Hepatitis for the General Practitioners

1
Hepatitis for the General Practitioners

• This set of educational slides is made
• possible by
• The Hepatitis Information Network
• Schering-Plough of Canada
• (www.HepNet.com)

2
The Hepatitis Viruses
Virus
Chronic Disease ()
A
0
B
5-10
C
gt 85
D
45

E
0
F


G
Infects only hepatitis B patients.
Data not yet available.
Gastroenterol Clin North Am.
Alter MJ, et al.
199423437-455.
Semin Liver Dis.
Alter MJ.
1995155-14.
3
Annual Hepatitis B
Infections in the United States
HBV Acute Infections
300,000
5 to 10 chronicity
Chronic Hepatitis B
15,000 - 30,000
1.0-1.25 million people in the United States
are chronic carriers of HBV
MMWR.
1991401-17.
Gastroenterol Clin North Am.
Alter MJ, et al.
199423437-455.
4
Annual Hepatitis C
Infections in the United States
HCV Acute Infections 180,000
Asymptomatic 112,500
Symptomatic 37,500
Chronic Liver Disease 93,000
Cirrhosis 30,700
Deaths 9,000
MMWR.
1991401-17.
Alter MJ, et al.
Gastroenterol Clin North Am.
199423437-455.
5
The Hepatitis Epidemic
Nationwide prevalence of chronic viral hepatitis
HCV--3.5 million
HBV--1.0 million-1.25 million
Most patients are asymptomatic until irreversible
liver damage occurs
Diagnosis depends on a high index of suspicion
and
proper screening
MMWR.
1991401-17.
Alter MJ, et al.
Gastroenterol Clin North Am.
199423437-455.
6
Risk Factors Associated
With Viral Hepatitis
IVDA 20
Unknown 35
Health Care Providers 3
Homosexual 10
Sexual 15
Transfusions 5
Unknown 27
Sexual 40
45 IVDA
Alter MJ, et al.
Gastroenterol Clin North Am.
199423437-455.
Alter MJ, et al.
19902642231-2235.
JAMA.
Alter MJ, et al.
JAMA .
19902631218-1222.
Donahue JG, et al.
N Engl J Med
. 1992327369-373.
7
Chronic Viral Hepatitis
Identifying Patients at Risk
IV drug users prior or current use
Recipients of blood transfusions prior to 1990
Multiple sexual partners
Male homosexuals
Health care professionals
Dialysis patients
Tattooed persons/body piercing
Needle-stick accident victims
Alter MJ, et al. JAMA.

19902642231-2235.
MMWR.
1991401-25.
8
Etiologic Agents of Chronic
Viral Hepatitis
Koff RS, et al.
Viral Hepatitis.
2nd ed. 1994.
9
Chronic Hepatitis C
Importance of Detection
Chronic hepatitis C is a progressive disease
Treatment is available
10
Long-Term Mortality After
Transfusion-Associated NANB Hepatitis
Retrospective study
568 patients with transfusion-associated NANB
hepatitis
Clinical course of hepatitis patients compared
with two
matched controls
Average follow-up 18 years
The majority of study subjects received
transfusions
while undergoing open-heart surgery
Average age 50 years
Seeff LB, et al.
N Engl J Med.
19923271906-1911.
11
Long-Term Mortality After
Transfusion-Associated NANB Hepatitis
Results
NANB
Controls
Hepatitis
Mortality from
3.3
1.5
liver disease
Mortality from all
51
50
causes
N Engl J Med.
Seeff LB, et al.
19923271906-1911.
12
Long-Term Mortality After
Transfusion-Associated
NANB Hepatitis
Analyzing the Results
Retrospective study
Subjects were relatively old at the time of acute
hepatitis
Average age 50 years
Study subjects had severe comorbid conditions
Mortality rate of 51 over 18 years
Most patients may have died of their underlying
illness
before complications of NANB hepatitis became
evident
13
Natural History of Chronic
Hepatitis C
Prospective Studies
65 patients followed for an average of 10 years
after
developing posttransfusion hepatitis
69 developed chronic hepatitis
20 developed cirrhosis
12 developed end-stage liver disease
20 patients underwent serial liver biopsies
5 progressed from CPH to CAH over 2 years
Progression could not be predicted by liver
enzymes
or patients' symptoms
Dr. Bisceglie AM, et al.
Hepatology.
199114969-974.
14
Natural Course of Chronic
Hepatitis C
Progression of the Disease
57 patients with chronic hepatitis C underwent
serial
liver biopsies
50 with CPH progressed to CAH or cirrhosis over
11 years
70 with CAH progressed to cirrhosis over 7 years
Takahashi M. et al.
Am J Gastroenterol.
199388240-243.
15
Chronic Hepatitis C
Progression of the Disease
100 patients with chronic hepatitis C followed
for an
average of 11 years
42 developed cirrhosis
19 developed hepatocellular carcinoma
Average number of years between acute hepatitis C
and histologic diagnosis
CPH---12 years
CAH---18 years
Cirrhosis---24 years
Takahashi M. et al.
Am J Gastroenterol.
199388240-243.
16
Natural Course of Hepatitis C
Lessons From Prospective Studies
Chronic hepatitis C is a progressive disease
CPH histology is not necessarily associated with
benign long-term prognosis
Levels of liver enzymes and patients' symptoms do
not correlate with progression of the disease
17
Chronic Hepatitis C
Progression of the Disease
10-25 years
Acute Hepatitis C (150,000/yr)
gt85
Chronic Hepatitis C (gt127,500/yr)
20 - 50
Cirrhosis (gt25,000/yr)
up to 20
up to 20
Hepatic Failure
Hepatocellular
(up to 5,000/yr)
Carcinoma
(up to 5,000/yr)
Alter MJ, et al.
Gastroenterol Clin North Am
. 199423437-455.
Gastroenterol Clin North Am.
Davis GL, et al.
199423603-613.
Koretz RL, et al.
Ann Intern Med.
1993119110-115.
Takahashi M. et al.
Am J Gastroenterol.
199388240-243.
National Instiitute of Health Consensus
Development Statement March, 1997.
18
Screening for Viral Hepatitis
Patients depend on their
Primary Care Physician to
detect chronic viral hepatitis
even in the absence of symptoms.
19
The Hepatitis Epidemic
in Perspective
Patients acquire the infection at a younger age
The acute infection is usually asymptomatic
Chronic infection is asymptomatic until
irreversible
liver damage has occurred
Liver test abnormalities may be minimal or even
absent despite significant liver inflammation on
biopsy
20
Chronic Hepatitis C
Clinical Presentation
Asymptomatic
Minimal to moderate elevation of ALT (SGPT)
or AST (SGOT)
Positive hepatitis C antibody test with normal
liver
enzymes
Any degree of liver enzyme abnormality
should be evaluated!
21
Screening for Viral Hepatitis in the
Primary Care Setting
Serum ALT alone is not sufficient for screening
with risk
factors for hepatitis
gt70 of patients who were HBsAg-positive and 4
of
patients who were HBeAg-positive had normal or
near
normal ALT (SGPT)
Chronic active hepatitis can be found in 35 of
anti-HCV-positive blood donors with normal ALT
(SGPT)
ALT (SGPT) may be intermittently normal in
a significant number of patients with chronic
viral hepatitis
Ann intern Med.
de Franchis R, et al.
1993118191-194.
Ann Intern Med.
Esteban JI, et al.
1991115443-449.
22
Screening for Hepatitis by the
Primary Care Provider
Ask your patients about risk factors!
Risk factors present

Obtain liver enzymes and appropriate serologic
tests
No risk factors

Consider obtaining an ALT (SGPT) as part of
routine health care
Many infected patients have no known risk factors!
Alter MJ, et al.
JAMA.
19902642231-2235.
JAMA .
Alter MJ, et al.
19902631218-1222.
23
Screening for Chronic Viral Hepatitis
Anti-HCV
HBsAg
Who should be screened?
Risk factors for hepatitis
Abnormal liver tests
Herrera JL
. South Med J.
199487677-684.
24
Hepatitis C Antibody Test
Anti-HCV
A positive test suggests viremia until proven
otherwise
Sensitivity 94 to 100
May take 4 to 6 weeks to become positive in
patients
with acute hepatitis C
A positive test in a patient with elevated liver
enzymes
and risk factors for hepatitis C is usually
diagnostic
Mayo Clin Proc.
Gross JB, et al.
199570296-297.
Alter MJ.
Semin Li.ver Dis
. 1995155-14.
de Medina M, et al.
Semin Liver Dis.
19951533-40.
25
Hepatitis C Antibody Test
Anti-HCV
False-positive results
Autoimmune hepatitis
Hypergammaglobulinemia
Normal liver enzymes and no risk factors for
hepatitis C
False-negative results
Immunosuppression
organ transplant recipients
Herrera JL.
Postgrad Med
. 199393119-132.
Hsu HH, et al.
Gastroenterology.
19911011724-1727.
26
Recombinant Immunoblot Assay
(RIBA)
Confirmatory assay for hepatitis C
Not mandatory in classical cases
Consider obtaining in anti-HCV () patients and
Suspected autoimmune hepatitis
Hypergammaglobulinemia
Normal liver enzymes levels
Nakatsuji Y, et al.
Hepatology.
199216300-305.
27
Indeterminate RIBA
RIBA assay tests for bands of reactivity to 4 HCV
antigens
2 or more bands reactive positive
0 bands reactive negative
1 band reactive INDETERMINATE
Up to 57 of patients with indeterminate RIBA
results
are infected with the hepatitis C virus
Patients with "indeterminate" RIBA test results
should
undergo HCV RNA testing
Semin Liver Dis.
de Medina M, et al.
19951533-40.
Zanella A, e al.
Hepatology.
199521913-917.
Chemello L, et al.
Hepatology.
199317179-182.
28
Hepatitis C RNA Tests
Measure the presence of the actual virus, not the
antibodies
Helpful in patients with normal liver enzymes and
positive anti-HCV and RIBA
A positive RNA test indicates the presence of
viremia
RNA tests are expensive and require special
handling
Davis GL, et al. Hepatology. 1994191337-1341.
29
Hepatitis C RNA Tests
HCV RNA by PCR
Most sensitive and specific test to detect HCV
viremia
Detects low levels of viremia
Qualitative test
HCV RNA by bDNA (Quantitative HCV RNA)
Less sensitive than PCR
requires gt350,000 viruses/cc blood to be positive
Quantitative test
Useful in following response to treatment
de Medina M, et al.
Semin Liver Dis.
19951533-40.
Urdea MS. Bio/Technology. 199412926-928.
30
Diagnosis of Hepatitis C
Anti-HCV ()
and
RIBA ()
Serum ALT levels are usually
elevated, but may be normal
31
Significance of a Normal ALT in
Patients With Chronic Hepatitis C
16 asymptomatic patients, HCV (), RIBA (),
normal ALT
9/16 were HCV RNA ()
All 16 underwent liver biopsy
Biopsy Results
HCV RNA ()
HCV RNA (-)
Normal
0/9
7/7
Mild hepatitis
6/9
Severe hepatitis
2/9
Cirrhosis
1/9
Alberti A, et al. Lancet. 1992340697-698.
32
Normal ALT in Chronic Hepatitis C
13 asymptomatic blood donors
Anti-HCV (), RIBA (), HCV RNA (), normal ALT
All underwent liver biopsies
Results
10/13 (77) - abnormal liver biopsy
4/13 (30) - mild chronic hepatitis
6/13 (46) - severe chronic hepatitis
Positive hepatitis serologies are frequently
associated with
the existence of liver disease regardless of
transaminase
activity
Serfaty L, et al. Hepatology. 199521725-729.
33
LIVER ENZYMES ARE NOT
LIVER FUNCTION TESTS!
In chronic hepatitis,
there is poor correlation
between the magnitude of the
liver enzyme elevations and the
degree of liver injury
34
Approach to the Patient With
() Anti-HCV and Normal ALT
RIBA
positive or
indeterminate
HCV RNA by PCR
positive
Liver Biopsy
abnormal histology
Consider Treatment
35
Assessing Liver Function
Clinical Tests of Liver Function
Prothrombin time
Serum albumin
Serum bilirubin
These tests are insensitive and nonspecific
Abnormalities occur only after significant,
usually
irreversible, liver damage has occurred
36
Assessing Severity of Disease
Ultrasound
Excellent test to evaluate the biliary tree and
detect focal
lesions in the liver


-
Not a good test to assess liver function



Cannot differentiate a normal liver from chronic
hepatitis,
fibrosis, or early cirrhosis


Most accurate in the advanced stages of liver
disease


Cannot reliably distinguish between fatty liver,
cirrhosis,
and acute hepatitis
Needleman L, et al.
AJR.
19861461011-1015.
Hepatology A Textbook of Liver Disease.
Zakim D, et al, eds.
2nd ed. 1990667-689.
37
Assessing Severity of Disease
Liver Biopsy
Only accurate method for determining severity and
activity of the disease
Histology findings do not always correlate with
symptoms, liver enzyme levels, or ultrasound
findings
Biopsy results may help in the decision to
proceed with
treatment
38
Treatment of Chronic Hepatitis C
Patient Selection
Anti-HCV and RIBA ()
and
Abnormal Liver Biopsy
ALT levels are of secondary
importance.
39
Chronic Viral Hepatitis
Treatment
INTRON A (Interferon alfa-2b, recombinant) for
7
Injection is the only product demonstrated to be
safe and effective for the treatment of chronic
hepatitis B and C in patients with compensated
liver disease
40
7
INTRON A (Interferon alfa-2b,
R
recombinant) for Injection
Mechanism of Action
Suppresses viral replication
Increases the ability of the immune system to
recognize and attack the virus
Decreases inflammation in the liver by
attacking the virus
Sci Am.
Johnson HM, et al.
May 199468-75.
41
Chronic Hepatitis C
ALT Response to Interferon Treatment




of Patients


n55
n55
n23
n23
n17
n17
U.S. Multicenter
France-Causse
France-Marcellin
p.001
p.02
p.005
Return to normal, near normal, or gt50 decrease
Davis GL, et al.
N Engl J Med.
19893211501-1506
Causse X, et al.
Gastroenterology.
1991101497-502.
Hepatology.
Marcellin P, et al.
199113393-397.
Ann Intern Med.
Shindo M, et al.
1991115700-704.
42
Interferon Treatment for
Chronic Hepatitis C
3 million units subcutaneously or intramuscularly
three times per week for 24 weeks ALT response
rate of 45, Sustained ALT of 14
3 million units subcutaneously or intramuscularly
three times per week for 48 weeks
ALT response rate of 45, Sustained ALT of 35
Poynard Meta-Analysis of Interferon Randomized
Trials Hepatology1996 24778-789
43
Treatment of Chronic Hepatitis C
Predicting Response to Interferon
PATIENTS LIKELY TO RESPOND
Mild histologic disease
Low pretreatment viral load
Viral genotype
Short duration of disease
Younger age
Lin R, et al.
Aust N Z J Med.
199121387-392.
Hepatology.
Pagliarlo L, et al.
199419820-828.
Lau JYN, et al.
Lancet.
19933411501-1504.
Hepatology.
Okada SI, et al.
199216619-624.
Causse X, et al.
Gastroenterology.
1991101497-502.
44
Treatment of Chronic Hepatitis C
Response According to Histology
Initial
Sustained
Histology
Response
Response
Mild CAH
93
35
Severe CAH or
33
0
cirrhosis
Lin R, et al.
Aust N Z J Med.
199121387-392.
45
Chronic Viral Hepatitis
Who Should Be Treated?
All patients with compensated chronic hepatitis B
or C should be evaluated for possible treatment
Evaluation should be done even if
ALT is normal or near normal
Patient has no symptoms
Ultrasound and tests of liver function are normal
46
Treatment of Chronic Hepatitis B With
Interferon Alfa-2b
INTRON A (Interferon alfa-2b, recombinant) for
7
Injection is the only product demonstrated to be
safe
and effective for the treatment of chronic
hepatitis B
in patients with compensated liver disease
Careful interpretation of the patient's serologic
profile
is needed for proper patient selection
All HBsAg () patients should be referred for
further
evaluation and consideration for treatment
Perrillo RP, et al. Gastroenterol Clin North Am.
199423581-601.
Alter MJ, et al. Gastroenterol Clin North Am.
199421437-455.
McMahon BJ, et al. Arch Intern Med.
19901501051-1054.
47
Chronic Hepatitis B
Virologic Response to Interferon Treatment


of Patients




n38
n42
n24
n22
n24
n27
U.S. Multicenter
NIH
Argentina - Perez
p.009
p.005
p.n/a
Loss of HBeAg and HBV-DNA by 6 months
posttreatment
Perrillo RP, et al.
N Engl J Med.
1990328295-301.
Perez V, et al.
J Hepatology.
199011S113-S117.
Korenman J, et al.
Ann Intern Med.
1991114629-634.
48
Relative Contraindications to
Interferon Therapy
Leukopenia (PMN lt750/mm
)

Thrombocytopenia (lt75,000/mm
)

Severe psychiatric disorder
Decompensated liver disease
Terminal comorbid condition
Unreliable patient
History of autoimmune disease
Immunosuppressed transplant recipients
49
Chronic Viral Hepatitis
End Points of Therapy
Suppression or reduction of viremia


Cessation or diminution of necro-inflammatory
activity in the liver


Cure


Prevention of cirrhosis


Prevention of hepatocellular carcinoma
50
Chronic Viral Hepatitis
Treatment Decisions
Patient follow-up
Liver enzymes not helpful
Patients are usually asymptomatic
Serial liver biopsies
Risk of progression to cirrhosis and
hepatocellular carcinoma
51
Common Reasons Why
Chronic Viral Hepatitis Is Not Treated
"The ALT elevation is minimal"
ALT levels do not correlate with
necro-inflammatory activity
"The patient is asymptomatic"
Symptoms usually occur when irreversible liver
damage is
present
"The liver biopsy does not look too bad"
These are the patients most likely to respond
"The patient may never develop cirrhosis"
50 will progress to severe chronic hepatitis or
cirrhosis
"Too many side effects"
Side effects requiring discontinuation of therapy
are
infrequent
Davis GL, et al. Gastroenterol Clin North Am.
199423603-613.
52
Interferon Side-Effect Profile
Side effects requiring discontinuation of
therapy lt3
Side effects or cytopenias requiring dose
reduction lt2
Flu-like syndrome is the most common side effect
Treatable
Usually diminishes after the 2nd or 3rd week of
treatment
53
Interferon Alfa-2b Therapy Warnings
Use with caution with patients with debilitating
conditions
Cardiovascular disease
Pulmonary disease
Coagulation disorders
Severe myelosuppression
Diabetes mellitus prone to ketoacidosis
54
Chronic Hepatitis C
Most Common Adverse Experiences
With Interferon Alfa-2b Therapy
2
Flu-like symptoms
Gastrointestinal symptoms
Alopecia
Irritability, depression
Occur in gt10 of patients.
3 MIU TIW
2
55
Chronic Hepatitis B
Interferon Alfa-2b Treatment-Related
Adverse Experiences---Flu-Like Symptoms














56
Adverse Experiences
Modification/Discontinuation of
Interferon Alfa-2b Therapy
Adverse Event
Moderate
Severe
Interferes with daily
Fatigue
Requires bed rest
routine
Daily, with
Vomiting more than
Nausea
occasional vomiting
twice daily
Granulocytopenia
lt750/mm

lt500/mm

Thrombocytopenia
lt50,000/mm
lt30,000/mm


Recommendation
Reduce dose
Discontinue
Gastroenterology.
Causse X, et al.
1991101497-502.
Davis GL, et al.
N Engl J Med.
19893211501-1506.
Marcellin P, et al.
Hepatology.
199113393-397.
57
Chronic Viral Hepatitis
Take-Home Messages
Chronic viral hepatitis is a common disease
Frequently asymptomatic
Patients depend on their primary care physician
to
identify persons at risk and make the diagnosis
in a
timely fashion
All patients with serologic evidence of chronic
viral
hepatitis should be referred for evaluation and
consideration for treatment
58
Sustained Biochemical Response to 6 or 12 Month
IFNa Treatment for Hepatitis C According to HCV
Genotype





9/14
17/28
8/14
6/12
6/20
Papatheodoridis GV, AASLD, Oct. 1995 Chicago
59
Comparison of Cost-Effectiveness with Other
Medical Interventions
,
Dusheiko G.. Exec Summ of a Sem on Hep C.
199410-12.