The ABCs of Viral Hepatitis

1
The ABCs of Viral Hepatitis

• Scott A. Zela, MSN, APRN, BC
• Liver Associates of Texas, PA
• January 11, 2006

2
Objectives

• Discuss causes of acute and chronic viral
  hepatitis
• Hepatitis A course
• Hepatitis B course including long-term
  complications and treatment options
• Hepatitis C course including long-term
  complications and treatment options

3
Detection of Viral HepatitisLiver Function Tests

• LFTs Do not reflect true functioning of the
  liver
• Alanine aminotransferase (ALT/SGPT)
• Normal range 10 to 32 U/L in men, 9 to 24 U/L in
  women
• Higher specificity than AST
• Aspartate aminotransferase (AST/SGOT)
• Normal range 8 to 20 U/L
• Elevations indicate some degree of hepatocellular
  injury
• Tests do not provide information as to cause of
  injury

Management of Hepatitis C. NIH Consensus
Statement, 2002.
4
Detection of Viral HepatitisLiver Function Tests

• Tests of Liver Function
• Albumin - protein
• Bilirubin - by-product of breakdown of hemoglobin
• Prothrombin Time (PT) - coagulation status

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Diagnosis of Viral Hepatitis in the Primary Care
SettingPatients Who Have Risk Factors

• A single normal ALT level does not rule out
  chronic viral hepatitis
• ALT levels may be intermittently normal in a
  significant number of patients who have chronic
  hepatitis C

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Diagnosis of Chronic Viral HepatitisSerologic
Testing

• Patients should be tested if they
• Have known risk factors for viral hepatitis
• Indicate possible risk factors for hepatitis
• Have elevated liver enzymes

Management of Hepatitis C. NIH Consensus
Statement, 1997.
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Epidemiology of HBV

• Global health problem
• 400M infected
• 30 lifetime risk of liver failure/OLT/death due
  to cirrhosis and/or cancer
• causes 80 of of all liver cancer
• second most important carcinogen behind tobacco
• carrier rates range from 0.1 in Western
  countries to 15 is some Asian African nations
• HBV is 100 times more contagious than HIV

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Worldwide Prevalence of Chronic Hepatitis B
Infection
400 million people worldwide
HBsAg Prevalence ()
?8 High
2-7 Intermediate
lt2 Low

HBsAg hepatitis B surface antigen. Source
World Health Organization/Centers for Disease
Control and Prevention.
13
Prevalence of HBV in the U.S.

• New infections have declined due to routine
  vaccination, more stringent blood screening
  programs and increased awareness of risk factors
  - only 80,000 new infections per year - down 50
  since 1987.
• However, incidence in USA due to immigration from
  endemic countries - 25.8 million foreign born in
  USA.
• Net Effect HBV prevalence is expected to slowly
  increase until about 2015.

HBsAg screening of pregnant women recommended
Vaccine licensed
Infant immunization recommended
Adolescent Immunization recommended
OSHA rule enacted
Decline among injecting drug users
Decline among MSM HCWs
Historical and Forecasted HBV Prevalence
Sources 1NNDSS.
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Hepatitis B Disease Progression
5-10 of chronic HBV-infected individuals1
Liver Cancer (HCC)
30 of chronic HBV-infected individuals1
Liver Transplantation
Acute Infection
Death
Chronic Infection
Cirrhosis

• gt90 of infected children progress to chronic
  disease
• lt5 of infected immunocompetent adults progress
  to chronic disease1

Liver Failure (Decompensation)
Chronic HBV is the 6th leading cause of liver
transplantation in the US 4
23 of patients decompensate within 5 years of
developing cirrhosis 3
1. Torresi J et al. Gastroenterology. 2000. 2.
Fattovich G et al. Hepatology. 1995. 3. Moyer LA
et al. Am J Prev Med. 1994. 4. Perrillo R et al.
Hepatology. 2001.
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Hepatitis B Panel
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Serological Markers1

• Definition/Diagnostic Use
• General marker of infection
• First serologic marker to appear
• Persistence for gt 6 months chronic infection
• Indicates active replication of virus
• Absent in Pre-core mutant HBV infection
• Indicates virus no longer replicating patient can
  still be positive for HBsAg

• Markers
• HBsAg Hepatitis B surface antigen
• HBeAg Hepatitis B e antigen
• Anti-HBe Antibody to hepatitis B e antigen

1 Lok A, Heathcote E, Hoofnagle J,
Gastroenterology 2001.
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HBV and Risk of HCC
12 10 8 6 4 2 0
HBsAg, HBeAg (RR 60.2)
Percent cumulative incidence
HBsAg, HBeAg- (RR 9.6)
HBsAg-, HBeAg-
0 1 2 3 4 5 6 7 8 9 10
Year
Yang HI, et al. N Engl J Med. 2002347168-174.
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The Goals of Therapy for Chronic HBV

• Prevent cirrhosis and its long-term
  complications1
• Normalize ALT level2
• Reduce histologic necroinflammatory activity2
• Sustain loss of HBV DNA and HBeAg2
• Develop antibody to HBeAg (anti-HBe)2
• Prevent transmission to family members and others

1 Lok A, Heathcote E, Hoofnagle J,
Gastroenterology 2001. 2 Gordon S, Post Graduate
Medicine, 2000. 3 Source Hepatitis B, CDC 2001.
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Hepatitis B Therapies

• Acute Hepatitis B
• Support and Follow
• If total bilirubin or INR increases, refer to GI
• Chronic Hepatitis B
• Treatment based on number of factors including
  biopsy and HBV DNA
• Need screening at least every 6 months for HCC
• Agents include
• Interferon
• Nucleosides (Epivir, Entecovir)
• Nucleotides (Adefovir)

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Hepatitis C Virus (HCV)

• Discovered in 1989 as a small RNA blood-borne
  virus with a large reservoir of chronic carriers
  worldwide
• Major cause of posttransfusion hepatitis prior to
  1992
• Major cause of chronic liver disease, cirrhosis,
  and hepatocellular carcinoma worldwide
• Prevalence is 1.8 of the US population
• 1990-2015 estimated 4-fold increase in the
  number of patients diagnosed with HCV in the
  United States

NIH Consensus Development Conference Panel
Statement Management of Hepatitis C, 2002
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Hepatitis C A Global Health Problem
170 Million Carriers Worldwide, 3-4 MM new
cases/year
EAST MEDITERRANEAN 20M
WEST EUROPE 9 M
FAR EAST ASIA 60 M
U.S.A. 4 M
SOUTH EAST ASIA 30 M
AFRICA 32 M
SOUTH AMERICA 10 M
AUSTRALIA 0.2 M
Source WHO 1999
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Acute Hepatitis C Clinical Presentation and
Natural History

• HCV RNA can be detected in blood within 1-3 weeks
  after exposure
• Average time from exposure to seroconversion is
  8-9 weeks
• Average time from exposure to symptoms period 6-7
  weeks
• Liver injury (elevations in ALT) with 4-12 weeks
• Symptoms develop in only of 20 of patients
• Nonspecific 10-20
• Jaundice in only 20-30

CDC. MMWR. 1998 47(No. RR-19)1-39. Hoofnagle
JH Hepatology. 199726 (suppl 1) 15S-20S NIH
Consensus Development Conference Panel Statement
Management of Hepatitis C, 2002
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Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
Symptoms /-
Normal
Adapted from MMWR 1998 47(No. RR19)
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Chronic Hepatitis C

• A leading cause of cirrhosis in the US
• 10,000-20,000 deaths/yr
• This number expected to triple in the next 10 to
  20 years (without therapy)
• Associated with an increased risk of liver cancer
• Most common reason for liver transplantation in
  the United States

CDC. MMWR. 1998 47(No. RR-19)1-39.
NIH Consensus Development Conference Panel
Statement Management of Hepatitis C, 2002
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Risk Factors for Acute Hepatitis C
United States, 1991-1995
Alter MT. Hepatology. 199726 (suppl 1) 62S-65S.
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Other Risk Factors for Hepatitis C
History of military service
Medical
Lifestyle
Occupational
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Natural History of Hepatitis C
Acute Hepatitis C
10-20 years
Chronic Hepatitis 75-85
Cirrhosis 20
Hoofnagle JH Hepatology. 199726 (suppl 1)
15S-20S Di Bisceglie, Hepatology, 2000
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Natural History of Hepatitis C
Annual rate
Hoofnagle JH Hepatology. 199726 (suppl 1)
15S-20S Di Bisceglie, Hepatology, 2000
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Impact of HCV Infection in the US
Approximately 4.0 million persons are chronically
infected with HCV
10-15 years
20 will develop cirrhosis (/- 780,000 patients)
10-15 years
4 will develop HCC (/- 31,000 patients)
Adapted from Di Bisceglie, Hepatology, 2000
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Hepatitis C and Hepatocellular Carcinoma (HCC) in
the US

• Chronic HCV infection substantially increases the
  risk of HCC
• HCV accounts for 60 of HCC cases
• 5- to 7-fold higher risk for developing HCC for
  HCV-positive patients

EASL International Consensus Conference, J.
Hepatology, 1999 Di Bisceglie AM. Semin Liver
Dis. 1995 1564.
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Modeling of Liver Fibrosis in Chronic Hepatitis
C, n1157 Patients
Rapid progressors
Intermediate progressors
Slow progressors
Poynard et al, Hepatology 1999
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Factors which Might Influence the Outcome of
Hepatitis C
Virus - Load - Genotype - Quasispecies
Host - Sex - Age - Race - Genetics -
Immuneresponse
Environment - Alcohol - HBV - HIV
- Drugs - Steatosis - Iron -
NASH
Alberti, J of Hepatology, 1999
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Future HCV Disease Burdenin the United States
Davis et al. Hepatology, 1998
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Predictions for 2010-2019

• 193,000 HCV deaths
• 720,700 million years of advanced liver disease
• 1.83 million years of life lost
• 11 billion in direct medical care costs
• 21.3 and 54 billion societal costs from
  premature disability and mortality

Wong Am J Pub Health 2000
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Diagnostic Approach to Chronic Hepatitis Elevated
ALT Levels
Elevated ALT levels risk factors for hepatitis
Anti-HCV (EIA) testing
Negative
Positive
lt5 chance of hepatitis C
Diagnosis of hepatitis
Cgt95 certain
Refer to specialist for evaluation and treatment
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Hepatitis C Screening and Diagnosis Summary

• Suspect disease on the basis of risk factors, not
  symptoms
• Positive anti-HCV result indicates current
  infection until refuted
• Measurement of HCV RNA may be required to
  establish diagnosis in selected cases

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Rationale for Pegylation of Protein
Pharmaceuticals

• Pegylation binding of ethylene oxide polymers
  to drug molecule
• Decreases clearance
• Prolonged half-life
• Sustained blood levels
• Decreases proteolysis
• Decreases immunogenicity

Youngster S, et al. Curr Pharm Des.
2002899.Harris JM, et al. Clin Pharmacokinet.
200140539.
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Concentration Time Profiles
(PEG-IFN ?-2b) SC once weekly
Glue et al, Clin. Pharmacology Ther. 2000
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REBETOL (Ribavirin, USP) Capsules

• Synthetic nucleoside analogue
• Activity against some RNA viruses
• Ribavirin monotherapy ineffective for the
  treatment of chronic hepatitis C,

Bodenheimer HC Jr., Lindsay KL, Davis GL, et al.
Hepatology. 1997 26473-477. Di Bisceglie AM,
Conjeevaram HS, Fried MW, et al. Ann Intern Med.
1995 123897-903.
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Sustained Virological Response
Produce a response to Tx
Maintain a response to Tx
Sustain a response after completion of Tx
Viral load
Sustained virological response
Adapted from Pawlotsky JM, Hepatology vol. 32,
5, 2000
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Goals of HCV Therapy

• Primary HCV RNA below limits of detection at
  end of treatment
• Secondary
• Inhibition of disease progression
• Reduction of incidence of hepatocellular
  carcinoma
• Reduction in need for liver transplant

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Approach to Treatment of Chronic
Hepatitis C

• The decision to treat should be individualized,
  taking the following factors into consideration
• Patients age
• Histologic severity of the disease
• Comorbid conditions
• Efficacy of currently available treatments

NIH Consensus Development Conference Panel
Statement Management of Hepatitis C 2002.
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PEG-IFN ?-2b ribavirin
IFN ?-2b ribavirin 1000-1200 mg/daily
N505
3 MIU TIW (48 wks)
Screening
PEG-IFN ?-2b ribavirin 1000-1200 mg/daily
N514
0.5 ?g/kg QW (44 wks)
1.5 ?g/kg QW (4 wks)
PEG-IFN ?-2b ribavirin 800 mg/daily
N511
1.5 ?g/kg QW (48 weeks)
Endpoint
48 weeks
24 weeks
Follow-up
Primary Endpoint Loss of serum HCV RNA 24 weeks
posttreatment
Manns M et al., Lancet 2001.
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SVR Overall Patients

• Overall Study population
• Manns Study
• 68 US patients2
• 29 fibrosis/cirrhosis3
• 74 genotype 1,gt2 million copies/mL4
• 50 of total study population is genotype 1, gt2
  million copies/mL4

References 1. Data on file, Schering
Corporation, 2. FDA Advisory Committee Briefing
Document. Food and Drug Administration Web site.
Available at http//www.fda.gov/ohrms/dockets/ac/
01/briefing/3819b1_03_FDA-Clinical20review.htm.
Accessed January 28, 2003. 3. Manns M et al.,
Lancet, 2001, 4. http//www.fda.gov/ohrms/dockets/
ac/cder01.htmAnti-Viral, slides.
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PEG-IFN ?-2a ribavirin
IFN ?-2b ribavirin 1000-1200 mg/daily
N444
3 MIU TIW (48 wks)
Screening
PEG-IFN ?-2a
N224
180 ?g QW (48 wks)
PEG-IFN ?-2a ribavirin 1000-1200 mg/daily
N453
180 ?g QW (48 weeks)
Endpoint
48 weeks
24 weeks
Follow-up
Primary Endpoint Loss of serum HCV RNA 24 weeks
posttreatment by Cobas PCR Amplicor
Fried M et al., NEJM, 2002.
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SVR Overall IFN alfa-2b ribavirin vs. PEG-IFN
alfa-2a ribavirin1

• Overall Study population
• Fried Study
• 61 genotype 1, gt2 million copies/mL2
• 41 US patients1
• 40 of total study population is genotype 1, gt2
  million copies/mL2
• 12 fibrosis/cirrhosis2

Reference 1. FDA Advisory Committee Briefing
Document. Food and Drug Administration Web site.
Available at http//www.fda.gov/ohrms/
dockets/ac/02/briefing/3819B1_02_FDA-Clinical20br
iefing20package20.pdf. Accessed January 28,
2003. 2. Fried et al, NEJM 2002.
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Important Safety Information on
PEG-INTRON/REBETOL Therapy

• Pregnancy
• Psychiatric
• Cardiovascular
• Blood
• Endocrine
• Pulmonary
• Pancreatitis
• Ophthalmologic
• Flu-like symptoms

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Monitoring the Patient

• Acute hypersensitivity reactions
• Thyroid abnormalities
• Autoimmune disorders
• Ophthalmologic disorders (patients should have
  baseline eye exam)
• Pregnancy at baseline, during therapy, and for 6
  months post therapy (therapy should not be
  initiated until a negative pregnancy test has
  been obtained)

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Conclusions

• Hepatitis A usually symptomatic and short-lived
• All patients with chronic viral hepatitis need to
  be referred to GI/Hepatology for evaluation and
  treatment
• Hepatitis B
• Increased risk for HCC
• Disregard term healthy carrier
• Treatment needed if high viral load
• Hepatitis C
• Main cause of HCC in USA
• Most patients are asymptomatic
• All hepatitis C patients are candidates for
  treatment