Treatment of Chronic Hepatitis C: Peginterferon and Ribavirin

1
Treatment of Chronic Hepatitis CPeginterferon
and Ribavirin

• Sidney G. Smith, M.D.

2
Case

• 43 yo WM presents to establish care at
  DHP-recently moved to this area
• PMH of substance abuse (IVDU) and multiple
  traumas- ? Hx of hepatitis
• Currently going to methadone clinic-denies
  current drug or alcohol use
• Complains of palpitations and weight loss
• AF/VSS with unremarkable PE--no stigmata of liver
  disease

3
Case (Cont)-Labs

• ALT 43 (ULN 36)
• Hepatitis C Antibody
• - HIV antibody
• -Hepatitis B core antibody and surface antigen
• TSH 0.08

• Labs at next visit--
• Hepatitis C genotype 1a
• Viral load 2.2 million copies/ml

4
Clinical question

• The patient inquires about Hepatitis C and is
  very concerned over his diagnosis.
• What are the treatments? How effective are they?

5
HCV-Virology

• First identified in 1989 as primary cause of
  non-A/non-B Hepatitis
• RNA Virus-family flaviviridae
• Single RNA genome codes for a large polyprotein-
  cleaved into multiple proteins

• RNA polymerase coded for and required for
  replicationLacks proofreading capability
• Rapid rate of virion production (trillions/d) and
  short serum half life (3-4 hours)

6
Virology (Cont)

• Six different genotypes (1-6)
• Large degree of variation between genotypes and
  even within same genotype
• Quasispecies (5-10) variation
• Subtype (15-30) variation
• Genotype (30-50) variation
• Genotype does not affect progression but is
  important predictor of response to therapy

7
Virology- Geographic variation
8
HCV-Epidemiology

• Viral Pandemic-170 million people infected
  worldwide
• Prevalence varies worldwideEgypt has highest
  prevalence (average 22)
• In U.S. is the most common chronic blood borne
  illness and most common reason for liver
  transplantation

9
Epidemiology (Cont)-U.S.

• Based on NHANES III data, 1. 8 (3.9 million) of
  U.S. population has HCV antibody
• 73.9 (2.7 million) of this group have HCV RNA
  indicating chronic infection
• Demographic Characteristics Poverty, lt12 yrs
  education, divorced/separated
• Strongest independent risk factors Illegal drug
  use and high risk sexual behavior

10
HCV-Risk Factors

• Hepatology 2002 36(5) S93-S98.

11
HCV-Transmission

• Household transmission rare, but can occur (avoid
  sharing razors, toothbrush, any items with
  exposure to blood)
• Role of tattooing controversial
• No role for post-exposure immune globulin

12
HCV- Acute Clinical Manifestations

• Largely asymptomatic
• lt20 become clinically jaundiced-when occurs
  assoc. with fatigue, lethargy, N/V, fevers, and
  RUQ pain
• Symptoms occur around 7-8 weeks post exposure
  (range 2-12 weeks)
• Fulminant hepatic failure rare but has been
  documented
• 75-80 progress to chronic HCV (defined as HCV
  RNA for 6 months)

13
HCV-Course of Acute to Chronic

• Hepatology2002 36(5)S21-S29

14
HCV-Chronic HCV Manifestations

• Chronic infection asymptomatic in large majority
  of patients
• Symptoms when present include
• Fatigue (most common)
• RUQ pain
• Nausea, anorexia, myalgias
• No association between symptoms and disease
  activity
• Most patients have ALT in range of 1-2X ULN. 1/3
  patients will have normal ALT.

15
HCV-Extrahepatic Manifestations

• Essential Mixed Cryoglobulinemia
• Renal involvement (cryoglobulins, MPGN,
  membranous nephropathy)
• Autoantibody formation (thyroid disease)
• Dermatologic manifestations
• ? Association with DM, lymphoma, and gammopathies

16
Diagnosis of HCV

• Screening test is for HCV Antibody
• 3rd generation test now in use
• gt95 sensitive
• Generally positive 7-10 weeks post infection
• In low risk population (blood donors) false
  positives occur with greater freq. (Confirmatory
  testing required-RIBA or PCR)
• False negatives more common in immunocompromised
  and in patients with cryoglobulinemia

17
Diagnosis (Cont)

• PCR used to directly measure viral load (lower
  limit of detection lt50 copies/ml)
• HCV RNA detectable 1-3 weeks post infection
• Viral load helpful in predicting response to
  therapy
• Useful as confirmatory test and in setting of
  Acute HCV infection
• Used to follow response to treatment
• Genotype testing not required for diagnosis-
  helpful in determining response to therapy
• Liver biopsy

18
HCV-Natural history

• Course of chronic HCV variable
• Markedly different outcomes in various studies as
  to with ESLD/cirrhosis
• In general, 20 will develop cirrhosis
• 1/3 develop cirrhosis in lt20 years (rapid
  fibrosis)
• 1/3 require 30 years or more to develop cirrhosis
  if ever (slow fibrosis)
• Multiple factors affect rate of
  fibrosis/progression

19
HCV-Natural History (Cont)

• New England Journal of Medicine 2001 345(1)41-52

20
HCV-Natural history(Cont)
21
HCV-Treatment

• Rationale for treating vast majority of patients
  with chronic HCV is prevention of cirrhosis/ESLD
• Symptomatic improvement doubtful (especially
  fatiguewill get worse with treatment)

22
HCV-Treatment/History

• Prior to discovery of HCV in 1989, interferon
  shown to be useful in treatment of Non-A/Non-B
  Hepatitis
• Interferon Alpha approved by FDA in 1990 for
  treatment of chronic HCV
• Sustained Virological Response (defined as
  undetectable HCV RNA 24 weeks post therapy) rates
  very low with interferon monotherapy for 24 weeks
  (5-10)
• Extending treatment to 48 weeks improved SVR
  marginally (10-15)
• Addition of Ribavirin to Interferon improved SVR
  to near 40 (1998)
• Peginterferon monotherapy shows SVR 23-29

23
HCV-Treatment (PEG)

• The role of pegylation

24
PEG-interferon alfa
Peginterferon?-2a
IFN?
IFN tiw dosing
qw dosing
14
30
12
25
10
20
8
Concentration (ng/mL)
Concentration (U/mL)
15
6
10
4
5
2
0
0
0
8
24
48
72
96
120
144
168
0
24
49
72
97
120
155
Time (hours)
Time (hours)
Multiple Dose (Week 48)
Xu Z-X et al. Hepatology. 199828(4 pt 2)702A.
25
HCV-Treatment (Contraindications)

• New England Journal of Medicine 2001 345(1)41-52

26
HCV-Treatment

• Two recent studies have focused on combination
  peginterferon/ribavirin for treatment of chronic
  HCV.

27
HCV-Treatment (Manns)

• Manns et al. Peginterferon alfa-2 b plus
  ribavirin compared with interferon alfa-2b for
  initial treatment of chronic HCV a randomized
  trial. Lancet 2001.
• Design randomized trial carried out at 62
  centers in Europe, Argentina, Canada, and U.S.
• Primary endpoint SVR (undetectable HCV RNA 24
  weeks post therapy)

28
HCV Treatment (Manns)

• Patients 1530 patients, 65 male, average age
  43, 5-7 cirrhosis, 68, genotype 1, 29-30
  genotype 2 or 3

29
HCV-Treatment (Manns)

• Exclusion Criteria
• Decompensated cirrhosis
• Elevated AFP
• HIV
• Other causes of liver disease
• Preexisting Psych. disease

• Inclusion Criteria
• No previous treatment
• HCV RNA
• Liver Bx within 1 year
• Elevated ALT
• Normal Renal Fx and CBC wnl

30
HCV-Treatment (Manns)

• Treatment 3 treatment arms
• 511 Patients received 1.5mcg/kg/sq peg q week
  plus ribavirin 800 mg po QD x 48 weeks
• 514 Patients received 1.5mcg/kg/sq peg q week x 4
  weeks, then 0.5mcg/kg/sq q week x 44 weeks plus
  ribavirin 1000mg/1200mg (weight based) po qd x 48
  weeks
• 505 Patients received standard interferon 3
  million units sq/tiw plus ribavirin 1000mg/1200mg
  (weight based) x 48 weeks

31
HCV-Treatment (Manns)

• Results

32
HCV-Treatment (Manns)

• Results by Ribavirin dose

33
HCV-Treatment (Manns)

• Adverse Events
• No new class of side effects
• Flu symptoms higher in high dose PEG group
• Neutropenia higher in high dose PEG group
• Dose reduction higher in high dose PEG group
• Discontinuation rate similar between groups

34
HCV-Treatment (Manns)Conclusions

• Overall SVR higher with high dose PEG (54 vs.
  47)
• In genotype 1, high dose PEG achieves higher SVR
  than standard interferon (42 vs. 33)
• No difference in SVR between groups in those with
  genotype 2 or 3

35
HCV-Treatment (Manns)

• Variables associated with increased SVR
• Genotype other than 1
• Baseline viral load (lt2 million copies)
• Younger age
• Absence of cirrhosis/bridging fibrosis
• Weight based dosing of Ribavirin (gt10.6 mg/kg)

36
HCV-Treatment (Manns) Conclusions

• Comparing high dose PEG vs. standard interferon
• Overall ABI 7, NNT 14
• Genotype 1 ABI 9, NNT 11

37
HCV-Treatment (Fried)

• Fried et al. Peginterferon Alfa-2a Plus Ribavirin
  for Chronic HCV. NEJM 2002.
• Design Randomized controlled trial conducted at
  81 centers worldwide
• Primary Endpoint SVR, defined as HCV RNA 24
  weeks post therapy
• Patients 1121 patients, 71 male, average age
  42, 84 white, 61-65 genotype 1, 12-15 with
  bridging fibrosis or cirrhosis

38
HCV-Treatment (Fried)

• Inclusion Criteria
• No previous treatment
• Elevated ALT
• Liver Bx
• Positive HCV RNA

• Exclusion Criteria
• Neutropenia (1,500)
• Thrombocytopenia (lt90,000)
• Anemia (lt12g F, lt13g M)
• HIV
• Decomp. Liver Disease
• Psych. Dz (poor control)
• Alcohol/drug abuse within 1 year
• Crgt1.5 x ULN

39
HCV-Treatment (Fried)

• Treatment 3 treatment arms
• Peginterferon Alfa-2a 180mcg sq/week plus
  ribavirin (weight based) 1000/1200mg po qd x 48
  weeks
• Peginterferon Alfa-2a 180 mcg sq/week plus
  placebo x 48 weeks
• Interferon Alfa-2b 3 million units/sq tiw plus
  ribavirin (weight based) 1000/1200mg po qd x 48
  weeks

40
HCV-Treatment (Fried)

• Results

41
HCV-Treatment (Fried)
42
HCV-Treatment (Fried)

• Adverse events
• No new class of side effects with peginterferon
• Similar number of patients withdrawn from each
  group (most due to depression)
• Flu symptoms less common in peg groups
• Neutropenia/ thrombocytopenia more common in peg
  groups

43
HCV-Treatment (Fried)

• Conclusions Peginterferon Alpha-2a/ribavirin for
  48 weeks is superior to standard
  interferon/ribavirin, irrespective of genotype
• Higher SVR also noted in patients with high
  baseline viral load
• If no response by week 12, chance of achieving
  SVR very low
• Variables assoc. with higher SVR
• Genotype other than 1
• Younger age (lt40)
• Weight lt75kg

44
HCV Treatment- (Fried)

• Conclusions comparing Peg/ribavirin vs. standard
  interferon/ribavirin
• Overall ABI 12, NNT 8
• Genotype 1 ABI 10, NNT 10
• Genotype 2 or 3 ABI 15, NNT 6

45
HCV-Treatment-Expense

• The Medical Letter 2003 45 19-20

46
HCV-Treatment

• Improvements are being made in the treatment of
  HCV---BUT
• Can we apply these results to our patient
  population?

47
HCV-Treatment

• Ytter et al. Surprisingly Small Effect of
  Antiviral Treatment in Patients with Hepatitis C.
  Annals of Internal Medicine 2002.

48
HCV-Treatment

• Design Retrospective case series of consecutive
  patients referred to a liver clinic in Cleveland,
  Ohio.
• Patients 327 pts. with ELISA for HCV
• Objective Measurement of treatment rates and
  reasons for non-treatment
• Criteria for treatment HCV RNA and elevated
  ALT on two occasions over 6 months
• Exclusion Criteria Decompensated cirrhosis,
  other liver disease, alcohol or drug abuse,
  nonadherence (missing 2 visits), poorly
  controlled psych. disease or sz. d/o, autoimmune
  dz, symptomatic CAD, neutropenia (lt1,500),
  thrombocytopenia (lt75,000)

49
HCV-Treatment (Ytter)

• Conclusion Many (if not most) patients are not
  candidates for treatment with the current
  interferon based regimens

50
HCV-Conclusions

• Treatments for chronic HCV have shown continual
  improvement over the last decade.
• Peginterferon/Ribavirin is superior to standard
  interferon/Ribavirin and is now the standard of
  care
• No direct comparison of the two peginterferons
  currently available has been done, but they
  appear to be equally effective

51
HCV-Conclusions

• The decision on who to treat is very difficult
• In theory everyone is candidate for treatment
• Must be made on an individual basis
• Patient preferences very important
• Patients need to understand reasons for treatment
  and adverse effects of current regimen

52
HCV-Conclusions

• In general, patients with genotype 2 or 3 should
  be offered treatment if no contraindications
• Decision more difficult in patients with genotype
  1, based on continued poor SVR
• Only reliable way to determine which pts. will
  benefit most from treatment is by histological
  evaluation
• Liver bx results should be used to guide clinical
  decision making

53
HCV-Back to the case

• The pt. was not felt to be a candidate for
  treatment
• Noncompliance (multiple no-shows)
• Resumption of drug use
• Autoimmune thyroid disease (initially)
• He was vaccinated against Hep A/B
• Counseled regarding transmission of HCV
• Urged to seek therapy for drug abuse AND abstain
  from alcohol

54
THANKS

• Dr. Brandi Salomone
• Dr. Jim Peacock
• Dr. Joel Bruggen