<2,000 IU/ml or undetectable ALT normalizes HBeAg undetectable, anti-hbe present No liver inflammation, fibrosis may regress Reactivation DNA levels increase ALT normal or elevated HBeAg remains undetectable Antiviral therapies are generally ineffective Risk of drug resistance if treated Most children still show no signs or symptoms of disease Age at serocoversion appears to be influenced by HBV genotype Risk of developing cirrhosis and HCC declines Occurs in % of patients e-antigen-negative disease Usually due to a mutant virus Children Who Should Be Screened for Chronic HBV Infection Children born in countries endemic for HBV even if they received hepatitis B vaccine in their country of origin All of Asia All of Africa South- and mid-pacific Islands Europe (Eastern and Mediterranean countries), Greenland, and Russia Middle East South America: Amazon Basin Caribbean Indigenous populations from the Arctic, Australia, and New Zealand Children born in the US to immigrant parents from endemic areas Infants born to HBsAg+ mothers Haber, BA, et al. Pediatrics. published online Oct 5, (doi: /peds ) 2

3 Recommended approach to monitoring children with chronic hepatitis B infection Antiviral Therapy 7 antiviral drugs are currently approved for use in adults 4 of these are labeled for use in children (<18 years old) Only 2 are available for younger children a ALT and WBC/Plt are generally part of a hepatic function panel and CBC b Greater than the testing laboratory ULN, or 40 IU/L, whichever is lower c ALT and AFP q6-12 mos; HBeAg/Anti- HBe and HBV DNA q12 mos; Also consider ultrasound q1-2 yr, particularly with elevated ALT or AFP, or family history of HCC Drug Labeled for Note Adefovir 12 years old Less potent Risk of drug resistance Entecavir 16 years old Older teens only Interferon alfa-2b 12 months old Potential adverse effects Lamivudine 3 years old Less potent Risk of drug resistance Hepatitis B Foundation Haber et al. Pediatrics 124: e , Haber, BA, et al. Pediatrics. published online Oct 5, (doi: /peds ) Summary for HBV Children at high risk for HBV, especially those born in endemic countries, should be screened for HBV markers (HBsAg and anti-hbs) even if they received HBV vaccine in their country of origin Hepatitis C Virus Routine monitoring of children with chronic HBV infections and timely consultation with a pediatric liver specialist are essential Any child with an elevated ALT and/or AFP level, and/or a positive family history for liver disease, especially liver cancer, should be referred to a pediatric liver specialist capsid c22 envelope protein protease/helicase 33c c-100 RNA-dependentRNA polymerase The specialist can advise on opportunities to treat and/or the need for further evaluation, and recommend a strategy for long-term monitoring for progression of disease 5 core E1 E2 NS2 NS3 NS4 NS5 3 A successful partnership between the primary practitioner and pediatric liver specialist can enhance the success of screening, management, ) and monitoring of children with this lifelong infection hypervariable region 3

4 HCV- Monitoring and Anticipatory Guidance of Treatment Naive Evaluate annually Laboratory: Serum aminotransferases, bilirubin (total and direct), albumin, HCV RNA levels, complete blood count and coagulation studies Liver biopsy generally only if the result will influence medical decision-making May be useful to investigate unexplained clinical hepatic decompensation in a previously stable patient In children who are being considered for antiviral treatment in order to assess severity of liver disease HCV- Monitoring and Anticipatory Guidance of Treatment Naive Screening for hepatocellular carcinoma (HCC) There are only a few reported cases of children with chronic HCV infection developing HCC In those with significant liver disease (hepatic fibrosis or cirrhosis), abdominal ultrasonography and serum α-fetoprotein should be considered annually to screen for HCC Monitoring of children younger than 3 years of age with HCV infection Vertical transmission currently accounts for the majority of pediatric HCV infections Infants with detectable HCV RNA should be periodically monitored as spontaneous viral clearance may occur during childhood, particularly in HCV genotype 3 infections Recommendations for Treatment Candidacy Therapy Accepted >18 years of age HCV RNA + in serum Liver biopsy shows significant fibrosis Acceptable hematologic and biochemical indices Willingness to be treated and comply with treatment requirements Ghany MG, et al. Hepatology. 2009;49: Individualize Therapy Failed previous IFN/pegIFN alfa + ribavirin therapy Current user of illicit drugs or alcohol but willing to be in support program No or mild fibrosis on liver biopsy Acute HCV infection Coinfection with HIV (HBV) < 18 years of age Chronic renal disease Decompensated cirrhosis Liver transplant recipient Issues to Consider Before Therapy in Children with HCV Age (therapy approved >3 years of age) Viral genotype (2 or 3 vs. 1) Degree of liver injury Decompensation Liver biopsy findings Contraindications 4

5 Contraindications to HCV Therapy Uncontrolled depressive illness, psychosis, or epilepsy Untreated anemia (hemoglobin < 12 g/dl) Renal, heart, or lung transplantation Autoimmune hepatitis or other autoimmune condition known to be exacerbated by IFN/pegIFN and RBV Untreated thyroid disease Pregnancy or unwillingness to comply with adequate contraception Severe concurrent medical disease Known hypersensitivity to drugs used to treat HCV Ghany MG, et al. Hepatology. 2009;49: Preparing Patients for HCV Therapy Topics to review and discuss with patients Need for effective contraception Prognosis Treatment options Predictors of response to therapy/likelihood that they will respond Adverse event management School and job-related issues Importance of medication adherence, need for visits/lab follow-ups Educate about avoidance of alcohol, drugs and potential hepatotoxins Encourage patient s active participation in treatment decisions and ability to ask questions HCV Therapy Options FDA approved PegIFN/RBV constitutes standard of care for children (>3 years) infected with all major HCV genotypes Genotypes 1 and 4: 48 wks of therapy Genotypes 2 and 3: 24 wks of therapy Adults (>18 years) with genotype 1 HCV have new options with the FDA approval of 2 protease inhibitors: telaprevir and boceprevir Each agent used in combination with pegifn/rbv Adults with genotype 2, 3, or 4 HCV continue to receive pegifn/rbv Baseline Predictors of Response to PegIFN/RBV Useful for advising patients on their likelihood of a SVR Absence of favorable factors should not be used to deny therapy Patient Factors Age Sex Race Weight Insulin resistance Fatty liver disease Vitamin D status Depression Drug/alcohol use Fibrosis/cirrhosis HIV coinfection IL28B status Virus Factors Genotype HCV RNA level 5

6 Impact of HCV Genotype on SVR to PegIFN/RBV PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800 mg/day for 48 Wks[1] 1. Manns MP, et al. Lancet. 2001;358: PegIFN alfa-2a 180 µg/wk + Weight-Based RBV (1000 or 1200 mg/day) for 48 Wks[2] 2. Fried MW, et al. N Engl J Med. 2002;347: Host Genotypic Response: IL28B Polymorphism Genetic polymorphism near IL28B, which encodes for IFN lambda-3 CC genotype strongly correlates with response to pegifn + RBV in individuals infected with genotype 1 HCV Comparable outcomes observed in whites, blacks, and Hispanics However, only accounts for approximately one half of disparity in response rates in genotype 1 infected patients treated with pegifn + RBV, particularly among whites vs blacks Ge D, et al. Nature. 2009;461: Response Rates by IL28B Polymorphism: IDEAL Trial GT 1 Treated With PegIFN/ RBV Impact of Baseline HCV RNA (<600,000 IU/ ml) on SVR to PegIFN/RBV Hadziyannis SJ, et al. Ann Intern Med. 2004;140: % Patients SVR % Patients SVR Ge D, et al. Nature. 2009;461: Genotype 1 48 wks of pegifn alfa-2a + RBV mg/day Genotype 2/3 24 wks of pegifn alfa-2a + RBV 800 mg/day 6

7 FDA Approved PEG-IFN Peginterferon alfa-2b (PEG-IFN-α-2b) (Peg- Intron; Merck & Co.) contains a linear 12kDa PEG moiety The optimal dose of PEG-IFN-α-2b is 60 mcg/m2/week given SC PEG-IFN-α-2a (Pegasys; Genentech/ Roche) contains a larger, branched 40kD PEG moiety PEG-IFN-α-2a is given at a dose of 180 mcg/1.73 m2 weekly SC PEDS-C: Pegylated Interferon alfa 2a +/- Ribavirin for Children With Hepatitis C Inclusion Criteria: Male or female patients who are 5-18 years of age at enrollment (not yet reached 18th birthday at screening). HCV viremia (by any test) present on 2 tests separated by at least 6 months. Chronic liver disease, as indicated by inflammation and/ or fibrosis, consistent with chronic hepatitis C infection on a liver biopsy obtained within the past 24 months, as assessed by a qualified pathologist, not consistent with other known liver disease and not normal. Compensated liver disease Interferon-alfa and Ribavirin Combination Therapy Either PEG-interferon should be given in combination with ribavirin at a dose of 15 mg/kg/day PO divided twice daily for chronic HCV The recommended length of therapy: 48 weeks of treatment for genotypes 1 or 4 24 weeks duration of treatment for genotypes 2 or 3 If HCV RNA does not become undetectable by 24 weeks, there is no evidence that prolonged treatment improves clinical outcome Percent of Patients with Adverse Events During PEG IFN /Treatment Adverse Event Fever, flu-like illness Fatigue Headache Anorexia Myalgia/arthralgia Nausea Vomiting Decreased weight Neutropenia Anemia Depressed mood/depression 4 Irritability Insomnia/trouble sleeping 3-11 Injection site reaction Rash 20 Alopecia 17 Percent range Schwarz et al. Gastroenterology 2011;140:450; Wirth et al. J Hepatol 2010;52:501; Abdel-Aziz et al. J Pharm Prac 2011;24:203 7

8 HCV RNA Assessments: Time Points to Consider With PegIFN/ RBV Key time points Wk 4 : RVR (rapid virologic response) undetectable serum HCV RNA (<50 IU/ml) Wk 12: EVR (early virologic response) undetectable or >2 log drop in serum HCV RNA Strongest predictor of SVR (sustained virologic response), trumping HCV genotype May be used to shorten therapy to wks Wk 24 or 48: ETR (end of treatment) undetectable serum HCV RNA Wk 48 or 72: SVR undetectable HCV RNA 24 weeks after EOT Recommendations for Monitoring During Therapy Laboratory test to be monitored CBC with diff.; Absolute Neutrophil Count Hepatic panel, glucose TSH/total T4 0, 12, 24, 36, 48 Urine HCG (for females 13 years old) 0, 24 Prothrombin time Urinalysis HCV RNA 0, 24, 48, 72 Obtain on following week of therapy 0, 1, 2, 4, 8, 12 and every 4-8 wks. thereafter 0, 1, 2, 4, 8, 12 and every 4-8 wks. thereafter 0; only repeat if clinically indicated 0; only repeat if clinically indicated % Patients SVR SVR to PegIFN/RBV in Children Combination Therapy: Safety Summary Side effects of combination therapy consistent with profile of each drug as monotherapy No apparent synergistic toxicity when interferon and ribavirin combined Defining toxicity of combination therapy is hemolysis Manageable with patient monitoring and dose reduction Contraindicated in pregnancy (teratogenicity) 8

9 SUMMARY Children at high risk for HBV, especially those born in endemic countries, should be screened for HBV markers (HBsAg and anti-hbs) even if they received HBV vaccine in their country of origin Children at high risk for HCV should be screened for HCV-Ab and confirmed with HCV RNA PCR Routine monitoring of children with chronic HBV or HCV infections and timely consultation with a pediatric liver specialist are essential Any child with an elevated ALT and/or AFP level, and/or a positive family history for liver disease, especially liver cancer, should be referred to a pediatric liver specialist There are several FDA approved treatments for use in children with chronic HBV and HCV A successful partnership between the primary practitioner and pediatric liver specialist can enhance the success of screening, management, and monitoring of children with these infections References Haber BA, Block JM, Jonas MM, Karpen SJ, London WT, McMahon BJ, Murray KF, Narkewicz MR, Rosenthal P and Schwarz KB. Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B. Pediatrics 124: e , Jonas MM, Block JM, Haber BA, Karpen SJ, London WT, McMahon BJ, Murray KF, Narkewicz MR, Rosenthal P, Schwarz KB and McMahon BJ. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology 52: , Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas MM, Rosenthal P, Mohan P, Balistreri WF, Narcewicz MR, Smith L, Lobritto SJ, Rossi S, Valsamakis A, Goodman Z, Robuck PR and Barton BA for the Peds-C Clinical Research Network. The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology 140: , Mack CL, Gonzalez-Peralta RP, Gupta N, Leung D, Narkewicz MR, Roberts EA, Rosenthal P and Schwarz KB. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Practice Guidelines: Diagnosis and Management of Hepatitis C Infection in Infants, Children and Adolescents. 9