Transcript Hepatitis A-E (2).ppt

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