INTERFERON and RIBAVIRIN

1
INTERFERON and RIBAVIRIN

• Irteza Inayat, MD.

2
OUTLINE

• Background Pharmacodynamics of Interferon
• Background Pharmacodynamics of Ribavirin
• Clinical Use of Interferon/Ribavirin in Chronic
  Hepatitis C Infection

3
OUTLINE

• Background Pharmacodynamics of Interferon
• Background Pharmacodynamics of Ribavirin
• Clinical Use of Interferon/Ribavirin in Chronic
  Hepatitis C Infection

4
BACKGROUND INTERFERONS

• Japanese virologists noticed that rabbit-skin
  inoculated with inactivated virus interfered with
  viral growth when re-infected with live virus.
  Postulated an innate facteur inhibiteur .
• Isaacs and Lindenmann, discovered interferon in
  1957.
• Interferon (IFN) produced by nearly all animals
  and cells.
• Infection of human WBC induced expression of
  IFNs. Found in the conditioned medium of WBCs
  used for clinical trials.

5
Types of Interferon

• The interferons (IFNs) represent a subset of
  cytokines that have existed in vertebrates for
  about 500 million years
• About 10 mammalian interferons species have been
  discovered, but only seven are found in humans
• 1) IFN-a
• 2) IFN-ß
• 3) IFN-e
• 4) IFN-?
• 5) IFN-?
• 6) IFN-d
• 7) IFN-t
• 8) IFN-?
• 9) IFN- ?
• 10) IFN-?

Type I
Type II
6
Biological Activities of Interferons

• Antiviral
• - MHC-I upregulation
• - inhibits viral entry into cells
• - inhibits viral replication
• - enhances cytolytic (killer) T-cell activity

• Antiproliferative
• - expression of tumor associated antigens
• - repression of antiapoptotic genes
• -induction of proapoptotic genes
• - modulation of cell differentiation and
  antiangiogenic activity

7
Interaction between Viruses and Interferon
8
THERAPEUTIC USES

• To date, IFN-as are approved for the treatment of
  
• 1) hairy cell leukemia
• 2) malignant melanoma
• 3) follicular lymphoma
• 4) condylomata acuminata (genital warts)
• 5) AIDS-related Kaposis sarcoma
• 6) chronic hepatitis B and C
• -IFN-ßs
• 1) multiple sclerosis
• -IFN-?
• 1) chronic granulomatous disease
• 2) malignant osteropetrosis
• - Off-label use of IFN-a is prevalent in many
  cancers, especially in bladder and renal cancers,
  often as an adjuvant with other therapeutics.

9
PHARMACODYNAMICS / KINETICS

• Absorption Filtered and absorbed at the renal
  tubule
• Distribution Vd 0.223-0.748 L/kg
• Metabolism Primarily renal filtered through
  glomeruli and undergoes rapid proteolytic
  degradation during tubular reabsorption ?
  obviates renal dosing
• Bioavailability I.M. 83 SubQ 90
• Half-life elimination I.V. 3.7-8.5 hours (mean
  5 hours)
• Time to peak, serum I.M., SubQ 6-8 hours

10
OUTLINE

• Background Pharmacodynamics of Interferon
• Background Pharmacodynamics of Ribavirin
• Clinical Use of Interferon/Ribavirin in Chronic
  Hepatitis C Infection

11
BACKGROUND RIBAVIRIN

• Ribavirin (1-ß-D-ribofuranosyl-1,2,4-triazole-3-ca
  rboxamide) a guanosine analogue with a broad
  anti-viral activity.
• First synthesized in 1970
• In 1972, ribavirin found to be active against a
  variety of RNA and DNA viruses in culture and in
  animals
• Ribavirin protected mice against mortality from
  both A and B strains of influenza
• Results in human trials against influenza were
  mixed so the FDA ultimately did not approve this
  indication for ribavirin
• In 1980 ribavirin was marketed in inhalant form
  for RSV infection in children

12
PHARMACODYNAMICS / KINETICS

• Absorption by GI tract by nucleoside
  transporters. Absorption is 45, and modestly
  increased (to about 75) by a fatty meal
• Distribution all tissues, including the brain
• Pharmacokinetics
• - trapping of the phosphorylated form inside
  cells, esp RBCs
• - RBCs lack the enzyme to remove the
  phosphorylated form and thus high
  concentrations of the drug.
• - adenine kinase converts to active form this
  enzyme is more active in virally-infected
• Half-life about 12 days, (in RBCs, half-life 40
  days).
• Excretion 1/3 of absorbed ribavirin is excreted
  into the urine unchanged, and the rest is
  excreted into urine as the de-ribosylated base,
  and the oxidation product of this base

13
Proposed mechanisms to explain the efficacy of
ribavirin in HCV Rx

• The mechanisms by which ribavirin inhibits viral
  replication and prevents relapses during
  IFN-ribavirin combination therapy are totally
  unknown
• - Direct inhibition of HCV RNA-dependent RNA
  polymerase
• - Inhibition of inosine monophosphate
  dehydrogenase (IMPDH).
• - Immunomodulatory properties.
• - Mutagenic properties leading to error
  catastrophe.

14
SIGNIFICANT ADVERSE EFFECTS of IFN RBV
Combination Rx

• A flu-like syndrome (92)
• CNS Fatigue (60 to 70), headache (43 to 66),
  fever (32 to 46), depression (20 to 36)
• Dermatologic Alopecia (27 to 36), pruritus
  (13 to 29)
• GI Nausea (33 to 47), anorexia (21 to 32),
  wt loss (10 to 29), diarrhea (10 to 22)
• Hematologic Neutropenia (8 to 27 40 with HIV
  coinfection), Hgb decreased (25 to 36), anemia
  (11 to 17), lymphopenia (12 to 14), ANC lt0.5
  x 106/L (5 to 11),
• Neuromuscular skeletal Myalgias (40 to 64),
  rigors (40 to 48), arthralgia (22 to 34),
  musculoskeletal pain (19 to 28)

15
OUTLINE

• Background Pharmacodynamics of Interferon
• Background Pharmacodynamics of Ribavirin
• Clinical Use of Interferon/Ribavirin in Chronic
  Hepatitis C Infection

16
Role of Interferon and Ribavirin in the Rx of
Chronic Hepatitis C Infection
17
Disease Progression ofHepatitis C Virus (HCV)
Acute HCV
NIH Consensus Development Conference Statement.
Hepatology. 200236(suppl. 1)S3. Davis GL et al.
Gastroenterol Clin North Am. 199423603. Koretz
RL et al. Ann Intern Med. 1993119110. Takahashi
M et al. Am J Gastroenterol. 199388240.
Adapted from Brown RS. Epidemiology and Natural
History of Hepatitis C. Presented at ACG
Clinical Implications meeting April 6, 2000
Dallas, TX.
18
Why Do We Treat Chronic HCV?
1000
HCC
800
4
ALT
3
2
1
600
Fibrosis?Cirrhosis
ALT (U/L)
400
Anti-HCV
HCV RNA
200
0
0
0.5
1
2
5
10
15
20
25
30
35
40
45
50
Years After Exposure
Hoofnagle JH. Hepatology. 200236S21.
19
Benefits of IFN RBV Therapy

• Reduction in fibrosis
• - May occur in absence of viral clearance
• Reduce risk of end-stage liver disease and HCC
• Patient may feel better
• Public health benefit reducing transmission of
  HCV

NIH Management of Hepatitis C Consensus
Conference Statement. June 10-12, 2002. Available
at http//consensus.nih.gov/2002/2002HepatitisC20
02116html. Accessed April 10, 2007.
20
Schematic representation of the HCV life cycle
GASTROENTEROLOGY 200713219791998
21
Definitions of Treatment Response Early
Milestones
Pawlotsky JM. Hepatology. 200236(suppl
1)S65-S73. Sethi A, et al. Clin Liver Dis.
20059453-471.
22
Early Patterns of Response to Initial HCV Therapy
Peg-IFN RBV
7
Nonresponder
6
Nullresponder
5
Partialresponder
HCV RNA (log10 IU/mL)
2 log10 decline
4
3
Limit of detection
2
Rapid responder
1
0
1
2
3
7
14
21
28
84 (12 weeks)
Days on Treatment
23
Definitions of Treatment Response
Pawlotsky JM. Hepatology. 200236(suppl
1)S65-S73.Sethi A, et al. Clin Liver Dis.
20059453-471.
24
Milestones in the Rx of HCV
25
IFN-a as Lone Therapy for HCV

• Initially IFN was approved for a 6-mo course of
  tiw injections
• In earlier studies (pre-1989) primary end-point
  was a biochemical response i.e. normalization of
  ALT
• ETRs ? in only 29 of treated patients compared
  with 5 of controls
• SVRs ? in 8 of treated patients compared with 1
  of controls
• Higher doses, frequent injection schedules,
  different preparations, and induction therapy
  with high initial doses failed to improve
  virologic responsiveness
• Doubling of the duration of therapy to 12 months
  increased the frequency of SVR to approximately
  20
• Poynard T, et al. Hepatology
  199624778-789
• Carithers RLJ, et al. Hepatology
  19972683S-88S

26
Combined Therapy IFN-a and Ribavirin

• Ribavirin monotherapy has been shown to be
  ineffective
• The addition of ribavirin to IFN was a major
  breakthrough in the treatment of HCV infection
• In a Cochrane review of 6 trials, compared with
  IFN monotherapy, combination therapy increased
  the response rate by 26 in naive patients
• Multiple studies have consistently demonstrated a
  dramatically improved responses to combination
  therapy, especially for patients with genotypes 2
  and 3
• McHutchison et al and Poynard et al also
  reinforced the importance of longer duration
  therapy for 48 weeks in patients with genotype 1
  infection

27
IFN alone vs IFN RBV
McHutchison J et al. N Engl J Med
19983391485-1492
28
Advantages of Pegylated Interferon-a

• Polyethylene glycol (PEG)
• Delays clearance of interferon
• Maintains higher blood levels of interferon
• Once-weekly injection
• Avoids peaks and troughs of 3-times-weekly
  dosing
• Less fatigue and malaise
• No drug-drug interaction with methadone

Pharmacokinetics
Peg-IFN alfa-2a SC once weekly T1/2 80 hours
20,000
15,000
1000
Peg-IFN ?-2bSC once weekly T1/2 40 hours
pg/mL
100
IFN TIW T1/2 2-3 hours
10
1
0
10
20
40
60
80
100
120
140
160
180
Hours
29
PEG-IFN a Monotherapy Why Bother?

• The current role of PEG-IFN monotherapy is
  imprecisely defined.
• Patients with contraindications to ribavirin
• 1) Patients with renal insufficiency
• 2) Hemoglobinopathies
• 3) Ischemic cardiovascular or cerebrovascular
  disease
• No clinical trials have been reported to date in
  these populations
• For patients with contraindications to ribavirin
  but who have indications for antiviral therapy,
  PEG-IFN represents the best available treatment

30
PEG-IFN ?-2b RBV vs. IFN ?-2b RBV
Therapy(Pegintron-Schering product)
100
Patients With SVR
80
P0.01
60
54
47

40
20
N505
N511
0
IFN ?-2b 3 MU tiw RBV 1000-1200 mg/day for 48
weeks
PEG-IFN ?-2b 1.5 ?g/kg/wk RBV 800 mg/day for
48 weeks
Randomized controlled trial PEG-IFN, pegylated
interferon RBV, ribavirin
Manns MP et al. Lancet 2001358958.
31
PEG-IFN ?-2a RBV vs. IFN ?-2b RBV
Therapy(Pegasys -ROCHE product)
100
Patients With SVR
Plt0.001
80

56
60

44
40
20
N453
N444
0
PEG-IFN ?-2a 180 ?g/wk RBV 1000-1200 mg/day for
48 weeks
IFN ?-2b 3 MU tiw RBV 1000-1200 mg/day for 48
weeks
Fried MW et al. N Eng J Med. 2002347975.
Randomized controlled trial
32
SVR with PegIFN alfa-2a or IFN alfa-2b and RBV
according to Genotype
Strader et al, Hepatology 39, 42004.
33
Predictability of SVR Once Started on Therapy
Fried MW, et al, NEJM 34713975-982
34
Pre-Treatment Predictors of Response
35
SVR By Degree of Fibrosis
100
No/Minimal Fibrosis
Bridging Fibrosis/ Cirrhosis
80
P0.04
P0.62
57

60
49
Patients With SVR
44
41
40
20
N333
N132
N136
N336
0
IFN ?-2b3 MU RBV 1000-2000 mg
IFN ?-2b3 MU RBV 1000-2000 mg
PEG-IFN ?-2b 1.5 ?g/kg RBV 800 mg
PEG-IFN ?-2b 1.5 ?g/kg RBV 800 mg
Manns MP et al. Lancet 2001358958.
36
NIH Recommended HCV Therapies

• Goal of treatment is SVR
• Defined as
• No detectable serum RNA 24 weeks after the end
  of treatment
• Tested using sensitive HCV RNA assay with lower
  limit of detection of 50 IU/mL

• Peg-IFN RBV more effective than standard IFN
  RBV combination or peg-IFN alone
• Genotype 1
• Peg-IFN RBV 1000-1200 mg/ day ? 48 weeks
• Genotype 2 or 3
• Peg-IFN RBV 800 mg/day ? 24 weeks

NIH Management of Hepatitis C Consensus
Conference Statement. June 10-12, 2002. Available
at http//consensus.nih.gov/2002/2002HepatitisC20
02116html. Accessed April 10, 2007.
37
CONCLUSION

• Interferon is an integral part of innate immunity
  with antiviral and antiproliferative properties
• Addition of Ribavirin has dramatically improved
  response rates
• Future therapies of HCV will still likely
  incorporate IFN based therapies