S401- Updates in the Treatments of Hepatitis B & C

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1 S401- Updates in the Treatments of Hepatitis B & C Ruben Gonzalez-Vallina, MD Director of Gastroenterology Outpatient Initiatives Miami Children s Hospital Miami, Florida

2 Disclosure of Relevant Relationship Dr. Gonzalez-Vallina (or spouse/partner) has not had (in the past 12 months) any conflicts of interest to resolve or relevant financial relationship with the manufacturers of products or services that will be discussed in this CME activity or in his presentation. Dr. Gonzalez-Vallina will support this presentation and clinical recommendations with the best available evidence from medical literature. Dr.Gonzalez-Vallina does not intend to discuss an unapproved/investigative use of a commercial product/device in this presentation.

3 Hepatitis B

4 Objectives Identify infants, children, and adolescents at risk of Hep B infection Provide recommended primary care management of chronic Hep B Appropriately test, monitor and refer pediatric patients with chronic Hep B who may require treatment Utilize recommended immunoprophylaxis regimens for newborns of mothers infected with Hep B

5 History 1988: Screening of pregnant women for post-exposure prophylaxis 1991: Universal childhood Hep B immunization 1995: Universal adolescent Hep B immmunization 2005: Universal Hepatits B birth dose administration In the US, without post-exposure prophylaxis: 12,000 infants would be infected annually and without routine childhood vaccines, 16,000 would be infected annually.

6 The Present

7 Hepatitis B Hepatitis B virus is a double-stranded DNA virus 8 known genotypes (A through H) Incubation period: days Clinical manifestation is variable: Asymptomatic anorexia, malaise, N/V, abdominal pain, jaundice, dark urine and clay or light colored stools Extrahepatic manifestations: skin rash, althralgias and arthritis

8 Modes of HBV Transmission Perinatal (newborns) Horizontal (infants and young children) Sexual (most common in adolescents and adults) Parenteral using shared medical supplies, dialysis equipment, multiuse medication vials (underdeveloped countries) adolescents with high risk behavior Acupuncture, tattoos Unknown *Breast-feeding of non-immunized infants by infected mother DOES NOT increase risk of hepatitis transmission

9 Epidemiology Each year approx. 600,000 HBV related death occur worldwide Among adults with normal immune status, most (94-98%) recover completely from newly acquired HBV Infants, young children and immunosuppressed persons with newly acquired HBV will develop chronic infection Infants have 90% risk of developing chronic infection if infected at birth Although consequences of acute hep B can be severe, most serious illness occur in those with chronic infection (15-25% die from cirrhosis or liver cancer)

10 90% 50% 20%

11 Diagnostic Criteria Acute Hep B: Acute illness with discrete onset of symptoms and jaundice or elevated LFTs. Markers: anti-hbc positive or HBsAg positive. Chronic Hep B: Variable clinical picture. Markers: IgM anti HBc negative AND positive: HBsAg, HBeAg or HBV DNA HBsAg positive or HBV DNA positive or HBeAg positive 2 times atleast 6 months apart Perinatal infection: HBsAg positive aged > 1-24 months born to HBsAg positive mother

12 Review Laboratory Data HBsAg Anti-HBc Anti-HBs Interpretation Acute infection possibilities: 1) Acute infection (IgM anti-hbc) 2) Chronic hep B (high ALT, IgG anti-hbc) 3) Inactive carrier (normal enzymes, IgG anti-hbc) possibilities: 1) Remote infection 2) Immunized Remote infection possibilities: 1) Window disease 2) Remote infection 3) False positive More than 1 infection; acute and chronic

13 Who Should be Tested for HBsAg? Infants born to HBsAg- positive women Household contacts of HBsAg-positive individuals Children who live in community with high HBV prevalence 1st and 2nd generation immigrant children of highly prevalent areas (even if immunized) International adoptees Children who will be receiving cancer chemotherapy or long term immunotherapy Adolescents who engage in high risk behaviors

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15 Chronic Hep B Phases Immune tolerant HBeAg+ immune active Inactive HBsAg carrier Reactivation HBsAg and HBeAg detectable HBV DNA > 20,000 IU/mL ALT normal Absent or minimal liver inflammation HBsAg and HBeAg remain detectable HBV DNA > 20,000 IU/mL ALT persistently elevated Liver inflammation and fibrosis can develop HBsAg present HBeAg undetectable, anti-hbe present HBV DNA < 2000 ALT normal Absent or minimal liver inflammation, fibrosis will regress over time DNA levels increase ALT normal or elevated HBeAg remains undetectable

16 Initial Management of HBV

17 Primary Care Management of Chronic HBV Provide Hep A immunization series Test and immunize household contacts for Hep B Do not restrict from school, sports or other activities Consider testing for coinfections (HIV or HDV) that can accelerate liver disease Optimal age for screening for HCC is unknown No consensus Patients > 35 at higher risk are at much higher risk for HCC than those < 35 years

18 Therapies for Chronic HBV IFN-alfa-2b : preferred for 1-12 years of age with compensated disease Entecavir: first-line nucleoside analogue; however, it is only labeled for children ages 16 and older Tenofovir is preferred nucleoside analogue for children ages Lamivudine: labeled for ages >3, least favored because of high risk of developing antiviral resistance

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20 Challenges of management Chronic HBV Minority of children require treatment Therapeutic options are limited, especially in younger children Inappropriate treatment confers potential for viral resistance to current and future therapies Patient selection and timing of treatment are critical

21 Perinatal Transmission of HBV

22 Perinatal Hep B infection HBIG (0.5 ml for infants) and Hep B vaccine should be given within 12 hrs of birth, followed by 2 nd and 3 rd doses of vaccine at 1 and 6 months of age, respectively Post-vaccination testing for HBsAg and anti-hbxag is recommended 3 to 6 months following completion of vaccine series.

23 Post-exposure prophylaxis HBIG and Hep B vaccine is 85-95% effective in preventing HBV infection when given at birth to infants born to HBsAg positive mothers Prophylaxis should also be given to unvaccinated infants whose mother or primary caregivers have acute hep B, sexual contacts of persons with Hep B and healthcare workers after occupational exposure to HBsAg positive blood

24 Pre-term infants Typically vaccination of pre-term infants should be delayed until 1 month old or until discharge from hospital. Pre-term infants receive SAME immunoprophylaxis if born to HBsAg positive women

25 Prevention of HBV Ensure all pregnant women are tested for HBV and results are available at time of delivery Ensure all newborns of HBsAg-positive women receive HBIG and vaccine prior to discharge Test newborns of HBsAg positive women at 1 year of age for HBsAg and anti-hbs Ensure all newborns receive full series of HBV vaccine Recognize and test children in high risk groups, households; immunize susceptible children Immunize all children and adolescents who escaped routine vaccination Recognize children with comorbidities associated with poor HBV vaccine response: Celiac disease, obesity, IBD

26 Barriers to successful HBV immunization Incorporation of 3 doses of HBV vaccine into primary care practice Access to primary care for immigrants and other high risk groups Vaccine acceptance by parents concerns regarding mercury toxicity from thimerosal in older vaccines Lack of knowledge about which children should be tested for vaccine response Born to HBsAg positive mother or living with HBsAg Immune suppressed Celiac disease Obese On hemodialysis

27 Hepatitis C: Epidemiology, Diagnosis and Treatment

28 Hepatitis C Virus Infection Magnitude of the Problem 115 M infected persons in the world 11 M < than 15 y/a 8 million are viremic, of whom 5 million < than 15 y/a Approximately 35,000 new cases yearly 85% of new cases become chronic Global health care costs for HCV-infected children and their families are hundreds of millions of dollars annually Leading cause of Chronic liver disease Cirrhosis Liver cancer Liver transplantation

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30 Chronic HCV Infection May Lead to Chronic Liver Disease and Liver Cancer Fibrosis Chronic HCV infection can lead to the development of fibrous scar tissue within the liver Cirrhosis Over time, fibrosis can progress, causing severe scarring of the liver, restricted blood flow, impaired liver function and eventually liver failure HCC Cancer of the liver can develop after years of chronic HCV infection

31 Deaths Due to HCV Infection Now Exceed Those with HIV Infection

32 Projected Numbers of Decompensated Cirrhosis and Cases of HCC TO Rise Through 2020 Decompensated cirrhosis became more common after 1995, and is presently estimated 11.7% of cirrhosis cases; the number of cases is expected to continue to increase through HCC rose steeply after Based on the model, the incidence of HCV- related HCC is expected to peak in 2019 at almost 14,000 cases per year if the risk in HCV- infected persons with fibrosis remains the same

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34 Mode of Transmission

35 Perinatal transmission Vertical transmission occurs in 3-10% Transmission Rate - Mother HCV RNA (+) 5-10% - Mother HCV HIV (+) 10-20%

36 Hepatitis C Virus Infection Population at Risk Children with clinical evidence of hepatitis, including unexplained elevation of ALT /AST, even if asymptomatic. Children whose mothers are HCV + or have a history of IDU. Children international adoptees or refugees, Children and adolescents with HIV infection. Adolescents or children victims of a sexual assault, or adolescents with a history of multiple sexual partners. Adolescents with a history of illicit IDU. Individuals who received blood products before Individuals with a history of care in a neonatal intensive care unit (NICU) prior to 1992, whether or not they are aware of a history of blood transfusion. Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: Accessed February 1, 2006.

37 Hepatitis C Virus Infection Natural History Acute HCV Resolved 15% (15%) Chronic HCV 85% (85%) Stable 80% (68%) Cirrhosis 20% (17%) HCC, hepatocellular carcinoma Slowly progressive 75% (13%) HCC Liver failure 25% (4%)

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39 Screening of Baby Boomers May Prevent > 120,000 Deaths Due to HCV infection new cases of HCV identified with birth-cohort screening patients treated Patients cured deaths averted - Baby boomers patients born from 1945 to Up to 75% of people with HCV in the US are undiagnosed - An estimated 35% of undiagnosed baby boomers with HCV currently have advanced fibrosis

40 HCV Testing Hepatitis C Ab Negative (-) If no concern for acute infection or immunosuppression, STOP here. If so, screen further with HCV RNA Positive (+) Positive (+) Check HCV RNA (viral load) Confirm ation Negative (-) Patient has likely cleared prior infection consider retesting RNA in 4-6 months Hepatitis C infection LOOK FOR GENOYPE (1-6) A baby born from mother HCV + can have a positive HCV Ab until 12 months of age

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43 Viral Hepatitis Role of Diagnostic Testing Identify patients with viral hepatitis infection Active infection Inactive infection Resolved infection Assess response to therapy Prior to onset of treatment During and following treatment

44 False positives Autoimmune disorders Spontaneous resolution of viral infection False negatives HCV Antibody Testing Limitations Chronically immune suppressed Transplant recipients Chronic renal failure on dialysis HIV positive

45 Management of Chronic HCV Tests Utilized Disease Severity AST/ALT Bilirubin Albumin Pro-time (INR) Platelet count Liver histology LFTs Response to Therapy ALT HCV RNA HCV genotype Liver histology

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47 Headaches Weight loss Myalgia Neutropenia Depression Ischemic retinopathy (rare) Uveitis (Rare)

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51 Treatment History 1. IFN by itself (1990) 2. Ribavirin + IFN (2001) 3. Boceprevir & Telaprevir + Ribavirin and IFN (2003) 4. Sofosbuvir + IFN + Ribavirin (2013) 5. Sofosburin + Ribavirin (without IFN) 6. Sofosburin + Ledispasvir (no need of Ribavirin or IFN).

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53 Factors Associated with Treatment HCV Genotype - 1,2,3,4,5,6 Stage of liver fibrosis and Cure - Cirrhosis vs No cirrhosis HCV Treatment status - Naive vs treatment experienced (Relapse, partial responder, null responder) Special population - Transplant, chronic kidney dis, age > 70, children, HIV BMI

54 Goal of Treatment = Cure Sustained Viral Response (SVR) approximates a cure Cure: Negative viral load after 24 weeks of treatment. All SVR are equal SVR achieved by all regimens will provide same long-term cost-benefit via reduction in complications. One life saved for every three SVR Cost per SVR is a key metric

55 Treating Children with HCV Contraindications Active neuropsychiatric disorder Pregnancy Decompensate liver disease Autoimmune disease Renal dysfunction Active cancer Hemoglobinopathy

56 Conclusions We need to do a better job screening and avoiding perinatal transmission HCV Rapidly changing treatment paradigm in HCV Genotype 1 has the first approved, highly efficacious oral regimen 90% cure rate with 12 weeks treatment

57 References AAP. Red Book Report on infectious diseases VPD Surveillance Manual, Hep B: Chapter th Edition, 2011 Uptodate. Hepatitis C management and treatment in pediatric population

58 Thanks to Carla Perez and Lina Castillo