Viral Hepatitis: State of the Art

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Viral Hepatitis State of the Art

• Rudy Rai, MD
• Gastroenterology Hepatology

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Human Hepatitis Viruses

• Enterically Transmitted
• HAV
• HEV

• Percutaneous/ permucosally Transmitted
• HBV
• HCV
• HDV

• Non-Hepatotrophic agents
• SEN
• TTV
• HGV
• ?

DNA viruses RNAViruses
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Other agents in Acute Hepatitis(non A-E)

• CMV
• EBV
• VZV
• HSV
• Parvovirus B19
• Reovirus
• Mumps

• Yellow fever
• Coxsackie B
• Syncytial Giant cell
• Adenovirus
• Rubella
• Hemorrhagic fevers

4
Hepatitis A Virus

• Single strand RNA virus
• Family Picornaviridae
• Genus Hepatovirus
• Phases
• Replicative
• Necroinflammatory
• Outcome
• Worse in older patients
• Mild in children
• Superinfection in Hep C (40 mortality)

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Hepatitis A Age Dependent Jaundice
Anicteric
Icteric
gt14
lt6
6-14
Age in Years
6
Acute Hepatitis A Age specific Case Fatality
Rates
2.7
Case Fatality Rate ()
1.1
0.4
0.1
0-14
15-39
40-49
gt50
Age in Years
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Hepatitis A

• HAV vaccine protects against all human HAV
  strains
• No reservoir of viremic/intestinal carriers
• Infection occurs from acutely infected to
  susceptibles
• Oral-fecal transmission
• Water
• Food- seafood, mollusks
• Intimate
• Institutional
• Household

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Hepatitis A Sequence
IgG
IgM
Fecal HAV
Serum HAV
Elevated ALT
! 30
! 90
! 60
Days after Exposure
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Hepatitis A vaccine Recommendations ACIP (1999)

• Community attack rate gt20/100,000
• consider routine childhood vaccination
• High HAV Endemic areas
• Travelers, military, Native Americans

• Outbreaks
• Children/young adults
• Other
• Chronic liver disease
• IDUs
• Men who have sex with men
• Patients with clotting factor disorders

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Parvovirus B19

• Erythema infectiosum
• Acute Hepatitis
• Fulminant liver failure
• Transient dysfunction
• Aplastic anemia

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Herpes Simplex

• Immunocompromised or pregnant
• Diagnosis IgM Ab
• Mucocutaneous lesions/ DIC common
• Liver Biopsy confluent coagulative necrosis,
  eosinophilic ground-glass inclusions w/clear halo
• Rx Acyclovir, OLTx
• 20-40 survival

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Hepatitis E

• Developing world
• Largely waterborne
• Incubation 6-7 weeks
• Virus shed 2-3 weeks before symptoms
• Transient ALT elevation
• Pregnant- Acute Liver Failure

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Treatment

• Hepatitis A and E
• No chronic form
• May need supportive care
• Passive (Immunoglobin) and/or active (Hep A
  vaccine) immunization for contacts in infectious
  period
• Recommend preventative vaccine for Hep A
  w/underlying liver disease
• Caution for pregnant women traveling to Hep E
  endemic areas

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Serodiagnosis of Acute Viral Hepatitis

• Hepatitis A
• HAV IgM
• Hepatitis B
• HBSAg() HBCore Ab IgM ()
• Hepatitis C
• HCV RNA (PCR/TMA) HCV Ab (50-60)
• Hepatitis D
• HDV Ab IgM HepBSAg ()
• Hepatitis E
• HEV Ab IgM

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Model of Human Hepatitis C Virus
Lipid Envelope
Capsid Protein
Nucleic Acid
Envelope Glycoprotein E2
Envelope Glycoprotein E1
Reprinted with permission. Henderson, LE.
Available at www.hepcprimer.com.
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Projected Public Health Burden for HCV
60000
50000
HCV-related mortality, maximal
40000
HCV-related mortality, minimal
Annual Incidence
HIV-related mortality, maximal
30000
HIV-related mortality, minimal
20000
10000
0
2010
1990
2030
2050
2070
Year

• The HCV disease burden is projected to peak with
  an estimated 14,000-19,000 deaths/year

Deuffic-Burban et al. AASLD October 24-28, 2003
Boston, MA. Abstract 552.
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Hepatitis C A Global Health Problem
170-200 Million (M) Carriers Worldwide
Far East Asia 60 M
Eastern Europe 10 M
Western Europe 5 M
United States 3-4 M
Southeast Asia 30-35 M
Africa 30-40 M
Americas 12-15 M
Australia 0.2 M
World Health Organization. Weekly epidemiological
record. 199974421-428.
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Prevalence of HCV Infection United States 1990
7
MexicanAmerican
6
African American
5
3.5
4
3.2
Anti-HCV ()
3
Caucasian
2
1.1
1
0






Age (yr)
Alter et al. N Engl J Med. 1999341556-562.
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Liver Histology in Patients With Elevated and
Normal Serum ALT
Cirrhosis 6
Bridging 6
Cirrhosis22
No Fibrosis(KSlt5)19
No Fibrosis(KSlt5)40
Portal26
Inflammation(KSgt5)19
Bridging16
Inflammation(KSgt5)23
Portal24
Elevated ALT
Normal ALT
KS, Knodell score.
Shiffman et al. J Infect Dis. 20001821595-1601.
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Hepatitis C Scenarios

• HCV Ab
• -

HCV RIBA -/ -
HCV PCR - -
Interpretation True Ab, cleared infxn True infxn,
Immune deficiency False Ab, infants Chronic
Infxn
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Type 1 IFNs Exhibit Multiple Activities
0
Stark GR, et al. Annu Rev Biochem.
199867227-264. Theofilopoulos AN, et al. Annu
Rev Immunol. 200523307-335. Brierley M, et al.
J Interferon Cytokine Res. 200222835-845.
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Biphasic Decline of HCV Load During IFN a-2b (10
mIU QD) Therapy
7
Lag period 412 hr (ISG expression)
6
Block in virus production direct action of ISGs
Clearance of infected cells immune cell
modulation
Viral Load (log10 HCV RNA eq/mL)
5
Many weeks- months selection for escape mutants
4
3
14
0
1
5
10
Days of Therapy
Neumann AU, et al. Science. 1998282103-107
Dixit NM, et al. Nature. 2004432922-924.
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Factors That Speed Progression of Liver
DiseaseNot Within Patients Control

• Disease acquisition at gt40 years
• Male gender
• HIV coinfection
• HBV coinfection
• Fatty liver disease

Hezode et al. EASL April 14-18, 2004 Berlin,
Germany. Abstract 68. Ivanova et al. EASL April
14-18, 2004 Berlin, Germany. Abstract 484. NIH
Consensus Development Conference Statement.
Bethesda, Md National Institutes of Health June
10-12, 2002. Poynard et al. Lancet.
1997349825-832.
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Factors That Do NOT Speed Progression of Liver
Disease

• ALT
• Viral load
• Mode of transmission
• Genotype

NIH Consensus Development Conference Statement.
Bethesda, Md National Institutes of Health June
10-12, 2002. Poynard et al. Lancet.
1997349825-832.
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Role of Liver Biopsy
Utility of Liver Biopsy

• Confirm clinical diagnosis

Assess severity of necroinflammation
Evaluate possible concomitant disease processes
Assess therapeutic intervention
Assessfibrosis
Brunt et al. Hepatology. 200031241-246.
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Hepatic Histopathologic Evaluation
GradeNecro- inflammation

• Measure of severity and ongoing disease activity
• May fluctuate with disease activity or
  therapeutic intervention

• Indicates long-term disease progression
• Relatively constant in relation to disease
  activity or therapeutic intervention

StageFibrosis
Brunt et al. Hepatology. 200031241-246.
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Progression of Fibrosis on Biopsy
Stage 4 Fibrous expansion of portal areas with
marked bridging (portal to portal and portal to
central)
No Fibrosis
Stage 1 Fibrous expansion of some portal areas
Stage 5,6 Cirrhosis, probable or defined
Stage 3 Fibrous expansion of most portal areas
with occasional portal to portal bridging
Cirrhotic liver Gross anatomy of cadaver
Courtesy of Gregory Everson, MD.
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Hepatic Fibrosis Scoring Systems

Knodell

Ishak

METAVIR

Absent

0

0

0

Portal fibrosis (some)

1

1

1

Portal fibrosis (most)

1

2

1

Bridging fibrosis (few)

3

3

2

Bridging fibrosis (many)

3

4

3

Incomplete cirrhosis

4

5

4

Cirrhosis

4

6

4



Brunt. Hepatology. 200031241-246.
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0
Rates of Fibrosis Progression
RAPID Men gt40 years of age Alcohol gt50 g/d
4
MEDIUM
3
Fibrosis stage
2
SLOW Women lt40 years of age Alcohol lt50 g/d
1
0
10
20
30
Duration of infection (y)
Marcellin P, et al. Hepatology. 200236S47-S56.
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Serum Fibrosis MarkersIs This a Viable Option to
Liver Biopsy?

• Minimally-invasive algorithmic-based serum marker
  assays are being evaluated
• HCV FIBROSURE (LabCorp)
• FibroSpectSM (Prometheus Laboratories)
• Accurately reflect mild fibrosis
• No utility demonstrated with intermediate
  fibrosis
• Role in patient management remains controversial

Poynard et al. 54th AASLD. October 24 - 28, 2003.
Boston, Mass. Abstract 3. Ratziu et al. 39th
EASL. April 14-18, 2004. Berlin, Germany.
Abstract 597.
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Treatment for Hepatitis C
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Goals of Antiviral Therapy
Target the virus
Viral clearance
Delay decompensation
Target the disease
Prevent HCC
Prevent HCV recurrence after liver transplantation
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Identifying Nonresponders and Relapsers HCV
Patterns of Response to Therapy
0
Nonresponder
Relapser
Nonresponder
HCV RNA
SustainedResponder
HCV RNA negative
12
24
48
72
Time (wks)
Adapted from Davis GL, et al. Hepatology.
200338645-652. Fried MW, et al. N Engl J Med.
2002347975-982.
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FDA Approved, Marketed HCV Drugs
Ribavirin is not approved for monotherapy, but
as part of combination with interferon alfa
Interferon relapsers and nonresponders
Pawlotsky JM, et al. Hepatology. 200439554-567.
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SVR Rates in HCV Populations
0
60
52-53
42-53
50
43-44
41-44
27-40
40
17-9
SVR ()
30
19-26
20
10
0
AA genotype 1
HCV
Genotype 1
HVL(all genotypes)
Advancedfibrosis andcirrhosis (stages 3 and 4)
HIV/HCV
HIV/HCVgenotype 1
ITT Populations
SVRsustained virologic response HCVhepatitis C
virus HIVhuman immunodeficiency virus
ITTintent-to-treat. Torriani FJ, et al. N Engl J
Med. 2004351438-450. Jeffers LJ, et al.
Hepatology. 2004391702-1708. Carrat F, et al.
JAMA. 20042922839-2848. Muir AJ, et al. N Engl
J Med. 20043502265-2271. Fried MW, et al. N
Engl J Med. 2002347975-982. Manns MP, et al.
Lancet. 2001358958-965.
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Key HCV Treatment Trials
QW, once a week TIW, three times a week wks,
weeks. Fried et al. N Engl J Med.
2002347975-982. Hadziyannis et al. Ann Int
Med. 2004140346-357. Manns et al. Lancet.
2001358958-965.
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HCV RNA Structure
Transcription, Replication
IRES, Translation
Structural
Non-Structural
5' UTR
3' UTR
Structure
Processing
Replication
IRES internal ribosomal entry site UTR
untranslated region C nucleocapsid core E1
envelope protein 1 E2 envelope protein 2
NS non-structural
Hoofnagle JH. Hepatology. 200236(5 suppl
1)S21-S29.
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Potential HCV Therapies
HCV-086 ViroPharma/ Wyeth
Albuferon Human Genome Sciences
VX-950 Vertex
R803 Rigel
HCV/MF59 Chiron
Phase I
JTK 003 AKROS Pharma
Oral IFN alpha Amarillo Biosciences
SCH-6 Schering
HepX-C XTL
NM283 Idenix
ANA245 ANADYS
Ceplene Maxim
Multiferon Viragen
IDN-6556 Idun
Time to Market
ISIS 14803 Isis
VX-497 Vertex
Phase II
Infergen/gamma IFN InterMune
Civacir NABI
E-1 Innogenetics
Omega IFN Biomedicine
IP-501 Indevus
Viramidine Valeant
REBIF Ares-Serono
Amantadine Endo Labs Solvay
Zadaxin SciClone
Phase III
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Side Effects of Interferon

• Flu-like symptoms
• Headache
• Fatigue or asthenia
• Myalgia, arthralgia
• Fever, chills
• Neuropsychiatric disorders
• Depression
• Mood lability

• Alopecia
• Thyroiditis
• Nausea
• Diarrhea
• Injection-site reaction
• Lab alterations
• Neutropenia
• Anemia
• Thrombocytopenia

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Side Effects of Ribavirin

• Hemolytic anemia
• Teratogenicity
• Cough and dyspnea
• Rash and pruritus
• Insomnia
• Anorexia

Rebetron? package insert. Kenilworth, NJ
Schering Corp 2002.
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Predictors of SVR

• Gt 2
• Gt 3 more difficult to treat than Gt 2
• Low baseline viral load
• Early virologic response, Week 12-24
• Modifiable through adherence
• Absence of cirrhosis
• Female gender
• Aged ?40 years
• Low hepatic iron stores
• Short duration of disease (lt5 years)

Manns et al. Lancet. 2001358958-965. McHutchison
et al. Hepatology. 200032223A. Poynard et al.
Hepatology. 200031211-218. Zeuzem et al. N Engl
J Med. 20003421666-1672.
Fried et al. N Engl J Med. 2002347975-982.
Hadziyannis et al. Ann Int Med.
2004140346-357. Mangia et al. EASL April
14-18, 2004 Berlin, Germany. Abstract 93.
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Summary

• Hepatitis C is a complex but treatable disease
• Early identification is key
• Normal ALT does not equal mild or no disease
• Treatment modalities are rapidly evolving

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Hepatitis B
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Chronic Hepatitis B

• Tenth leading cause of death worldwide
• 400 million worldwide
• 1.25 million in the US
• 4 million in Western Europe
• 80 of HBV carriers in Asia
• 4,000 to 5,500 deaths annually in the US
• In 30 of patients with chronic HBV
• Infection, cirrhosis or HCC will develop

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Hepatitis B Historical perspective

• Vaccine recommended for adults and adolescents
  with significant risk factors

• Mass immunizations implemented in infants,
  pregnancy screening, infant post-exposure
  perinatal prophylaxis

Year
2005
1982
1991
1998
2002

• Entecavir approved
• Peginterferon alfa-2a injectable approved

• Adefovir approved

• Lamivudine first oral therapy approved

• a-interferon injection first treatment for
  hepatitis B approved

MMWR. 2004521252-1254. HepB.Org. Available at
www.hepb.org/professionals/approved_hbv_drugs.htm.
Accessed June 16, 2005.
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Questions Asked Before Treating

• Who do I treat?
• HBV DNA ()
• HBeAg () or (-)
• Elevated ALT or AST
• Liver biopsy evidence of chronic hepatitis
• What do I use?
• Nucleoside? Which?
• Interferon?
• Combination therapy ?

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Nucleoside Analogues Pros
Cons Oral administration Long duration of
treat- ment ( gt 1 yr )virustatic Minimal
side effects Drug-resistant
mutants Useful in decompensated Type of
response differs cirrhosis and post-OLT
from IFN (HBsAg loss rare) Much
less expensive Post-withdrawal ALT than
IFN flares ( 20-25)
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Incidence of Lamivudine Resistance in Chronic HBV
Infection
90
Resistance gt HBeAg loss
HIV- Pos
Percent Lamivudine Resistant
53
Years of Lamivudine





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Chronic Hepatitis B Treatment Options

• Interferon/ PEG IFN- FDA approved Jul 2005
• Nucleoside Analogues
• Lamivudine
• Adefovir
• Entecavir - FDA approved in Mar 2005
• Emtricitabine
• Tenofovir
• Telbivudine - Phase III enrollment completed

Off label use









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Questions?

• Thank You for your attention!