Hepatitis C Current Disease Management

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Hepatitis CCurrent Disease Management

• HENRY GONZALEZ-RIVERA M.D.
• ASSISTANT PROFESSOR OF MEDICINE
• GASTROENTEROLOGY SECTION
• U.P.R. SCHOOL OF MEDICINE

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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
• 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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Phylogenetic Tree of HCV TypesGreat
Heterogeneity Is Now Appreciated
P Simmonds. Gut 199740291
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Worldwide Distribution of Genotypes
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Serologic Pattern of Acute HCV Infection with
Progression with Recovery
anti-HCV
Symptoms /-
HCV RNA
Titer
ALT
Normal

Months Years
Time after Exposure
Adapted from MMWR 1998 47(No. RR19)
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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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Definitions of Response

• RVR - HCV RNA lt 50 IU/mL at 4 weeks into
  treatment
• EVR - gt 2 log reduction from baseline HCV RNA at
  12 weeks of treatment
• ETR - undetectable HCV RNA at the completion of
  treatment
• SVR - undetectable HCV RNA at 24 weeks after
  completion of treatment
• Relapse - undetectable viremia during and/or at
  the end-of-treatment but virus is detectable
  after treatment is stopped
• Nonresponse - detectable HCV RNA through
  treatment

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Pretreatment Assessments

• Medical History
• Psychiatric History
• Screening for depression and alcohol
• CBC, CMP, TSH
• Pregnancy
• HIV
• Hepatitis Profile
• HCV genotype and Viral Load
• Eye exam and EKG in patients with
• Diabetes
• HBP
• gt 45 years

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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
• HCV RNA-positive status

NIH Consensus Development Conference Panel
Statement Management of Hepatitis C 2002.
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Clinical Trial Results
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SVR Overall Data

• There are no head-to-head data for
• pegylated interferon alfa-2b andpegylated
  interferon alfa-2a. 
• These slides are not intended to be used
  forcomparative purposes. 

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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
• 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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SVR Genotype 1- All Patients

• Overall Study population
• Manns Study
• 68 US patients2
• 29 fibrosis/cirrhosis3
• 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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SVRGenotype Non-1 All Patients

• Overall Study population
• Manns Study
• 68 US patients1
• 29 fibrosis/cirrhosis2
• 50 of total study population is genotype 1, gt2
  million copies/mL3

References 1. 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. 2. Manns M et al.,
Lancet, 2001, 3. http//www.fda.gov/ohrms/dockets/
ac/cder01.htmAnti-Viral, slides.
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Fixed-Based Dosing with interferon ?-2b is
Associated with a Decrease in SVR with Increasing
Patient WeightIFN ?-2b 3 MU TIW 48 weeks
Pooled data from McHutchison, JG. N Engl J Med.
19983391485, Poynard T. Lancet. 19983521426,
Data on file.
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All genotypesSustained virologic response
Controlling for ribavirin dose (mg/kg)
p0.01 plt0.01
Manns et al., Lancet 2001
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Genotype 1Sustained virologic response
Controlling for ribavirin dose (mg/kg)

n348
n226
n122
n343
n15
n328
?
ribavirin dose/weight (mg/kg)
p0.02
Manns et al., Lancet 2001
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Genotype -2/3Sustained virologic response
Controlling for ribavirin dose (mg/kg)
Manns et al., Lancet 2001
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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
• 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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SVR All-Genotype 1 IFN alfa-2b ribavirin vs.
PEG-IFN alfa-2a ribavirin1

• Overall Study population
• Fried Study
• 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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SVR All-Genotype Non-1 IFN alfa-2b ribavirin
vs. PEG-IFN alfa-2a ribavirin1

• Overall Study population
• Fried Study
• 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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Early Virologic ResponseMethods / Definitions

• Early Virologic Response
• Undetectable HCV RNA by RT-PCR
• Log decreases in HCV RNA
• Positive Predictive Value (PPV)
• If EVR is achieved, what is the chance that SVR
  will occur
• Negative Predictive Value (NPV)
• If EVR is not achieved, what is the chance that
  SVR will not occur

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Early Virological ResponseTreatment Outcome
PEG-IFN ?-2b 1.5 µg/kg ribavirin 800 mg
Week 72
Week 24
Start of study
No SVR 19 (n62/329)
EVR 64 (n329/511)
SVR 81 (n267/329)
Total study population (n511)
SVR 4 (n7/182)
No EVR 36 (n182/511)
No SVR 96 (n175/182)
Davis GL et al., Hepatology, Vol. 38, 3,
2003. EVR defined as PCR negative
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Early Virological ResponseTreatment Outcome
Peginterferon alfa2b 1.5 ?g/kg ribavirin ?10.6
mg/kg
Start of study
EVR 76 (n143/188)
Total study population (n188)
Davis G, et al, Hepatology, Vol. 38, 3, 2003
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Liver Biopsy

• May be guided by CT or ultrasound
• Provides information regarding
• Degree of inflammation
• Disease severity
• Tissue damage
• Presence/absence of cirrhosis
• Helps determine
• Degree of disease progression
• Cause of liver disease
• Need for treatment

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Histologic Staging
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PEG - IFN ADVERSE EVENTS

• FLU-LIKE SYNDROME
• MYALGIAS
• FATIGUE
• FEVERS
• CHILLS
• HEADACHE
• NEUROPSYCHIATRIC
• DEPRESSION
• IRRITABILITY
• INSOMNIA

• HEMATOLOGIC
• THROMBOCYTOPENIA
• NEUTROPENIA
• DERMATOLOGIC
• RASH
• INJECTION SITE REACTIONS
• ENDOCRINE
• THYROID DISEASE
• HYPERLIPIDEMIA

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RIBAVIRIN ADVERSE EVENTS

• ANEMIA
• TERATOGENICITY
• GI TOXICITY
• COUGH

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CONTRAINDICATIONS FOR TREATMENT

• HYPERSENSITIVITY TO INTERFERON OR RIBAVIRIN
• UNCONTROLLED AUTOINMMUNE DISORDERS ( RA, SLE,
  PSORIASIS )
• BONE MARROW COMPROMISE
• DESCOMPENSATED LIVER DISEASE

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CONTRAINDICATIONS FOR TREATMENT

• PREGNANCY OR PLANNED PREGNANCY
• ACTIVE OPORTUNISTIC DISEASE
• LIFE-DETERMINING EXTRAHEPATIC DISEASE
  (MALIGNANCY, COPD, UNSTABLE ANGINA)
• SEVERE UNCONTROLLED PSYCHIATRIC DISEASE

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CONTRAINDICATIONS FOR TREATMENT

• POOR COMPLIANCE WITH TREATMENT
• ONGOING INJECTION DRUG USE
• ONGOING ALCOHOL USE

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