Transcript Hepatitis Paul Martin 2003

Viral Hepatitis
Paul Martin M.D.
Medical Director, Liver Transplant Cedars-Sinai
Professor of Medicine, UCLA
Viral Hepatitis
• 5 major hepatitis viruses A-E
• “Hepatitis” indicates biochemical hepatic
dysfunction, not necessarily due to a virus
• Hepatitis can also occur as part of
multisystem viral disorder
• 95 % of viral hepatitis due to the 5 major hepatitis
• Other viruses ( EBV, CMV, HSV, etc.,) cause
hepatitis as part of systemic illness
• “Hepatitis” like picture can also result from other
etiologies e.g. drugs, autoimmune process
• Older terms such as “infectious hepatitis”
(fecal-oral spread) and “serum hepatitis” are
becoming obsolete as diagnostic testing
readily identifies specific virus
Acute Hepatitis
• Malaise, nausea, abdominal discomfort, jaundice
typical but not invariable
• Acute hepatitis can occur with any of the 5 major
viruses
• Recovery usual in acute hepatitis
• Fulminant course with liver failure a concern
Acute Viral Hepatitis
Source: CDC
Chronic Hepatitis
•
•
•
•
Implied by persistence of hepatitis > 6 mos
Occurs with hepatitis B, C and D
Hepatitis A and E do not become chronic
Spectrum of findings from mild biochemical
dysfunction to advanced cirrhosis
Hepatocellular Carcinoma Secondary to Childhood-acquired HBV
Infection
Diagnosis of viral hepatitis
• Based on serological workup
• Liver biopsy does not distinguish one type
from another, mainly used in chronic
hepatitis to assess prognosis
• Biochemical tests, ALT and AST, reflect
hepatic necrosis
Assess severity of necroinflammation
Confirm clinical
diagnosis
Role of
Liver Biopsy
Evaluate possible
concomitant disease
processes
Assess
fibrosis
Assess
therapeutic
intervention
Hepatitis A Virus Transmission
• Close personal contact
(e.g., household contact, sex contact, child day
care centers)
• Contaminated food, water
(e.g., infected food handlers, raw shellfish)
• Blood exposure (rare)
(e.g., injecting drug use, transfusion)
Hepatitis A Virus Transmission
• Close personal contact
(e.g., household contact, sex contact, child day
care centers)
• Contaminated food, water
(e.g., infected food handlers, raw shellfish)
• Blood exposure (rare)
(e.g., injecting drug use, transfusion)
Average Hepatitis A Rates
by State 1987-1997
Rate >20/100,000
Rate 10-20/100,000
Rate <10/100,000
Adapted from Advisory Committee on Immunization Practices MMWR 1999:48(RR12);1-37.
Hepatitis A Virus Infection
Typical Serologic Course
Symptoms
Total antiHAV
Titer
ALT
Fecal
HAV
0
1
IgM anti-HAV
2
3
4
Months after
5
6
1
2
2
4
Hepatitis E - Clinical Features
• Incubation period:
• Case-fatality rate:
Average 40 days
Range 15-60 days
Overall, 1%-3%
Pregnant,15%25%
• Illness severity:
Increased with age
• Chronic sequelae:
None identified
Hepatitis E Epidemiologic Features
• Most outbreaks associated with
fecally contaminated drinking water
• Minimal person-to-person transmission
• U.S. cases usually have history of
travel to HEV-endemic areas
Global Distribution of Chronic HBV
Infection
HBsAg Prevalence (%)
• 350 million chronic carriers worldwide
• Ninth leading cause of death
• Nearly 75% of HBV chronic carriers are Asian
8:
High
2-7: Intermediate
<2:
Low
Transmission of Hepatitis B Infection
Transfusion and
transplant recipients
Individuals with
multiple
sexual partners
Healthcare
workers
Newborns of long-term
carriers
Intravenous
drug users
Prisoners and other
institutionalised people
Cases per 100,000 Population
Estimated Incidence of Acute Hepatitis B
United States, 1978-1995
80
70
Vaccine
licensed
HBsAg screening
Infant
of pregnant women immunization
recommended
recommended
60
OSHA rule
enacted
50
Adolescent
immunization
recommended
40
30
20
Decline among
homosexual men
& HCWs†
10
Decline among
injecting
drug users
*
0
78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95
*
Provisional date
†Health Care Workers
http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_b/slide_15.htm. Accessed 11-02-02.
Risk of Developing Chronic
Hepatitis B by Age at Infection
100
80
%
60
40
20
0
Infant
1-5 years
>5 years
Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titer
HBsAg
0
4
8
anti-HBs
IgM anti-HBc
12 16 20 24 28 32 36
Weeks after Exposure
52
100
Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
Acute
(6 months)
Chronic
(Years)
HBeAg
anti-HBe
HBsAg
Total antiHBc
Titer
IgM anti-HBc
0 4 8 12 16 20 24 28 32 36
Weeks after Exposure
52
Years
Hepatitis D - Clinical
Features
• Coinfection
–severe acute disease
–low risk of chronic infection
• Superinfection
–usually develop chronic HDV infection
–high risk of severe chronic liver
disease
Hepatitis D Virus
Modes of Transmission
• Percutanous
exposures
–injecting drug use
• Permucosal
exposures
–sex contact
Hepatitis D (Delta)
• Incidence declining worldwide due to
vaccination and clean needle programs
• Only found in HBV infected patients,
consider when liver disease unusually
severe
Epidemiology of HCV
– In United States:
• 3.9 million people have been infected,
nearly 3 million are chronically infected
– Incidence
• Most common blood-borne infection
• Worldwide,170 million persons have been
HCV-infected
HCV Prevalence by Selected Groups
in the United States
Hemophilia
Injection-drug users
Hemodialysis
STD patients
General population adults
Surgeons, other HCWs
Pregnant women
Military personnel
0
10
20
30
40
50
60
70
Anti-HCV Positive
Centers for Disease Control and Prevention. MMWR. 1998;47(RR-18):1-39.
80
90
Natural History of HCV Infection
Exposure
(Acute phase)
85% (85)
15% (15)
Resolved
Chronic
20% (17)
HIV and alcohol
80% (68)
Stable
Cirrhosis
75% (13)
Slowly
Progressive
25% (4)
HCC,
Transplant,
Death
Alter, MJ. Epidemiology of Hepatitis C in the West. Semin Liver Dis. 1995; 15: 5-14.
Management of Hepatitis C. NIH Consensus Statement. 1997; March 24-26: 15(3).
Future Disease Burden
Related to HCV: 2008
Need for Liver
Transplantation
528%
Decompensation
279%
Liver-related
Deaths
223%
HCC
68%
Cirrhosis
61%
0%
100%
200%
300%
400%
500%
Estimated Increase by the Year 2008
Davis GL. Hepatology. 1998;28(4 pt 2):390a.
600%
Viral Hepatitis
• Acute hepatitis can be caused by A-E
viruses
• Presentation non-specific
• Chronic hepatitis and cirrhosis caused by
B,C and D
• Specific diagnosis is by serology
Number of Patients
Outcome of HAV Superinfection in
Patients With Chronic Viral Hepatitis
12
10
10
10
8
7
6
6/7
died
4
2
0
0
Hepatitis B
Hepatitis C
Underlying Disease
Uncomplicated Acute liver failure
Vento S et al. N Engl J Med. 1998;338:286.
HAV Vaccination in CLD
Seroconversion Rate
100%
80%
Month
Month
Month
Month
60%
40%
20%
0%
Controls
Chronic HBV Chronic HCV
Keeffe EB, et al. Hepatology 1998;27:881-886.
Misc CLD
1
2
6
7
HAV:Summary
• Higher Mortality in older patients and those
with preexisting liver disease
• Vaccine increasingly recommended for
patients with liver disease
Hepatitis B—Reported Cases per
100,000 Population, 1998
>4.0
2.4-3.9
1.5-2.3
NYC
DC
PR
0.0-1.4
NA
NA
NA
MMWR. 1998; 47:No.53:44.
VI
GUAM
AM SAMOA
CNMI
Childhood Acquired HBV
HBeAg/anti-HBe+
HBeAg+
Anti-HBe+
HBV-DNA
ALT
0
Cirrhosis
HCC
CPH
CAH
Immune tolerance
to HBV
Immune clearance of
HBV
10
20
30
Years
40
Residual Integrated
HBV
50
60
70
Lok 1990
Hepatitis B Mortality
• About 1/3 of chronic HBV infections in the
United States start in perinatal and early
childhood
• Except flu and pneumococcal infections, HBV
kills more people/year than any other vaccinepreventable disease (VPD) (>5,000 HBV
deaths/year)
• HBV causes hepatocellular carcinoma that kills
about 1,000 Americans annually
Estimated HBV Infections among US Born
Children (aged <10 years) of HBsAg-Negative
Mothers, 1990
Race/Ethnicity
Births/
year
# of Annual
Infections
3,656,618
Annual
Incidence/
100,000
23.7
White/Black/
Hispanic
Asian/
Pacific Islander
120,298
605
7280
8677
Elimination of Hepatitis B Virus
Transmission United States
Strategy
•
•
•
•
Prevent perinatal HBV transmission
Routine vaccination of all infants
Vaccination of children in high-risk groups
Vaccination of adolescents
– all unvaccinated children at 11-12 years of
age
– “high-risk” adolescents at all ages
HBV: who to treat
• Patients with chronic HBV
• Hepatic Inflammation: ALT > 2 upper limit of
normal
• Active HBV replication: HBV DNA +/- HBeAG
• Symptoms not a factor
Asia-Pacific Guidelines for
Management of Hepatitis B
APASL/JGH – JGH 2000; 15:825–841
Indications for treatment
– Those with normal ALT should not be treated
• Patients with ALT >2 x ULN should be considered for treatment
• Liver biopsy is recommended prior to antiviral therapy (especially
if ALT 1–2 x ULN)
Asia-Pacific Guidelines
APASL/JGH – JGH 2000; 15:825–841
Patients with ALT >5 x ULN should be treated with
lamivudine
• Patients with ALT 2–5 x ULN can be treated with
lamivudine or interferon: inform patients about
adverse effects, treatment duration, possible
emergence of drug-resistant HBV
• No firm recommendation on ALT 1–2 x ULN: consider
severity, HBeAg; monitor if don’t treat
Implications of HBeAg
Seroconversion

Usually (>80%) permanent suppression of HBV replication
(HBV DNA not detectable in serum)

Loss of HBsAg possible (10–30% with IFN)

Normalisation ALT; reduced necroinflammatory change


Functional improvement; abolishes risk of liver failure
or transplantation
Effect on HCC risk less clearcut; ~50% reduction
HBeAg Seroconversion Over 4 Years
Treatment in Patients with Elevated ALT
Seroconversion = HBeAg-ve and anti-HBe+ve
ALT >1 X ULN (n=41)
80
73
ALT >2 X ULN (n=26)
70
59
Patients
60
(%)
49
50
38
40
30
65
42
37
27
20
10
0
1
2
3
Duration of therapy (years)
4
HBV:Summary
• Most commonly diagnosed in patients with
early acquisition
• HBsAg to diagnose infection, HBeAg and
HBV DNA to assess replication
• IgM anti-HBc is absent in chronic infection
HBV:Summary
• Therapy indicated for chronically infected
patients with elevated ALT
• Lamivudine limited by viral resistance,
adevofir has recently received FDA
approval
Hepatitis C:
Transmission Factors
• Recipients of clotting factors made before 1987 (85%
transmission rate)
• Injection drug use/intranasal drug use (80% transmission rate)
• Long term hemodialysis patients (10% - 20% transmission
rate)
• Persons with multiple sex partners (5% transmission rate)
• Recipients of blood transfusions prior to July 1992 ( 5%
transmission rate)
Carithers RL. Am J Med. 1999;107:90S-94S.
Alter MJ, Kruszon-Moran D, Nainan O, et al. The prevalence of hepatitis C virus
in the United States, 1988-1994. New Engl Jour of Med.1999; 341:556-562.
Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C from mothers
to infants. New Engl Jour of Med. 1994: 330:744-750.
HCV Infection:
Utility of Diagnostic Tests
Method
Screen Confirmation
ALT/AST
x
Enzyme
immunoassay
x
Assess
response
to therapy
Predict treatment
response and
length of therapy
x
Recombinant
immunoblot assay
x
HCV RNA
qualitative assay
x
x
HCV RNA
quantitative assay
x
x
Genotype
Centers for Disease Control and Prevention. MMWR. 1998;47:11.
x
x
HCV Genotypes
• Genotypes are viral sequences
• Utilized for estimating potential for response to
treatment; not used to determine eligibility for
treatment
• Genotype 1 & 4: least responsive to therapy
• Genotype 2 & 3: more responsive to therapy
Factors Influencing
HCV Progression
•
•
•
•
•
•
•
Heavy alcohol intake
Male gender
Note: HCV progression has NOT
Obesity
been demonstrated to be influenced
Coinfection with HIV
by viral load, serum ALT, or mode of
Coinfection with HBV
transmission.
Iron in the liver, as detected via liver biopsy
>40 years of age at time of infection, particularly if
contracted via blood transfusion
Thomas DL, Astemborski J, Rai RM. et al The national history of hepatitis C Virus Infection:
Host, viral, and environmental factors. American Journal of Medicine. 2000; 284(4): 450-456.
Diagnosis of HCV:
Role of Liver Biopsy
Assess severity of necroinflammation
Confirm clinical
diagnosis
Role of
Liver Biopsy
Evaluate possible
concomitant disease
processes
Brunt EM. Hepatology. 2000;31:241-246.
Assess
fibrosis
Assess
therapeutic
intervention
Future Disease Burden
Related to HCV: 2008
Need for Liver
Transplantation
Decompensation
528%
279%
Liver-related Deaths
223%
HCC
68%
Cirrhosis
61%
0%
100%
200%
300%
400%
500%
Estimated Increase by the Year 2008
Davis GL. Hepatology. 1998;28(4 pt 2):390a.
600%
HCV Clinical Manifestations
• Present only 20 – 40% of time
• Frequently no symptoms until development of advanced
liver disease
• Frequently nonspecific, mild, and intermittent
• Most common symptoms:
• Malaise, weakness, anorexia (25 – 35% of cases)
• RUQ abdominal discomfort and pruritus
• Less common symptoms:
• Jaundice
• Intermittent nausea
• Vomiting
Management of Hepatitis C. NIH Consensus Statement, March 24-26, 1997;16(3): 1-41.
HIV-HCV Coinfection in the USA
Coinfected
Mono-infected
X100,000
40
30
20
10
0
Hepatitis C
HIV
1999 USPHS/IDSA Guidelines
for the Prevention of Opportunistic
Infections
HCV disease specific recommendations
– HIV-infected persons should be screened for HCV by
EIA
– Patients should be advised on alcohol use
– Screen for HAV IgG. If negative, vaccinate
– Patients should be evaluated for liver disease and
possible need for treatment
– Monitor liver enzymes after initiation of HAART
MMWR Vol. 48 / No. RR10 (http://www.cdc.gov)
HCV and Healthcare Workers:
Transmission Rate after Needle Stick
Risk of Transmission by Single Needle Stick to
Susceptible Healthcare Workers
Percent
40
30
~30%
20
10
3%
0.3%
HCV
HIV
0
HBV
Alter MJ. N Engl J Med. 1999;341:556 (NHANES III, 1988–1994).
HCV:Antiviral therapy
• Eradicate virus-negative PCR
• Arrest Progression of liver disease
• Improve Quality of Life
Treatment Responses
Biochemical
Virologic
End of treatment
(ETR)
Normal ALT HCV RNA response
negative
Sustained virologic
response (SVR)
Normal ALT
(6 mos posttreatment)
Lindsay KL. Hepatology. 1997;26(suppl 1):72S.
HCV RNA
negative
Clinical Significance of
Sustained Virologic Response
• >90% of those with 6 months post treatment SVR
maintain response during 1-6 years of follow-up
• Liver histology improves or stabilizes
Lindsay KL. Hepatology. 1997;26(suppl 1):75S.
Optimizing Interferon  Kinetics
Pegylated IFN 
Serum
IFN 
Levels
(U/mL)
HigherDose IFN 
Time
1 week
Pegylated IFNs
• PEG IFN alfa-2b
– Molecular weight 12 kDa
– Linear
– 1.0 ug/kg QW subcutaneous
(SC) injection with
monotherapy
– 1.5 ug/kg SC when given in
combination with ribavirin
PEG IFN alfa-2a
 Molecular weight 40 kDa,
linear structure

 180 ug QW subcutaneous
injection
Who Should Be Treated?
• Persistently elevated ALT levels
• Detectable HCV RNA levels
• Liver biopsy (not required) indicating portal or bridging fibrosis or at
least moderate degrees of inflammation and necrosis
• No active autoimmune disease
• No hepatic encephalopathy, variceal bleeding, ascites, or other clinical
decompensation
• Consider
– Co-morbid conditions
– Symptomatic cryoglobulinemia
– Continuing substance abuse
Who Should Not Be Treated?
• Pregnant or nursing mothers
• Current substance abusers
– CDC recommends patient be alcohol/drug free for >6
months prior to undergoing treatment
Caution in patients with:
Decompensated cirrhosis
Prior history of psychiatric disorders
Persistent ALT elevations, with less severe histological changes
Patients aged < 18 or > 60 years
Centers for Disease Control and Prevention, MMWR. 1998; 47:24
IFN alfa-2b/RBV:
Summary of Predictive Factors for a SVR
Genotype 2 or 3
Genotype 1
Minimal Fibrosis
Advanced Fibrosis
Low HCV RNA
High HCV RNA
Age  40
Age > 40
Female
Male
Weight  75 kg
Weight > 75 kg
Increasing usefulness
in predicting
sustained response
20
40
6
80
% Sustained Virologic Response
Adapted with permission from McHutchison JG et al. Semin Liver Dis. 1999;19(suppl 1):63.
PEG-IFN alfa-2b (12 kDa)/RBV vs.
IFN alfa-2b/RBV
IFN/RBV 1000 -1200 mg/d (n=505)
PEG (12 kDa) 0.5 qw /RBV 1000-1200 mg/d (n=514)
PEG (12 kDa) 1.5 qw /RBV 800 mg/d (n=511)
100%
82%
34%‡
42%‡§
33%
20%
54%†‡
40%
47%‡
60%
80%
79%
80%
47%
Sustained
viral
response*
*End-of-treatment
reported
†P=0.01 vs IFN/RBV
‡Not approved dosing for
PEG-IFN alfa-2b
§P=0.02 vs IFN/RBV
0%
Overall
Genotype 1
not
Genotype 2/3
Manns MP et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b
plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial.
The Lancet (358): 958-965.
SVR Genotype 1
60
51%
SVR (%)
50
40
30
41%
40%
n=118
n=250
29%
20
10
0
n=101
n=271
PEG-IFN -2a (40 KD) 180 µg
RBV 800 RBV 1000/1200
RBV 800 RBV 1000/1200
24 weeks
48 weeks
Hadziyannis SJ et al., EASL. 2002.
SVR Genotype Non-1
90
80
78%
78%
n=106
n=162
73%
77%
n=111
n=165
SVR (%)
70
60
50
40
30
20
10
0
PEG-IFN -2a (40 KD) 180 µg
RBV 800 RBV 1000/1200
RBV 800 RBV 1000/1200
24 weeks
48 weeks
Hadziyannis SJ et al., EASL. 2002.
HCV Genotype 1
• Commonest genotype
• Less responsive to therapy than genotype
2,3
• 80% of genotype 1 are high viral load
• 56% of all US patients are genotype1, high
viral load
SVR Genotype 1
Low Viral Load
70
61%
60
SVR (%)
50
40
51%
53%
n=71
n=60
41%
30
20
10
0
n=51
n=85
PEG-IFN -2a (40 KD) 180 µg
RBV 800 RBV 1000/1200
RBV 800 RBV 1000/1200
24 weeks
48 weeks
Hadziyannis SJ et al., EASL. 2002.
SVR (%)
SVR Genotype 1
High Viral Load
46%
50
45
40
35
30
25
20
15
10
5
0
35%
26%
16%
n=50
n=47
n=190
n=186
PEG-IFN -2a (40 KD) 180 µg
RBV 800 RBV 1000/1200
RBV 800 RBV 1000/1200
24 weeks
48 weeks
Hadziyannis SJ et al., EASL. 2002.
Viral Hepatitis:initial tests
• IgM anti-HAV
• HBsAg, IgM anti-HBc
• Anti-HCV
Viral Hepatis:management
• Vaccinate
• Educate (alcohol etc.,)
• Evaluate for therapy
Hepatitis A - Clinical
Features
• Incubation period:
• Jaundice by
age group:
• Complications:
Average 30 days
Range 15-50 days
<6 yrs,
<10%
6-14 yrs, 40%-50%
>14 yrs, 70%-80%
Fulminant hepatitis
Cholestatic
hepatitis
• Chronic sequelae:
Relapsing hepatitis
None