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Viral Hepatitis Susanne Burger, M.D. Jacobi Medical Center North Central Bronx Hospital
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Viral Hepatitis - Overview ABCDE Incubation Period 15-50 days (mean 28) 60-180 days (mean 120) 15-180 days (mean 42) 15-60 days15-60 days (mean 42) Tansmissionfecal-oralBloodborne Sexual Bloodborne Sexual Bloodborne Sexual fecal-oral Progression to chronicity noyes rarely CommentsVaccine available Occurs only as co- infection with HBV or as superinfection of chronic HBV Vaccine under develop ment Type of Hepatitis
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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: HCT48% WBC 9000/μl INR1.0 Alk Phos110 U/L AST1100 U/L ALT1700 U/L Total Bili3.0 mg/dl
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(A) Ab to hepatitis B surface antigen (anti-HBs) (B) Ab to hepatitis C virus (anti-HCV) (C) Indirect hemagglutination test for Entamoeba histolytica (D)IgM antibody to hepatitis A virus (IgM anti-HAV) (E)Ebstein-Barr virus DNA Which of the following laboratory tests is most likely to establish the diagnosis?
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Hepatitis A Virus RNA picorna virus, incubation period ~ 30 days Transmission: close personal contact, contaminated food or water Jaundice by age group: 14 yrs70-80% Rare complications:Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequilae:None Treatment: symptomatic
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Geographic Distribution Of Hepatitis A Virus Infection
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Reported Cases Of Hepatitis A, United States, 1952-2002 Hepatitis A Vaccine
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Events in Hepatitis A Virus Infection
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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
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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.
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Laboratory Studies Hb 14g/dlHAV IgMneg WBC 15,000/µlHBV SAgneg PLT 450KHBV DNAneg INR 4.7HCV Abneg Bili (total) 12.0 mg/dLANAneg Bili (direct) 9.0 mg/dlAnti smoothneg AST 3000 U/LAntimitochondrial Ab neg ALT 2870 U/LAlcohol neg Alk phos 400 U/LHerpes simplex virus (PCR) Alb 2.3 g/dlneg Ammonia 120 µg/dL
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What is the most likely cause of this patient’s fulminant hepatic failure?
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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
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Hepatitis E NEJM 2004,351;23
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Case 3 A 30 y/o man comes to the emergency department because of a 1- week 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 49%ALT1550 U/L WBC11,000/μLTotal Bili6.5 mg/dL INR1.1 Alk Phos 90 U/L AST850 U/L
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(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) Which of the following laboratory studies is most likely to establish the correct diagnosis?
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Hepatitis B 5% of the world’s population is chronically infected with hepatitis B (~350 million cases) Hepatitis B is the 10 th leading course of death globally leading to more than 600,000 premature deaths annually Half of all deaths are attributed to HCC
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Age of InfectionModes of Transmission Risk of Developing chronic HBV Infection BirthPerinatal90% 0-5 yearsHorizontal: person to person; interfamilial via open cuts and scratches Unsafe injections 25 – 30 % > 5 yearsHorizontal: person to person; interfamilial via open cuts and scratches Unsafe injections Sexual Transmission Injection-drug use 5 – 7% Routes of Transmission of HBV and Risk of Chronic Infection by Age
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Prevalence
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HBV vaccine efficacy
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Acute Hepatitis B Virus Infection with Recovery - Typical Serologic Course
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Progression to Chronic Hepatitis B Virus Infection - Typical Serologic Course
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Natural Course of Hepatitis B
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Stages of chronic hepatitis B: Summary HbeAgHbeAbHBV- DNA ALTHistology 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
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Stages of chronic hepatitis B: Summary HbeAgHbeAbHBV- DNA ALTHistology Immune tolerant chronic HBV +- (>10 5 ) 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
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Stages of chronic hepatitis B: Summary HbeAgHbeAbHBV- DNA ALTHistology Immune tolerant chronic HBV +- (>10 5 ) nl Chronic hepatitis B 1) HbeAg pos HBV+- (>10 5 ) 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
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Stages of chronic hepatitis B: Summary HbeAgHbeAbHBV- DNA ALTHistology Immune tolerant chronic HBV +- (>10 5 ) nl Chronic hepatitis B 1) HbeAg pos HBV+- (>10 5 ) Chronic hepatitis 2) HbeAg neg HBV-+ (>10 4 ) Chronic hepatitis Inactive HbSAg carrier state Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87
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Stages of chronic hepatitis B: Summary HbeAgHbeAbHBV- DNA ALTHistology Immune tolerant chronic HBV +- (>10 5 ) nl Chronic hepatitis B 1) HbeAg pos HBV+- (>10 5 ) Chronic hepatitis 2) HbeAg neg HBV-+ (>10 4 ) Chronic hepatitis Inactive HbSAg carrier state -+ (<10 4 ) nlVarious degree of fibrosis Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87
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Replication cycle of Hepatitis B
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HBV Disease Progression Chronic infection Acute infection Cirrhosis Liver failure (decompensation) Liver cancer (HCC) Liver transplantation Death 90% of children < 5% of adults 1 30% 1 5 – 10% 1,3 23% in 5 yrs 2 Chronic HBV is the 5 th leading cause of liver transplantation In the US 4 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
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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
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Treatment endpoints in chronic HBV Treatment endpoints Undetectable serum HBV DNA cccDNA clearance Decreased HAI and fibrosis Normal ALT HBsAg clearance HBeAg loss or seroconversion
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Cumulative Probability of LAM and ADV Resistance
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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.
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(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 Which of the following post-exposure options is most appropriate for this health care worker?
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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: AST24 U/L ALT 28 U/L HBV DNAundetectable HBsAgpositive
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Current labs: CBC normal Coagsnormal Alk Phos117 U/L AST900 U/L ALT 1050 U/L Total bili7.8 mg/dl HBV DNA undetectable HBsAgpositive HBeAgnegative HbeAb positive Physical examination today discloses jaundice. The liver is mildly tender; liver span is 15 cm.
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(A)Hepatitis D virus infection (B)Hepatitis E virus infection (C)Acute Ebstein-Barr virus hepatitis (D)Granulomatous hepatitis (E)Alcoholic hepatitis Which of the following is most likely the cause of this patient’s current clinical presentation?
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Case 6 A 25 y/o female IDU comes to the ER because of a 10- day 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: CBCWNLHBsAgnegative INR1.1Hep A Ab IgMnegative Alk Phos120 U/LHep C Ab negative AST1250 U/LHep B cor Ab IgMnegative ALT2120 U/L Total bili3.5 mg/dl
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(A)Hep A Ab IgG (B)Hep B cor Ab IgG (C)HCV RNA (D)HBsAb (E)Antimitochondrial antibody titer Which of the following tests is the most likely to establish the diagnosis?
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Diagnostic approach to hepatitis C virus infection
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Hepatitis C Elisa positivenegative
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Diagnostic approach to hepatitis C virus infection Hepatitis C Elisa positive Confirm chronic infection: Hep C PCR (qual/quant) positivenegative
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Diagnostic approach to hepatitis C virus infection Hepatitis C Elisa positive 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 negative
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Diagnostic approach to hepatitis C virus infection Hepatitis C Elisa positive 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 negative No HCV unless pt severely immunocompromised or high index of suspicion for acute Hep C
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Who should be tested? CDC Recommendations Test: –h/o IVDU –Received clotting factors before 1987, blood/organs before 1992 –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 Do not test: –Healthcare workers –Pregnant women –Household (non- sexual) contacts of HCV-positive persons –General population
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Serologic Pattern of Acute HCV Infection with Progression of Chronic infection
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Natural Course of Hepatitis C
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Treatment of chronic Hepatitis C Evolution of HCV therapy Mc Hutchinson et al., Lindsay et al. Zeuzem et al. Manns et al. Fried et al. 20041990s
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Response Patterns 2-log decline Limit of detection SVR
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Time to response and SVR Genotype 1 Week 12 35% Week 24 15% P Ferrenci et al. J Hepatology 2005;43:453-471
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Treatment of HCV Impact of STAT-C Drugs 2-log decline Limit of detection SVR
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Telaprevir – PROVE 1 Study Design PEGIFN+R+Telaprevir PEGIFN+Ribavirin 012 48 Weeks JM McHutchinson et al. EASL 2008 24 PEGIFN+R All patients GT 1 Treatment naive
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Telaprevir – PROVE 1 Phase 2 Final Results JM McHutchinson et al. EASL 2008
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Boceprevir – SPRINT 1 Study Design PEGASYS + Ribavirin 0 48 Weeks P Kwo et al. EASL 2008 244 PEG-INTRON + RBV PEG-INTRON + RBV + B PEG-INTRON + RBV PEG-INTRON + RBV + B
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Boceprevir – SPRINT 1 Lead In Phase Results P Kwo et al. EASL 2008
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