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Viral Hepatitis Susanne Burger, M.D. Jacobi Medical Center North Central Bronx Hospital Viral Hepatitis - Overview Type of Hepatitis A B C D E Incubation Period 15-50 days (mean 28) 60-180 days (mean 120) 15-180 days (mean 42) 15-60 days 15-60 days (mean 42) Tansmission fecal-oral Bloodborne Sexual Bloodborne Sexual Bloodborne Sexual fecal-oral Progression to chronicity no Comments Vaccine available yes Vaccine available yes yes Occurs only as coinfection with HBV or as superinfection of chronic HBV rarely Vaccine under develop ment Case 1 A 21 y/o female college student has a 1-week h/o malaise, anorexia, nausea, and vomiting. Three weeks ago, she returned from Guatemala, where she had engaged in missionary work. PE: T 101, mild jaundice and a palpable, tender liver. Labs: HCT 48% WBC 9000/μl INR 1.0 Alk Phos 110 U/L AST 1100 U/L ALT 1700 U/L Total Bili 3.0 mg/dl Which of the following laboratory tests is most likely to establish the diagnosis? (A) (B) (C) (D) (E) Ab to hepatitis B surface antigen (anti-HBs) Ab to hepatitis C virus (anti-HCV) Indirect hemagglutination test for Entamoeba histolytica IgM antibody to hepatitis A virus (IgM anti-HAV) Ebstein-Barr virus DNA Hepatitis A Virus RNA picorna virus, incubation period ~ 30 days Transmission: close personal contact, contaminated food or water Jaundice by age group: <6 years <10% 6-14 yrs 40-50% >14 yrs 70-80% Rare complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequilae: None Treatment: symptomatic Geographic Distribution Of Hepatitis A Virus Infection Reported Cases Of Hepatitis A, United States, 1952-2002 Hepatitis A Vaccine Events in Hepatitis A Virus Infection Hepatitis A vaccine Highly immunogenic 97-100% have protective levels of antibody within 1 month of receiving first dose; essentially 100% have protective levels after second dose Post vaccination testing NOT recommended Commercially available assay not sensitive enough to detect lower (protective) levels of vaccine-induced antibody Provides protection even when administered following exposure to the virus – now preferred approach in between 1 – 40 years of age Case 2 A 25 y/o woman is brought to the ER by her husband for yellowing of the eyes and increasing confusion and somnolence. The pt is 30 wks pregnant and just returned from visiting her parents in Africa. She has been previously healthy and only takes prenatal vitamins. She has been a social drinker until her pregnancy. PE: T 99.0 ºF, BP 90/40, HR 100, BMI 20 Exam reveals a gravid uterus and asterixis. Laboratory Studies Hb 14g/dl WBC 15,000/µl PLT 450K INR 4.7 Bili (total) 12.0 mg/dL Bili (direct) 9.0 mg/dl AST 3000 U/L ALT 2870 U/L Alk phos 400 U/L Alb 2.3 g/dl Ammonia 120 µg/dL HAV IgM neg HBV SAg neg HBV DNA neg HCV Ab neg ANA neg Anti smooth neg Antimitochondrial Ab neg Alcohol neg Herpes simplex virus (PCR) neg What is the most likely cause of this patient’s fulminant hepatic failure? What is the most likely cause of this patient’s fulminant hepatic failure? HEV Single most important cause of acute hepatitis in Central/S Asia and second only to HBV in Middle East and N Africa. Transmission by fecal-oral exposure to contaminated water In developed countries HEV related to international travel 5 domestic US cases, likely zoonotic spread Hepatitis E NEJM 2004,351;23 Case 3 A 30 y/o man comes to the emergency department because of a 1week h/o of N/V, arthralgias, and dark urine. The pt has a h/o multiple sexually transmitted diseases. He drinks ~ 2 glasses of wine/d and denies the use of illicit drugs and over-the-counter prescription medications. PE reveals jaundice and a tender, enlarged liver. There are no other stigmata of chronic liver disease. Labs: HCT WBC INR Alk Phos AST 49% 11,000/μL 1.1 90 U/L 850 U/L ALT Total Bili 1550 U/L 6.5 mg/dL Which of the following laboratory studies is most likely to establish the correct diagnosis? (A)IgM antibody to hepatitis B core antigen (HBV cor Ab IgM) (B)IgG antibody to cytomegalovirus (CMV Ab IgG) (C)Antibody to hepatitis B surface antigen (HBV S Ab) (D)Antibody to hepatitis B e antigen (HBV e Ab) (E)IgG antibody to hepatitis A virus (HAV IgG Ab) Hepatitis B 5% of the world’s population is chronically infected with hepatitis B (~350 million cases) Hepatitis B is the 10th leading course of death globally leading to more than 600,000 premature deaths annually Half of all deaths are attributed to HCC Routes of Transmission of HBV and Risk of Chronic Infection by Age Age of Infection Modes of Transmission Risk of Developing chronic HBV Infection Birth Perinatal 90% 0-5 years Horizontal: person to person; interfamilial via open cuts and scratches Unsafe injections 25 – 30 % > 5 years Horizontal: person to person; interfamilial via open cuts and scratches Unsafe injections Sexual Transmission Injection-drug use 5 – 7% Prevalence HBV vaccine efficacy Preimmunization Postimmunization Prevalence of HBSAg 16 14 12 10 8 6 4 2 0 14.76 12.8 12 9.3 8.8 8.2 6.2 5.4 4.1 3 1.9 0.9 South Africa Gambia 0.8 Taiw an Alaska 1.4 Indonesia 0.8 Thailand 0 Singapore 2.2 0.8 0.9 0.03 Egypt Japan 0.5 1.4 Urban China Rural China Acute Hepatitis B Virus Infection with Recovery - Typical Serologic Course Progression to Chronic Hepatitis B Virus Infection - Typical Serologic Course Natural Course of Hepatitis B Stages of chronic hepatitis B: Summary HbeAg Immune tolerant chronic HBV Chronic hepatitis B 1) HbeAg pos HBV 2) HbeAg neg HBV Inactive HbSAg carrier state Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87 HbeAb HBVDNA ALT Histology Stages of chronic hepatitis B: Summary Immune tolerant chronic HBV HbeAg HbeAb HBVDNA ALT Histology + - (>105) nl nl Chronic hepatitis B 1) HbeAg pos HBV 2) HbeAg neg HBV Inactive HbSAg carrier state Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87 Stages of chronic hepatitis B: Summary Immune tolerant chronic HBV Chronic hepatitis B 1) HbeAg pos HBV HbeAg HbeAb HBVDNA ALT Histology + - (>105) nl nl + - (>105) Chronic hepatitis 2) HbeAg neg HBV Inactive HbSAg carrier state Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87 Stages of chronic hepatitis B: Summary HbeAg HbeAb HBVDNA ALT Histology + - (>105) nl nl Chronic hepatitis B 1) HbeAg pos HBV + - (>105) Chronic hepatitis 2) HbeAg neg HBV - + (>104) Chronic hepatitis Immune tolerant chronic HBV Inactive HbSAg carrier state Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87 Stages of chronic hepatitis B: Summary HbeAg HbeAb HBVDNA ALT Histology + - (>105) nl nl Chronic hepatitis B 1) HbeAg pos HBV + - (>105) Chronic hepatitis 2) HbeAg neg HBV - + (>104) Chronic hepatitis Inactive HbSAg carrier state - + (<104) nl Various degree of fibrosis Immune tolerant chronic HBV Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87 Replication cycle of Hepatitis B HBV Disease Progression Liver cancer (HCC) 5 – 10%1,3 Acute infection Chronic infection 90% of children < 5% of adults1 30%1 Cirrhosis Liver transplantation Death 23% in 5 yrs2 Torres J, Gastroenterology. 2000;118:83 Fattovich G, Hepatology. 1995;21:77 Moyer LA, Am J prev med. 1994;10:45 Perillo R, Hepatology. 2001;33:424 Liver failure (decompensation) Chronic HBV is the 5th leading cause of liver transplantation In the US4 Therapy for chronic HBV approved by the FDA Interferon alfa-2b (1992) Lamivudine (1998) Adefovir dipivoxil (2002) Entecavir (2005) Peginterferon alfa-2a (2005) Talbivudine Viread Treatment endpoints in chronic HBV Undetectable serum HBV DNA HBeAg loss or seroconversion cccDNA clearance Treatment endpoints HBsAg clearance Decreased HAI and fibrosis Normal ALT Cumulative Probability of LAM and ADV Resistance 80% ADV (N236T or A181V) LAM (YMDD) 70% 60% 50% 40% ENT 30% 20% 10% TFV 0% year 1 year 2 year 3 year 4 Case 4 A 34 y/o nurse reports a needle stick injury. After drawing blood from a pt, the nurse inadvertently stuck the needle into his own finger. The source pt is known to be HBsAg +. The nurse was vaccinated against HBV when he was hired 3 yrs ago. He completed the series of three injections but has never had a serologic confirmation of his response. Which of the following post-exposure options is most appropriate for this health care worker? (A) Administer hepatitis B immune globuline immediately and restart his immunization sequence (B) Check his antibody response to the hepatitis B vaccination; if antibodies are inadequate, administer hepatitis B immune globulin and restart his immunization sequence. (C) Check his antibody response to the hepatitis B vaccination; if antibodies are adequate, administer only hepatitis B immune globulin (D) As the nurse has completed his hepatitis B vaccination series, no intervention is necessary Case 5 A 44 y/o male IDU has a 5 day h/o malaise, N/V, RUQ discomfort, and jaundice. He takes no medications and drinks ~ 6 cans of beer/d. He has not had any sexual contact for the past 18 months and has never traveled outside the United States. Review of his medical records shows normal serum aminotransferase values despite having repeated pos tests for HBsAg. Labs 8 weeks ago: AST 24 U/L ALT 28 U/L HBV DNA undetectable HBsAg positive Physical examination today discloses jaundice. The liver is mildly tender; liver span is 15 cm. Current labs: CBC normal Coags normal Alk Phos 117 U/L AST 900 U/L ALT 1050 U/L Total bili 7.8 mg/dl HBV DNA HBsAg HBeAg HbeAb undetectable positive negative positive Which of the following is most likely the cause of this patient’s current clinical presentation? (A)Hepatitis D virus infection (B)Hepatitis E virus infection (C)Acute Ebstein-Barr virus hepatitis (D)Granulomatous hepatitis (E)Alcoholic hepatitis Case 6 A 25 y/o female IDU comes to the ER because of a 10day h/o progressive fatigue, anorexia, and abdominal discomfort. The pt uses daily heroin and drinks ~ 2-3 cans of beer/d. PE: jaundice, tender, enlarged liver Labs: CBC WNL HBsAg negative INR 1.1 Hep A Ab IgM negative Alk Phos 120 U/L Hep C Ab negative AST 1250 U/L Hep B cor Ab IgM negative ALT 2120 U/L Total bili 3.5 mg/dl Which of the following tests is the most likely to establish the diagnosis? (A)Hep A Ab IgG (B)Hep B cor Ab IgG (C)HCV RNA (D)HBsAb (E)Antimitochondrial antibody titer Diagnostic approach to hepatitis C virus infection Diagnostic approach to hepatitis C virus infection Hepatitis C Elisa positive negative Diagnostic approach to hepatitis C virus infection Hepatitis C Elisa positive negative Confirm chronic infection: Hep C PCR (qual/quant) positive negative Diagnostic approach to hepatitis C virus infection Hepatitis C Elisa positive negative Confirm chronic infection: Hep C PCR (qual/quant) positive Chronic HCV Vaccinate against HBV, HAV negative HCV cleared, but repeat PCR once in 6 months Diagnostic approach to hepatitis C virus infection Hepatitis C Elisa positive negative Confirm chronic infection: Hep C PCR (qual/quant) positive Chronic HCV Vaccinate against HBV, HAV negative HCV cleared, but repeat PCR once in 6 months No HCV unless pt severely immunocompromised or high index of suspicion for acute Hep C Who should be tested? CDC Recommendations • Test: • Do not test: – h/o IVDU – Healthcare workers – Received clotting factors before 1987, blood/organs before 1992 – Pregnant women – Chronic hemodialysis – Evidence of liver disease – Intranasal cocaine users – h/o tattooing, body piercing – h/o STDs or multiple sex partners – Long-term steady sex partners of HCV-positive persons – Household (nonsexual) contacts of HCV-positive persons – General population Serologic Pattern of Acute HCV Infection with Progression of Chronic infection Natural Course of Hepatitis C Treatment of chronic Hepatitis C Patients with sustained virological response (%) Evolution of HCV therapy 70 63 60 54 56 Peginterferon alfa-2b 50 38 40 Peginterferon alfa-2a 40 IFN/RBV 30 20 IFN 25 18 10 1990s 2004 0 Mc Hutchinson et al., Lindsay et al. Zeuzem et al. Manns et al. Fried et al. Peginterferon alfa-2b/RBV (ITT) Peginterferon alfa-2a/RBV (ITT) Peginterferon alfa-2b/RBV (80/80/80) Response Patterns 8 Peginterferon/Ribavirin Log HCV RNA (IU/ml) 7 6 5 2-log decline 4 3 2 Limit of detection SVR 1 0 -6 0 4 6 12 18 24 30 36 42 48 54 60 66 72 WEEKS Time to response and SVR Genotype 1 Partial 15% Week 4 15% Week 12 35% Week 24 15% SVR (%) Null 20% 100 90 80 70 60 50 40 30 20 10 0 91 66 45 4 12 24 Week HCV RNA (-) P Ferrenci et al. J Hepatology 2005;43:453-471 Treatment of HCV Impact of STAT-C Drugs 8 Log HCV RNA (IU/ml) 7 6 5 2-log decline 4 3 2 Limit of detection SVR 1 0 -6 0 4 6 12 18 24 30 36 42 48 54 60 66 72 WEEKS Telaprevir – PROVE 1 Study Design PEGIFN+R+Telaprevir PEGIFN+R+Telaprevir PEGIFN+R+Telaprevir All patients GT 1 Treatment naive PEGIFN+R PEGIFN+R PEGIFN+Ribavirin 0 JM McHutchinson et al. EASL 2008 12 Weeks 24 48 Telaprevir – PROVE 1 Phase 2 Final Results 90 80 81 80 80 % of Patients 70 71 68 60 67 61 59 Week 4 Week 12 SVR 50 45 40 41 35 30 20 10 11 0 Control JM McHutchinson et al. EASL 2008 T+0 T+12 T+36 Boceprevir – SPRINT 1 Study Design PEG-INTRON + RBV + B PEG-INTRON + RBV PEG-INTRON + RBV + B PEG-INTRON + RBV + B PEG-INTRON + RBV PEG-INTRON + RBV + B PEGASYS + Ribavirin 0 P Kwo et al. EASL 2008 4 24 Weeks 48 Boceprevir – SPRINT 1 Lead In Phase Results 80 74 70 % HCV RNA (-) 60 60 62 56 50 PEG/RBV PEG/RBV/Bo/24wks PEG/RBV/Bo/48wks 40 34 30 20 10 8 0 P Kwo et al. EASL 2008 RVR SVR