Ribavirin in Hepatitis C

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Ribavirin in Hepatitis C

• Dr. Thomas Alexander
• VSM Hospital
• Mavelikara, Kerala, India

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Background

• Limited efficacy of IFN monotherapy
• Sustained Response rates poor
• Alternate treatment approaches

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Treatment Responses

• Biochemical SGPT normalization
• Virologic Serum HCV RNA undetectable
• lt100 copies/ml

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Treatment Responses - Contd
NIH Consensus Development Conference on Mx of
Hep C (March 97)

• End of Treatment Response (ETR)
• - Biochemical ETRbiochemical
• - Virologic ETRvirologic
• Sustained Response (SR)
• - Biochemical SRbiochemical
• - Virologic SRvirologic

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Gold Standard to assess Treatment Outcome

• SRvirologic SRbiochemical
• longlived
• decreases hepatic necro inflammation
• halts fibrosis

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Ribavirin

• Synthetic nucleoside analogue
• Structurally resembles guanosine
• Broad spectrum antiviral - DNA RNA
• Used in Rx of respiratory syncitial virus

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Ribavirin

• Synthetic nucleoside analogue
• Structurally resembles guanosine
• Broad spectrum antiviral - DNA RNA

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Ribavirin - mechanisms of action

• Antiviral
• - inhibits RNA polymerase
• - inhibits 5CAP
• - inhibits IMP dehydrogenase
• Immunomodulation
• - inhibits IL-4 production by TH2
• - maintains IL-2 production by TH1

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Ribavirin - mechanisms of action

• Inhibition of viral polymerase
• Depletion of intracellular phosphate pool
• Shift in cytokine profile
• inhibits IL-4 (an inhibitor of CTL)
• preserves IL-2 gamma interferon
• Blocks hepatic proinflammatory response

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Ribavirin - mechanisms of action
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Ribavirin therapy

• Monotherapy
• Combination therapy with IFN
• Relapsers
• Treatment Naïve
• Nonresponders
• Post Liver Transplant
• HIV coinfection

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Ribavirin Monotherapy

• Trials with duration of 3-12 months
• Normalized SGPT in 20 - 55
• 100 relapse on cessation
• Histologic improvement variable
• Viral load unchanged

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Ribavirin IFN combination

• Kakumu et al 1993 first report on synergy
• (Gastroenterology 1993105 507-512)
• Normalization of ALT
• Ribavirin alone 2/9
• IFN alone 5/9
• IFN Ribavirin 6/9

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Relapsers
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Pilot studies in IFN Relapsers
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Major Study in Relapsers

• 1995 - 1997
• Two identical, large, randomized, double blind,
  placebo controlled trials
• Compared 6 month IFNR to IFNPlacebo
• US International
• Results published as a single paper -
• Davis et al, NEJM 339 (November 1998)

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Davis study

• Entry Criteria
• Adults with chronic hepatitis C
• Alpha IFN 3-6 mu tiw for at least 5 months, but
  not more than 18 months without
  reductioninterruption
• ETR biochemical biochemical relapse within 1 yr

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Davis study

• Exclusion criteria
• Decompensation
• Hb lt 12g in women lt 13 gm in men
• Poorly controlled Diabetes Mellitus
• Cardiovascular disease Renal insufficiency
• Seizure disorder Psychiatric disease
• Prior organ Tx HIV infection
• WBC lt3000 Neutrophils lt1500 Platelets lt100,000

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Salient features - Davis study

• 24 weeks treatment 24 weeks follow up
• IFN alfa-2b, 3mU tiw plus
• Ribavirin 1000mg / 1200mg or placebo
• 375 patients
• IFN R 173 77 US / 96 Intl
• IFN P 172 76 US / 96 Intl

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ETR (Relapsers)
Plt0.001
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Sustained Response (Relapsers)
Plt0.001
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Overall Response - Relapsers
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Histologic Response (Relapsers)
Analysis of 277 patients from total of 345
Plt0.001
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Effect of Viral Load Genotype
( In Relapsers - Davis study )
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Adverse Events - Davis study
(Death - 1 patient in IFN mono group due to
suicide)
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Summary (IFN R in Relapsers)

• More effective than IFN monotherapy
• Sustained Response (BV) 10 fold
  increase
• Histological improvement
• Best response - low viral load, non 1 genotype
• Safe

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Naive
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Early trials - Rx Naive
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Early Trials - Rx Naive
SRvirologic
1995 1996
1998
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IFN Ribavirin- Initial Treatment
12 countries, 43 centres, IFN Ribavirin as
in US Trial
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IFN Ribavirin- Initial Treatment
44 centres, IFN 3mU tiw, Ribavirin 1000mg (wtlt75)
/ 1200mg(wtgt75)
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Salient features of IHIT US trials

• Chronic HCV not Rx with IFN or Ribavirin
• Stratification- Genotype, Viral load, Cirrhosis
• Histology- initial six months after Rx
• Se HCV RNA at single lab- 100 copies/ml
• End points similar- virol, biochem,histo
• Histologic improvement- HAI /gt 2 points

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Biochemical Response -(Pooled)
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SRbiochemical in Rx Naive
A B C D
C/D vs A/B p lt .001 Cvs D p ns C/D vs B p lt
.001 C vs D p lt.05
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SRvirologic in Rx Naïve
A B C D

C/D vs A/B p lt .001 C vs D p .05 C/D vs B p
lt .001 C vs D p .05
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Virologic Response (Pooled Data)
SRvirol IR 48w vs 24w p .008
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Overall SR (Naïve)
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Histologic Response
HAI improvement /gt 2 points
A B C
D
C/D vs B p lt .001 C vs D p ns C/D vs B p lt .05
Cvs D p .05
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Overall SR (Naïve)
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Histologic Response (Naïve)
HAI improvement /gt 2 points
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SRvirologic

• IFN alone
  IFNRibavirin
• Naive 13
  40
• Relapsers 4.6 46

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Timing of Initial VC SRv (US)
S u s t a i n e d VR
59
50
51
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Viral Clearance SRvirologic
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Adverse Events - IHIT study
(No deaths)
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Adverse Events - US study
(No deaths)
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Combination Rx in Relapsers - IHIT
SRvirologic
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Response in Relapsers

• (Biochemical Virologic)
• IFN alone
  IFNRibavirin
• ETR 40 77
• SR 5
  47

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Summary (IFN R as Initial Rx)

• More effective than IFN monotherapy
• Sustained Response (BV) 2 to 3 fold
• Significant improvement in histology
• Prediction of response, by Se HCV RNA at 12
  weeks inaccurate
• Increased incidence of adverse effects

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Non Responders
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IFN Ribavirin Non-responders

• Pilot study 1995
• 10 patients for 6 months
• ETR virologic biochemical in 4
• SR virologic in 3

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IFN Ribavirin Non-responders

• Schalm 1997 meta-analysis of European data
• SRv in 19
• Wedemeyer 1998 meta-analysis of 555 patients
• ETRv in 34
• SRv in 7

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Liver Transplant
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IFN Ribavirin Liver Tx

• Reinfection in almost 100
• Course often mild, cirrhosis does occur
• French pilot study - 21 patients Hepatology1997
• normalisation of ALT in all
• loss of HCV- RNA in 10 (48)
• graft rejection - in none
• Ongoing studies - treatment prevention

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HIV Coinfection
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HCV HIV Co-infection

• High viral load more severe liver disease
• IFN monotherapy somewhat comparable to HIV
  negative individuals
• Several studies of IFN in HIV coinfection
• Soriano et al , 58 patients ( J Infection 1995)
• ETR - 38 coinfected 47 HIV negative
• Boyer et al , 12 patients ( J Infect Dis 1992)
• SR - 8.3

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IFN Ribavirin in HIV Co-infection

• No data
• Ongoing multicentric, randomized study
• IFN
  monotherapy
• Treatment arms
• IFN
  Ribavirin
• Duration of Rx - 48 weeks
• Follow up 24 weeks

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Safety Profile

• Hemolytic anemia
• Teratogenicity
• Pruritus
• Anorexia
• Dyspnea

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Ribavirin IFN safety profile

• No synergism in toxicity
• Main cause of dose reduction - hemolytic anemia
• Main cause of discontinuation - depression,
  suicidal tendencies

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Hemolytic anemia Ribavirin

• Dose limiting toxicity
• Mechanism not known - concentration in RBC
• Not predictable or preventable
• Not related to duration of therapy
• Similar in naïve patients relapsers
• Compensatory reticulocytosis within 4 weeks

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Hemolytic anemia - Contd

• Anemia can exacerbate cardiac symptoms
• Initial Hb if normal - generally safe
• No intervention
• Careful monitoring of Hb levels
• Dose reduction extremely effective - no
  discontinuation reported
• Recombinant human erythropoietin - experimental

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Ribavirin - dose modification

• Reduce dose by 50
• Hb drop gt 2 gm
• Hb level lt 10 gm
• Discontinue
• Hb lt 12 gm after 4 weeks dose reduction
• Hb lt 8.5 gm at any time

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Special Situations

• Renal Failure caution with Cr Cl lt50ml/mt
• Hepatic dysfunction no adverse effect
• Pediatric, Geriatric not assessed

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Precautions

• Teratogenicity contraceptive cover
• 6 months after
  cessation
• females males

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Ribavirin IFN The Future

• Longer duration of treatment
• Induction therapy Ribavirin
• Pegylated Interferon Ribavirin
• Other Combinations - Triple Therapy
• IFN Ribavirin Amantidine / Rimantadine

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Summary

• Combination of Ribavirin and IFN
• safe highly effective in relapsers
• highly effective in naïve patients
• limited efficacy in non responders
• promising in liver transplant recipients
• data awaited in co-infection with HIV

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Summary - Contd

• Viral load, genotype, histology - most reliable
  predictive parameters
• Optimal dose duration uncertain - Rx for 48
  weeks in those with high risk of failure
• Daily dose in - 1000mg (wt lt75 kg)
• 2 divided doses p.o. - 1200mg (wt gt75 kg)
• Safety profile acceptable -
• hemolytic anemia, teratogenicity

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Recommendations for IFN R

• Relapsers Yes
• Naïve patients Yes
• Non-responders Context of clinical trial
• Liver Tx - do -
• HIV co-infection - do -

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Ribavirin plus Interferon therapy of chronic
hepatitis C an important step forward but not
the final goal !