1. Dr. B. K. Iyer

2. The Hepatitis Viruses
Virus Chronic Disease (%)
A 0
B 5-10
C > 85
D * 45
E 0
F **
G **
*Infects only hepatitis B patients.
**Data not yet available.
Alter MJ, et al.Gastroenterol Clin North Am.1994;23:437-455.
Alter MJ. Semin Liver Dis. 1995;15:5-14.

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. 1991;40:1-17.
Alter MJ, et al. Gastroenterol Clin North Am. 1994;23:437-455.

4. Annual Hepatitis C
Infections in the United States
HCV Acute Infections
180,000
Asymptomatic Symptomatic
112,500 37,500
Chronic Liver Disease
93,000
Cirrhosis
30,700
Deaths
9,000
MMWR. 1991;40:1-17.
Alter MJ, et al. Gastroenterol Clin North Am. 1994;23:437-455.

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. 1991;40:1-17.
Alter MJ, et al. Gastroenterol Clin North Am. 1994;23:437-455.

6. Etiologic Agents of Chronic
Viral Hepatitis
HBV/HDV HBV
5% 15%
Unknown
35%
HCV
45%
Koff RS, et al. Viral Hepatitis. 2nd ed. 1994.

7. Chronic Hepatitis C
Importance of Detection
Chronic hepatitis C is a progressive disease
Treatment is available

8. Chronic Hepatitis C
Progression of the Disease
10-25 years
Acute Hepatitis C (150,000/yr)
>85%
Chronic Hepatitis C (>127,500/yr)
20% - 50%
Cirrhosis (>25,000/yr)
up to 20% up to 20%
Hepatic Failure Hepatocellular
(up to 5,000/yr) Carcinoma
Alter MJ, et al. Gastroenterol Clin North Am . 1994;23:437-455.
(up to 5,000/yr)
Davis GL, et al. Gastroenterol Clin North Am. 1994;23:603-613.
Koretz RL, et al. Ann Intern Med. 1993;119:110-115.
Takahashi M. et al. Am J Gastroenterol. 1993;88:240-243.
National Instiitute of Health Consensus Development Statement; March, 1997.

9. Screening for Viral Hepatitis
Patients depend on their
Primary Care Physician to
detect chronic viral hepatitis
even in the absence of symptoms.

10. The Hepatitis Epidemic
in Perspective

11. 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

12. Chronic Hepatitis B

13. 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!

14. Screening for Viral Hepatitis in the
Primary Care Setting
Serum ALT alone is not sufficient for screening with risk
factors for hepatitis
>70% 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
de Franchis R, et al. Ann intern Med. 1993;118:191-194.
Esteban JI, et al. Ann Intern Med. 1991;115:443-449.

15. Screening for Chronic Viral Hepatitis
Anti-HCV
HBsAg
Who should be screened?
Risk factors for hepatitis
Abnormal liver tests
Herrera JL. South Med J. 1994;87:677-684.
JL.

16. 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
Gross JB, et al. Mayo Clin Proc. 1995;70:296-297.
Alter MJ. Semin Li.ver Dis . 1995;15:5-14.
de Medina M, et al. Semin Liver Dis. 1995;15:33-40.

17. 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. 1992;16:300-305.

18. 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
de Medina M, et al. Semin Liver Dis. 1995;15:33-40.
Zanella A, e al. Hepatology. 1995;21:913-917.
Chemello L, et al. Hepatology. 1993;17:179-182.

19. 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. 1994;19:1337-1341.

20. 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 >350,000 viruses/cc blood to be positive
Quantitative test
Useful in following response to treatment
de Medina M, et al. Semin Liver Dis. 1995;15:33-40.
Urdea MS. Bio/Technology. 1994;12:926-928.

21. Diagnosis of Hepatitis C
Anti-HCV (+)
and
RIBA (+)
Serum ALT levels are usually
elevated, but may be normal

22. 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

23. 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

24. 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

25. 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. 1986;146:1011-1015.
Zakim D, et al, eds. Hepatology: A Textbook of Liver Disease. 2nd ed. 1990:667-689.

26. 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

27. Treatment of Chronic Hepatitis C
Patient Selection
Anti-HCV and RIBA (+)
and
Abnormal Liver Biopsy
ALT levels are of secondary
importance.

28. Chronic Viral Hepatitis
Treatment
INTRON -A (Interferon alfa-2b, recombinant) for
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

29. Chronic Viral Hepatitis
Treatment
 Interferon therapy forms the backbone

30. What are they?

31.  In 1957
 Isaacs and Lindenmann did an experiment using
chicken cell cultures and found a substance that
interfered with viral replication
 was therefore named interferon
 Nagano and Kojima also independently discovered
this soluble antiviral protein

32.  Interferons are naturally occurring proteins and
glycoproteins made by cells in response to an
appropriate stimulus
 Interferons play an important role in the first
line of defense against viral infections
 Interferons are part of the non-specific immune
system substances that have antiviral properties
in adjacent, noninfected cells.

33.  Secreted by eukaryotic cells in response to viral
infections, tumors, and other biological inducers
 Structurally, they are part of the helical cytokine
family which are characterized by an amino acid
chain that is 145-166 amino acids long.
 Produce clinical benefits for disease states such
as hepatitis, various cancers, multiple sclerosis,
and many other diseases.

34.  Interferons are released by macrophages,
lymphocytes, and tissue cells infected with a virus.
1. When a tissue cell is infected by a virus, it releases
interferon.
2. Interferon will diffuse to the surrounding cells.
3. When it binds to receptors on the surface of those adjacent
cells, they begin the production of a protein that prevents
the synthesis of viral proteins.
4. This prevents the spread of the virus throughout the
body.

37. 3 TYPES OF INTERFERONS:
1. alpha,
2. beta and
3. gamma.
 Viral infection is the stimulus
for alpha and beta expression
and is used to mobilize our 1st
line of defense against invading
organisms
 Alpha interferons are produced
by leukocytes
 Beta interferons are produced by
fibroblasts
 gamma (immune interferon) are
produced by certain activated T
cells & NK cells

38.  Interferons are broken down into recombinant versions of a specific interferon
subtype and purified blends of natural human interferon. & many of these are in
clinical use and are given intramuscularly or subcutaneously
 Recombinant forms of alpha interferon include:
• Alpha-2a drug name Roferon
• Alpha-2b drug name Intron A
• Alpha-n1 drug name Wellferon
• Alpha-n3 drug name AlferonN
• Alpha-con1 drug name Infergen
 Recombinant forms of beta interferon include:
• Beta-1a drug name Avonex
• Beta-1b drug name Betaseron
 Recombinant forms of gamma interferon include:
• Gamma-1b drug name Acimmune

39.  Non-glycosylated Protein chain that is 165
amino acids long
 Produced using recombinant DNA technology
 Short half life, short terminal elimination of half
life, a large volume of distribution, and a larger
reduction in renal clearance.
 These problems were resolved by pegylating
alpha-2a resulting in peginterferon alpha-2a that
is named Pegasys.

40. Pegasys is recombinant interferon alpha-2a
that is covalently conjugated with bis-
monomethoxy polyethylene glycol (PEG)
Background:
• First developed by Davis, Abuchowski and colleagues in the 1970s
• In early 1990s PEG attached to alpha-2a, but it lacked the required profile of
improving pharmacokinetics
• Pegylation of interferon alpha-2b was achieved with the addition of a linear
PEG, designed to degrade to allow the full potency of the interferon, while
achieving a longer half-life.
• Increasing the size with PEG, the absorption and ½ life are prolonged and the
clearance of the interferon is decreased.
• Goal of pegylation is to decrease clearance, retention of biological activity, get
a stable linkage and enhance water solubility.

41. INTRON -A (Interferon alfa-2b,
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
Johnson HM, et al. Sci Am. May 1994:68-75.

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; Hepatology;1996; 24:778-789

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. 1991;21:387-392.
Pagliarlo L, et al. Hepatology. 1994;19:820-828.
Lau JYN, et al. Lancet. 1993;341:1501-1504.
Okada SI, et al. Hepatology. 1992;16:619-624.
Causse X, et al. Gastroenterology. 1991;101:497-502.

44. Treatment of Chronic Hepatitis C
Response According to Histology
Initial Sustained
Histology
Response Response
Mild CAH 93% 35%
Severe CAH or
33%
cirrhosis
Lin R, et al. Aust N Z J Med. 1991;21:387-392.

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
Injection is 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. 1994;23:581-601.
Alter MJ, et al. Gastroenterol Clin North Am. 1994;21:437-455.
McMahon BJ, et al. Arch Intern Med. 1990;150:1051-1054.

47. Relative Contraindications to
Interferon Therapy
Leukopenia (PMN <750/mm )
Thrombocytopenia (<75,000/mm )
Severe psychiatric disorder
Decompensated liver disease
Terminal comorbid condition
Unreliable patient
History of autoimmune disease
Immunosuppressed transplant recipients

48. 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

49. 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

50. 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. 1994;23:603-613.

51. Interferon Side-Effect Profile
Side effects requiring discontinuation of therapy: <3%
Side effects or cytopenias requiring dose reduction: <2%
Flu-like syndrome is the most common side effect
Treatable
Usually diminishes after the 2nd or 3rd week of
treatment

52.  monotherapy not very effective
 cumbersome dosing (TIW)
 multiple side effects

53. Interferon 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 Interferons 
Flu-like symptoms
Gastrointestinal symptoms
Alopecia
Irritability, depression
* Occur in >10% of patients.
 3 MIU TIW

55. Adverse Experiences:
Modification/Discontinuation of
Interferons
Adverse Event Moderate Severe
Interferes with daily
Fatigue Requires bed rest
routine
Daily, with Vomiting more than
Nausea
occasional vomiting twice daily
Granulocytopenia <750/mm <500/mm
Thrombocytopenia <50,000/mm
Recommendation Reduce dose
Causse X, et al. Gastroenterology. 1991;101:497-502.
Davis GL, et al. N Engl J Med. 1989;321:1501-1506.
Marcellin P, et al. Hepatology. 1991;13:393-397.

56. Take-Home Messages
 About 85% of people who are infected by the
hepatitis C virus (HCV) go on to develop chronic
hepatitis C - "persistent, detectable serum HCV
RNA for a period > than 6 months".
 Chronic HCV infection has a variable course but
usually includes many symptom-free years before
complications such as cirrhosis, liver failure, and
hepatocellular carcinoma develop.
 The specific HCV genotype is an important predictor
of clinical outcome with Genotype 1 being associated
with the poorest response to antiviral treatment.

57. Take-Home Messages
 The recommended regimen for patients who meet
the criteria for antiviral treatment is dual therapy
with "pegylated" interferon plus ribavirin (pegylated
refers to the addition of polyethylene glycol to delay
renal clearance).
 A sign that patients have responded to therapy is the
elimination of the viral RNA from the serum - this is known
as a viral response.
 A sustained viral response (SVR) is defined as the "absence
of detectable HCV RNA from the serum in the six months
after the end of therapy".

58.  Many times interferons and peginterferons are used in
combination with Ribavirin
 It is a purine nucleoside analogue with a modified base
and a D-ribose sugar moiety
 1st made in 1970 by Drs. Joseph Witkowski and Roland
Robins
 It inhibits the replication of a variety of RNA and DNA
viruses and is serves as an immunomodulator to enhance
type 1 cytokine production. This increases the end of
treatment response and reduces post-treatment relapse.
 Mechanism is not well known, but there are 4 proposed
mechanisms

59. 60% 56%
50%
44%
40%
29% monotherapy
30%
IFN+RBV
20% Peg+RBV
10%
0%
Pega2a IFN a2b+RBV Pega2aRBV
P=<0.001

60.  By attaching a protective barrier called
polyethylene glycol (PEG) to interferon,
pegylated interferon can survive in the body
longer than the un-pegylated form, thus
reducing dosing frequency.
 Pegylation was developed to overcome
disadvantages of standard interferon.

61.  Shields IFN from enzymatic degradation thus
lowers systemic clearance
 Achieve higher/sustained serum [interferon]
 Allows less frequent dosing - While regular
interferon is injected 3 times a week, pegylated
interferon is generally taken once a week.

62.  There are 2 types of pegylated interferons –
 Peg-interferon alfa-2a, &
 Peg-interferon alfa-2b.
 The major difference between the two is how
they are dosed:
 2a – The dose of pegylated interferon alfa-2a (Pegasys)
is the same for all patients, regardless of weight or
size.
 2b – The dosing of pegylated interferon alfa-2b
(PegIntron) is based on an individual’s weight.

63.  Peginterferon alfa-2b
 linear molecule
 weight 12 kDa
 Peginterferon alfa-2a
 larger, branched molecule
 weight 40 kDa
 While logic might lead one to assume that a dosage
customized for each individual would deliver safer
and more effective results, the data does not
completely support this view.

64. Peg alfa-2b Peg alfa-2a
Volume of 20 L 8L
distribution
Absorption half-life 4.6 50
(h)
Mean elimination 40 80
half-life (h)

65.  Comparing Pegylated Interferons for Hepatitis C
by Laura Dean, MD., National Center of
Biotechnology Information (NCBI) created on
October 1, 2007.
 Data are limited, but indirect analysis suggests
that there is no significant difference between the
efficacy of peginterferon alfa-2a (Pegasys®) plus
ribavirin and alfa2b (PEG-intron®) plus ribavirin
in eliminating the hepatitis virus RNA from
patients' serum

66.  In the August 2006 Journal of Hepatology, a small
Argentine study compared the pharmacokinetics,
pharmacodynamics, and antiviral activity of
Pegasys and PegIntron in participants with chronic
Hepatitis C genotype1.
 The researchers found that patients receiving PegIntron
had greater decreases in HCV viral load after 8 weeks of
therapy, despite lower levels of interferon in the blood of
these participants.
 Interestingly, this trial was sponsored by Schering-Plough,
the manufacturer of PegIntron.

67.  At the 38th annual Digestive Disease Week in
May 2007, Roche announced results of a small
study demonstrating that all patients who
discontinued treatment with PegIntron and
ribavirin due to adverse events within the first
12 weeks were able to complete 12 weeks of
treatment with Pegasys and ribavirin.
 The researchers concluded that Pegasys may be an
option for those who are unable to tolerate the side
effects of PegIntron.

68.  3 studies presented at the 43rd European
Association for the Study of Liver Diseases
(EASL) held in Milan, Italy in April of 2008
showed that Pegasys had a better cure rate for
Hepatitis C than PegIntron.
 The results of two Italian and one German trial
demonstrated that when the dosage of ribavirin was
kept at a constant, the cure rate for Hepatitis C was
greater in those treated with Pegasys than Pegintron.

69.  Also presented at the 43rd EASL were the results
of the IDEAL (Individualized Dosing Efficacy vs.
flat dosing to assess optimal pegylated
interferon therapy) trial sponsored by Schering-
Plough.
 Over 3,000 participants with Hepatitis C
genotype 1 were recruited.
 While relapse after the end of treatment was lower for
pts. receiving PegIntron, the end of treatment response
was higher for pts. taking Pegasys.

70.  In total, the IDEAL results demonstrated a
similar sustained virologic response, safety and
tolerability between the two pegylated
interferons.
 This study is being criticized by experts because those
receiving Pegasys received a different starting dose of
ribavirin than those on PegIntron.
 In addition, ribavirin dose reduction protocol for side
effects was not uniformly administered between these
two treatment arms

71.  An adjusted indirect analysis of trials comparing
dual therapy with Pegasys or PegIntron versus
dual therapy with non-pegylated interferon was
then conducted.
 After analyzing 16 trials for sustained virological
response and withdrawal due to side effect rates,
no statistically significant differences between
dual therapy with pegylated interferon alfa-2a and
dual therapy with pegylated interferon alfa-2b
were found.

72.  A recent systematic review by the Cochrane
Collaboration of randomized clinical trials
comparing the 2 pegylated interferons, which
included a meta-analysis of SVR rates in 8 trials
with a total of 4293 participants, found that
 Pegasys was slightly but significantly more
effective than PegIntron (relative risk 1.10; P =
0.004), with similar results for all subgroups;
adverse event profiles were similar.

73.  No studies directly compared the effects of different
doses or durations of the two pegylated interferons.
 The optimal dose of peginterferon alfa-2b, when
used as part of dual therapy with ribavirin, is 1.5
mcg/kg/week (the FDA-approved dose).
 Studies comparing different doses of peginterferon
alfa-2a have not been published. Almost all trials
evaluated the FDA-approved dose of 180 mcg/week.
 In patients with HCV genotype 1 infection, 48 weeks of dual therapy appears to be more
effective than shorter courses.
 In patients with HCV genotype 2 or 3 infection, shorter courses may be sufficient, eg. 12
week-course of therapy appears to be as effective as 24 weeks.