HEPATITIS C

1
HEPATITIS C

• Diagnosis
• and
• Clinical Management

2
Epidemiology

• WHO estimates 3 of worlds population - about
  170 million. (WHO Fact Sheet 164
  www.who.int/inf-fs/en/fact164.html)
• HCV infection ?80 since early 90s. Previously
  infected will progress to liver disease,
  cirrhosis, and hepatocellular carcinoma. 40 of
  chronic liver disease is related to hepatitis C.
• Age 30-49 at highest risk more prevalent in
  blacks. (CDC Recommendations for prevention and
  control of hepatitis C virus infection and HCV
  related chronic disease)

3
Transmission

• PERCUTANEOUS
• Blood product transfusions and illicit drug use
• NOSOCOMIAL
• Patient-to-patient patient-to-healthcare worker
• Healthcare worker-to-patient
• MISCELLANEOUS
• Tattoos and preventive vaccination campaigns
• SEXUAL
• Multiple sex partners and prostitution
• PERINATAL
• Infants born to HCV mothers

4

• Illegal drug use most common transmission
• 90 of users infected after 5yrs of IV drug use
• Nosocomial transmission is rare
• less than 10 needle stick HCV transmission
• Rule of 3s 30 HepB, 3 Hep C, 0.3 HIV
• Sexual transmission is not common
• Spouses w/o risk factors 0 - 4
• Higher risk in couples with risk factors ie IV
  drug use
• Mother to infant - in 5 to 6 of deliveries
  (Compans, Hogle et.al eds.. Current Topics in
  Microbiology and Immunology 1999 23725-41 and
  NEJM 1996 3341685-1690)

5
Natural History (Lancet 1997 349825-832)

• Acute infection asymptomatic in 60 - 70
• Average incubation 6-7wks, range 2-26wks
• 20 to 30 of patients will develop jaundice
• Chronic HCV develops in 50 - 85 of cases
• Acute symptomatic less likely to progress
• Chronic HCV prolonged, insidious, with few
  signs and symptoms if any for the first 20yrs.
• Moderate to severe HCV develops in 1/3 of pts
  20yrs or less after infection
• Inflammation and hepatic cell necrosis may lead
  to bridging fibrosis
• Cirrhosis develops in 15 - 20 of pts with
  chronic HCV

6
Who should be screened?(CDC Recommendations)

• Illegal IV drug users those who have used
  before.
• Recipients of transfusions before 1992.
• Hemophiliacs and patients receiving
  clotting-factor concentrates before 1987
• Chronic hemodialysis patients
• Organ, tissue or blood donors
• Transplant recipients before 1992
• Patients with persistently abnormal AKT
• Symptomatic individuals
• Those with recognized exposure after needle
  sticks
• Infants (gt 12 months) born to HCV mothers

7
Factors that promote progression of chronic
hepatitis(NEJM 2001 34541-52)

• Alcohol use
• Male sex
• Age over 40yrs at the time of infection
• Severe histology at time of initial diagnosis
• Co-infection with HIV and/or HBV is associated
  with earlier, more severe liver disease.

8

• Patients with cirrhosis may decompensate over
  time with ascites, jaundice, variceal bleeding,
  or encephalopathy.
• Patients with compensated cirrhosis have a 5yr
  mortality of 9 and 10yr mortality of 21
• Patients with decompensated cirrhosis have a 5yr
  mortality of 50 and 10yr mortality of 70
• Hepatocellular carcinoma occurs in 1 - 4 of
  pts/yr during first 5yrs after cirrhosis, 7
  after 5yrs and 14 after 10yrs (Gastroenterology19
  97112463-472)
• Risk is higher in men and older patients.

9
Diagnosis

• Elevated ALT on routine testing
• Antibody testing - Enzyme-linked immunoassay
  (EIA) and recombinant immunoblot assay (RIBA) can
  detect virus within 4-10wks of infection
• Viral RNA - qualitative or quantitative
• Qualitative most sensitive can detect lt 100
  copies of HCV RNA/ml. Used to confirm viremia and
  assess response
• Quantitative used to determine viral load,
  persistence of infection in antibody pts,
  monitor response to ttt and to detect the
  presence of infection in HIV pts.
• Viral load does not predict disease progression

10
Diagnosis (continued)

• Should use the same test serially
• Viral genotyping done with commercial assay using
  PCR products on genotype-specific hybridization
  probes.
• Liver biopsy used to determine status and
  prognosis of chronic liver disease
• Histologic staging is done according to degree of
  fibrosis and graded according to degree of
  inflammation and necrosis.

11
Goal of Therapy

• TO PREVENT PROGRESSION OF THE DISEASE, DECREASE
  PROGRESSION TO CIRRHOSIS, AND REDUCE LIKELIHOOD
  OF HEPATOCELLULAR CARCINOMA

12
Consensus Recommendations(National Institutes of
Health Consensus Development Conference Panel
Statement Management of Hepatitis C Hepatology
1997 262S-10S

• Choose patients at greatest risk of progression
  with no absolute contraindications
• Patients at greatest risk of progression include
• those with moderate liver histology
• have ALT gt 1.5 x ULN for more than 4-6months
• have HCV-RNA in serum
• Patients with decompensated cirrhosis or normal
  ALT should be considered for treatment in
  clinical trials.

13
Host and Viral Factors Associated with a Poor
Response to Treatment

• Failure of ALT to decline to normal in 4-6mos.
• High viral load - ? 2 million copies/ml
• reappearance of HCV-RNA on treatment
• Genotype 1
• African descent

14
Treatment Options

• Interferon alfa-2a and alfa-2b
• inhibits viral replication, attachment and
  uncoating
• induces host defenses
• amplifies host immune response to viruses
• Adverse effects
• flu-like symptoms, fatigue, arthralgia, bone
  marrow suppression and neuropsychiatric symptoms.
• Contraindications
• autoimmune disorders, psychiatric disorders,
  suicidal ideation, neutropenia, thrombocytopenia,
  uncontrolled seizures, organ transplantation, and
  symptomatic cardiac disease
• Dose
• 3 million units SQ 3 x a week

15

• Ribavirin-antiviral effects against RNA DNA
  viruses but ineffective when used alone in
  treating Hepatitis C
• depletes intracellular phosphate pools through
  inhibition of inosine monophosphate dehydrogenase
  
• inhibits viral polymerase
• blocks inflammatory cytokines and counters
  interleukin-4 mediated inhibition of cytotoxic T
  lymphocyte
• Adverse Effects - hemolysis, teratogenicity,
  nausea, anemia, pruritus.
• Contraindications - anemia, hemoglobinopathy,
  renal failure, severe cardiac disease, pregnancy,
  inability to practice birth control
• Dose - 1000mg/day (? 75Kg body weight) x 24 - 48
  weeks
• 1200mg/day (gt 75Kg body weight)
  x 24 - 48 weeks

16
Response to Treatment-Assessment

• End-of-treatment-response normal ALT
  (biochemical response) and no detectable HCV-RNA
  at end of treatment(virologic response)
• Sustained biochemical response normal ALT 6 or
  more months after therapy is discontinued.
• Sustained viral response no detectable
  HCV-RNA 6 or more months after therapy
  discontinued
• Nonresponse HCV-RNA detectable and abnormal ALT
  at the end of therapy.

17
Response to Therapies

• Monotherapy with Interferon at 3MU 3x/wk.
• End-of-treatment response 33 - 50
• Sustained response rate 10 - 15
• If sustained viral response was to occur, HCV-RNA
  was usually negative by week 12 of treatment
• Combination therapy Interferon 3MU 3x/wk plus
  ribavirin 1000mg - 1200mg/day wt based.
• Sustained viral response 40 up to 65 for
  genotypes 2 or 3
• Histologic improvement better with combination
• Factors that influence response genotype other
  than 1, HCV_RNA lt 2 mil copies/ml, minimal or no
  fibrosis, female gender, ? 40yrs old

18

• Side effects with combination therapy
• dyspnea, pharyngitis, pruritus, rash, nausea,
  insomnia and anorexia.
• Discontinuation rate with combination
• 20 vs lt 15 with monotherapy
• Duration of treatment
• 6 months for genotypes 2 and 3
• 12 months for genotypes 1 and 4
• Negative HCV-RNA at 24wks is predictive of
  sustained viral response.
• Positive HCV-RNA at 24wks (any genotype) is
  predictive of nonresponse and treatment should be
  discontinued

19
Pegylated Interferon alfa-2a

• Has delayed clearance, a longer half-life and
  allow for once a week dosing.
• Efficacy of Peg-INF vs INF in patients not
  previously treated with IFN and w/o cirrhosis
• Dose
• Sustained
• Response
• Hepatology2001 33433-438

20
INF alfa 2a vs PEG-INF alfa 2a dose rangeIn
patients with cirrhosis or bridging fibrosis
documented by biopsy

• NEJM 2000 3431666-1672

21
PEG-INF alfa 2b ribavirin is current standard
of care for the treatment of Hepatitis C

• Phase III study of 1530 randomized patients
• IFN ? 2b 3MU 3x/wk ribavirin 1000-12000mg/day x
  48wks
• PEG-IFN ? 2b 1.5mcg/kg 1x/wk ribavirin
  800mg/day x 48wks
• PEG-IFN ? 2b 1.5mg/kg 1x/wk ribavirin
  1000-1200mg/day x 4wks followed by PEG-IFN
  0.5mcg/kg 1x/wk ribavirin 1000-1200mg/day x
  44wks
• Sustained biochemical response 47, 54 and 48
  respectively
• Sustained viral response 47, 54 and 47
  respectively
• Hepatology 2001 34327A (abstract)

22
Treatment Recommendations

• Pegylated interferon alfa-2b and ribavirin is the
  current standard of care for chronic hepatitis C
• For patients unable to take ribavirin, PEG-IFN
  monotherapy is a viable treatment
• PEG-IFN alfa 2a monotherapy has proven efficacy
  in patients with cirrhosis
• For patients who have relapsed after IFN
  monotherapy consider the following options
• Unmodified IFN/ribavirin
• High dose IFN
• PEG-INF
• For patients who relapse or do not respond to
  combination therapy consider clinical trial
  settings.

23
Conclusions

• PEG-IFN ribavirin shows improved efficacy over
  unmodified IFN/ribavirin therapy
• PEG-INF/ribavirin has improved efficacy over
  IFN/ribavirin in hepatitis C refractory to
  treatment (African descent and genotype 1)
• PEG-IFN monotherapy has proven efficacy in
  patients with cirrhosis
• Weekly dosing of PEG-INF improves compliance and
  is more cost-effective than 3x/wk IFN treatment

24
Full Text References

• Treatment of Chronic Hepatitis C A Systematic
  Review
• Optimal Therapy of Hepatitis C
• Retreatment of Patients With Chronic Hepatitis C
• Treatment of Patients With Hepatitis C and Normal
  Serum Aminotransferase Levels
• Side Effects of Therapy of Hepatitis C and Their
  Management

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THANK YOU