Viral%20Hepatitis

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Viral Hepatitis

• Susanne Burger, M.D.
• Jacobi Medical Center
• North Central Bronx Hospital

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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 yes yes yes rarely
Comments Vaccine available Vaccine available Occurs only as co-infection with HBV or as superinfection of chronic HBV Vaccine under develop ment
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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
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
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Which of the following laboratory tests is most
likely to establish the diagnosis?
(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
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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 lt6 years lt10 6-14
  yrs 40-50 gt14 yrs 70-80
• Rare complications Fulminant hepatitis
  Cholestatic hepatitis Relapsing
  hepatitis
• Chronic sequilae None
• Treatment symptomatic

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Geographic Distribution OfHepatitis 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/dl HAV IgM neg
• WBC 15,000/µl HBV SAg neg
• PLT 450K HBV DNA neg
• INR 4.7 HCV Ab neg
• Bili (total) 12.0 mg/dL ANA neg
• Bili (direct) 9.0 mg/dl Anti smooth neg
• AST 3000 U/L Antimitochondrial Ab neg
• ALT 2870 U/L Alcohol neg
• Alk phos 400 U/L Herpes simplex virus (PCR)
• Alb 2.3 g/dl neg
• Ammonia 120 µg/dL

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What is the most likely cause of this patients
fulminant hepatic failure?
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What is the most likely cause of this patients
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 2004,35123
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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 ALT 1550
U/L WBC 11,000/µL Total Bili 6.5
mg/dL INR 1.1 Alk Phos 90 U/L AST 850 U/L
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Which of the following laboratory studies is most
likely to establish the correct diagnosis?

1. IgM antibody to hepatitis B core antigen (HBV cor
   Ab IgM)
2. IgG antibody to cytomegalovirus (CMV Ab IgG)
3. Antibody to hepatitis B surface antigen (HBV S
   Ab)
4. Antibody to hepatitis B e antigen (HBV e Ab)
5. IgG antibody to hepatitis A virus (HAV IgG Ab)

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Hepatitis B

• 5 of the worlds 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

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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
gt 5 years Horizontal person to person interfamilial via open cuts and scratches Unsafe injections Sexual Transmission Injection-drug use 5 7
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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
HbeAg HbeAb HBV-DNA ALT Histology
Immune tolerant chronic HBV
Chronic hepatitis B 1) HbeAg pos HBV
2) HbeAg neg HBV
Inactive HbSAg carrier state
Adapted from Lok AS, Hepatology. 2001341225
Keeffe EB, Clin Gastroenterol Hepatol. 2004 287
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Stages of chronic hepatitis B Summary
HbeAg HbeAb HBV-DNA ALT Histology
Immune tolerant chronic HBV - ?? (gt105) nl nl
Chronic hepatitis B 1) HbeAg pos HBV
2) HbeAg neg HBV
Inactive HbSAg carrier state
Adapted from Lok AS, Hepatology. 2001341225
Keeffe EB, Clin Gastroenterol Hepatol. 2004 287
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Stages of chronic hepatitis B Summary
HbeAg HbeAb HBV-DNA ALT Histology
Immune tolerant chronic HBV - ?? (gt105) nl nl
Chronic hepatitis B 1) HbeAg pos HBV - ?? (gt105) ? Chronic hepatitis
2) HbeAg neg HBV
Inactive HbSAg carrier state
Adapted from Lok AS, Hepatology. 2001341225
Keeffe EB, Clin Gastroenterol Hepatol. 2004 287
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Stages of chronic hepatitis B Summary
HbeAg HbeAb HBV-DNA ALT Histology
Immune tolerant chronic HBV - ?? (gt105) nl nl
Chronic hepatitis B 1) HbeAg pos HBV - ?? (gt105) ? Chronic hepatitis
2) HbeAg neg HBV - ?? (gt104) ? Chronic hepatitis
Inactive HbSAg carrier state
Adapted from Lok AS, Hepatology. 2001341225
Keeffe EB, Clin Gastroenterol Hepatol. 2004 287
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Stages of chronic hepatitis B Summary
HbeAg HbeAb HBV-DNA ALT Histology
Immune tolerant chronic HBV - ?? (gt105) nl nl
Chronic hepatitis B 1) HbeAg pos HBV - ?? (gt105) ? Chronic hepatitis
2) HbeAg neg HBV - ?? (gt104) ? Chronic hepatitis
Inactive HbSAg carrier state - ? (lt104) nl Various degree of fibrosis
Adapted from Lok AS, Hepatology. 2001341225
Keeffe EB, Clin Gastroenterol Hepatol. 2004 287
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Replication cycle of Hepatitis B
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HBV Disease Progression
Liver cancer (HCC)
5 101,3
Death
Chronic infection
Cirrhosis
Liver transplantation
301
Acute infection
90 of children lt 5 of adults1
23 in 5 yrs2
Chronic HBV is the 5th leading cause of liver
transplantation In the US4
Liver failure (decompensation)

• Torres J, Gastroenterology. 200011883
• Fattovich G, Hepatology. 19952177
• Moyer LA, Am J prev med. 19941045
• Perillo R, Hepatology. 200133424

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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
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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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Which of the following post-exposure options is
mostappropriate for this health care worker?

• Administer hepatitis B immune globuline
  immediately and restart his immunization sequence
• Check his antibody response to the hepatitis B
  vaccination if antibodies are inadequate,
  administer hepatitis B immune globulin and
  restart his immunization sequence.
• 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

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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 AST 24 U/L ALT 28 U/L HBV
DNA undetectable HBsAg positive
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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 undetectable HBsAg positi
ve HBeAg negative HbeAb positive
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Which of the following is most likely the cause
of this patients current clinical presentation?

• Hepatitis D virus infection
• Hepatitis E virus infection
• Acute Ebstein-Barr virus hepatitis
• Granulomatous hepatitis
• Alcoholic hepatitis

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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 CBC WNL HBsAg nega
tive 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
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Which of the following tests is the most likely
to establish the diagnosis?

• Hep A Ab IgG
• Hep B cor Ab IgG
• HCV RNA
• HBsAb
• Antimitochondrial antibody titer

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Diagnostic approach to hepatitis C virus infection
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Diagnostic approach to hepatitis C virus infection
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Diagnostic approach to hepatitis C virus infection
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Diagnostic approach to hepatitis C virus infection
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Diagnostic approach to hepatitis C virus infection
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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 CEvolution of HCV
therapy
2004
1990s
Mc Hutchinson et al., Lindsay et al. Zeuzem et
al. Manns et al. Fried et al.
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Response Patterns
2-log decline
Limit of detection
SVR
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Time to response and SVRGenotype 1
Week 12 35
Week 24 15
P Ferrenci et al. J Hepatology 200543453-471
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Treatment of HCVImpact of STAT-C Drugs
2-log decline
Limit of detection
SVR
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Telaprevir PROVE 1Study Design
PEGIFNRTelaprevir
All patients GT 1 Treatment naive
PEGIFNRTelaprevir
PEGIFNR
PEGIFNRTelaprevir
PEGIFNR
PEGIFNRibavirin
0
12
48
24
Weeks
JM McHutchinson et al. EASL 2008
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Telaprevir PROVE 1Phase 2 Final Results
JM McHutchinson et al. EASL 2008
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Boceprevir SPRINT 1Study 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
48
24
4
Weeks
P Kwo et al. EASL 2008
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Boceprevir SPRINT 1Lead In Phase Results
P Kwo et al. EASL 2008