Update on Liver Disease and Hepatitis

1
Update on Liver Disease and Hepatitis

• This set of educational slides
• is made possible by
• The Hepatitis Information Network
• Schering-Plough of Canada
• (www.HepNet.com)

2
Update on Liver Disease and Hepatitis

• Issues and Controversies in 1997

3
Faculty

• Canadian
• Victor Feinman Chair and Course
  Director
• Frank Anderson
• Bob Bailey
• William Depew
• Cameron Ghent
• Paul Gully
• Mel Krajden
• Gary Levy
• Eve Roberts
• Averell Sherker
• Urs Steinbrecher
• Mark Swain
• Ian Wanless
• Florence Wong

• Session Chairs
• Vince Bain
• Jenny Heathcote
• Sam Lee
• Pierre Pare
• Linda Scully
• Morris Sherman
• Bernard Willems
• Noel Williams

• International
• Alfredo Alberti
• Johannes Brouwer
• Gary Davis
• Robert Perillo
• Leonard Seef
• Norah Terrault
• Judy Wilber

4
Epidemiology and Natural History of Hepatitis C
Virus Infection

• Hepatitis C is seldom detected in acute stages
  and is therefore difficult to follow natural
  history
• Annual incidence in U.S. has dropped from 180,000
  to 35,000 in past decade.
• improved awareness and dangers of sharing needles
• elimination of blood donations from high-risk
  donors
• sensitive serologic tests used in blood banks
• The rate of seropositivity in general population
  is 1.8

5
Epidemiology and Natural History of Hepatitis C
Virus Infection

• Sexual transmission accounts for about 15 of
  acute cases
• efficiency of sexual transmission is low
• infection is rare in long-term, steady partners
• Perinatal transmission occurs in 5-6 of infected
  mothers (higher for HIV )
• Breastfeeding now considered safe
• Contaminated equipment used in folk medicine,
  tattooing, body piercing, sharing razors and
  toothbrushes are still risk factors

6
Time to Progression of Chronic Hepatitis C, from
Presumed Onset of Transfusion-Associated Hepatitis
Years After Transfusion
Outcome
(Adapted from Kiyosawa K. Hepatology
199012671 Tong M. N Engl J Med 19953321463)
7
Hepatitis C Quick Facts

• Hepatitis C is a simple RNA virus, with only
  about 10,000 bases in its genome
• The half-life of an HCV virion is about 7 hours
• Hepatitis C is the most common cause of chronic
  hepatitis, and the most common reason for liver
  transplants
• The cost of HCV infection (excluding drugs and
  research ) in the U.S. is 2 billion yearly

8
Genotypes of Hepatitis C in Canada

• Associations between genotype and mode of
  transmission exist
• genotype 3 much more prevalent in intravenous
  drug users
• Patients with genotype 1b have a significantly
  lower rate of response to interferon treatment

9
Genotype Distribution of HCV
Results Based on Different Population Studies
of Isolates in Sample
(Adapted in part from Bernier L. J Clin Microbiol
1996342815)
10
Relationship of Sustained Response Rate to
Interferon and Genotype
Sustained Response Rate ()
Davis, Gary ULDH 1997
11
Therapy of Chronic Hepatitis C

• Patients with mild disease should be treated
• high initial and sustained response rates
• therapy at this stage offers best chance of
  disease eradication
• single course of therapy increases survival and
  is cost-effective
• Patients with cirrhosis
• may progress to hepatic failure
• response rates lower, relapse rates higher
• high rate of progression
• attempts at treatment are imperative

12
NIH Development Conference Guidelinesfor
Treatment of Hepatitis C

• Initial therapy a-Interferon, 3MU tiw for 12
  weeks
• If ALT is normal (at 3 months), continue for a
  total of 12 months
• end of treatment response expected is 40 to 50
• sustained response expected is 20 to 30
• Relapse after 6 months of IFN
• Re-treat with 12 months of IFN
• sustained response expected is 30 to 40

13
NIH Development Conference GuidelinesWho Should
be Treated?

• Unequivocal gtALT, moderate-to-severe
  inflammation, periportal or bridging fibrosis
  acute hepatitis
• Individualized mild inflammation compensated
  cirrhosis
• No Treatment normal ALT decompensated cirrhosis
• Not Useful in Patient Selection genotype, viral
  levels, symptoms, ALT level

14
Prediction of Response to Interferon by ALT
Response at 12 Weeks
Response Rate ()
Davis, Gary ULDH 1997
15
IFN Treatment of Mild Chronic Hepatitis C Gain
in Life Expectancy
Years of Life Gained
Age at Time of Treatment (years)
Davis, Gary ULDH 1997
16
IFN Treatment of Mild Chronic Hepatitis C Cost
per Year of Life Gained
Cost Per Year of Life Gained (US)
Age at Time of Treatment (years)
Davis, Gary ULDH 1997
17
Response Rates to Interferon Therapy for Chronic
Hepatitis C
Response Rate () fromPooled Data
Davis, Gary ULDH 1997
18
A New Modality of Treatment for HCVInterferon
and Ribavirin in Combination

• Ribavirin is a guanosine analogue
• inhibits viral RNA polymerase and viral capping
• limited use as monotherapy
• Combination may be an effective treatment option
• Dose IFN 3 MU tiw Ribavirin 1000-1200 mg/day

19
A New Modality of Treatment for HCVInterferon
and Ribavirin in Combination

• Meta-analysis from 349 patients (using
  multivariate logistical regression) from 6
  European trials
• 85 IFN naïve patients, 264 were
  non-responders/relapsers
• The combination therapy gave a sustained response
  rate 17.6 times greater than IFN alone

Brouwer, Johannes ULDH 1997
20
A New Modality of Treatment for HCVInterferon
and Ribavirin in Combination
Response Rate with IFN/riba, alone or in
combination
IFN/Ribavirin Combination
Interferon
Response Rate ()
Ribavirin
Control
4 8 12 16 20 24 28
32 36
Weeks
Fig 8
Brouwer, Johannes ULDH 1997
21
Response Rate in Patients with Chronic Hepatitis
C, Treated with IFN, Ribavirin, or Combination
Therapy
Odds Ratio (Treatment IFN)
Brouwer, Johannes ULDH 1997
22
A New Modality of Treatment for HCVInterferon
and Ribavirin in Combination
Estimated sustained response rates at 6 and 12
months in .
Brouwer, Johannes ULDH 1997
23
Hemoglobin Levels in a Meta-Analysis of
Interferon Ribavirin, Alone Combination
Control
Interferon
Ribavirin
Hb mmol/L (mean)
IFN-Riba Combination
0 4 8 12 16 20 24 28
Weeks
Brouwer, Johannes ULDH 1997
24
A Preliminary Canadian Study With IFN-Ribavirin
Therapy

• 41 Chronic HCV patients in study
• 11 were IFN relapsers
• at 3 month follow-up all 11 relapsers had normal
  ALTs with 5 of 5 tested having negative HCV-RNA
• at 6 months, 6 of 6 patients maintained response
• 30 were IFN non-responders
• at 3 month follow-up 10 of 23 non-responders had
  normal ALTs
• Side effects minimal - only 2 patients dropped out

Bailey,B 1997
Bailey, Robert ULDH 1997
25
What is the Ideal Dose and Duration of IFN
Treatment for Chronic HCV?

• Phase I Induction
• lasts 3-4 months
• uncontrollables successful results depend upon
  HCV viral load, genotype, quasispecies emergence
• controllables IFN dose and schedule
• Phase II Consolidation
• length depends upon IFN schedule
• irradication or suppression of the virus
• Phase III Post-treatment
• lasts for years, time of possible relapse and
  retreatment

Alberti,A 1997
26
What is the Ideal Dose and Duration of IFN
Treatment for Chronic HCV?

• Tailored monotherapy
• dose and duration of IFN are tailored to
  individual patients
• patients with baseline characteristics suggesting
  less favorable outcome may require higher doses
  or prolonged treatment duration
• The benefits of prolonged treatment and higher
  dose during the induction phase is apparent in
  Albertis randomized trial
• a 12 month regimen is superior to a 6 month
  regimen
• an induction dose of 6 MU tiw is superior to 3 MU
  tiw

Alberti,A 1997
27
Long-term Response to Different Schedules of
Interferon Therapy in Chronic Hepatitis C
plt0.01
Response Rate ()
plt0.01
ALT Response HCV-RNA Sustained End of
Therapy Response Response (48 mos)
Alberti, Alfredo ULDH 1997
28
Meta-Analysis of Interferon Therapy for Chronic
Hepatitis C
Sustained ALT Response
plt0.001
plt0.001
Response Rate ()
3 MU, 3 MU, 5-6 MU, 5-6 MU, 6 mos 12-18 mos 6
mos 12 mos
Alberti, Alfredo ULDH 1997
29
Lee,S ULDH 1997
30
Overview of the Epidemiology of Hepatitis B

• Incidence has peeked in U.S. and is now falling
• Sharp decline in cases among homosexual men
• Increasing proportion among heterosexuals and IV
  drug users
• Chronicity after contracting acute HBV is 3-5
• higher rate in immunocompromised patients
• higher rate in those who acquired HBV in
  perinatal period or early childhood

Seef, L ULDH 1997
31
Overview of the Epidemiology of Hepatitis B
Estimated Incidence of Acute Hepatitis B United
States, 1978-1993
Decline among homosexual men
Hepatitis B vaccine introduced
Cases per 1,000,000
Decline among injecting drug users
Year of Report
Seeff, Leonard ULDH 1997
32
Risk Factors Associated with Acute Cases of
Hepatitis B U.S., 1992-1993
Unknown
Other
Health care employment
Household contacts
Drug abuse
Heterosexual exposure
Homosexual activity
Seeff, Leonard ULDH 1997
33
Overview of the Epidemiology and Treatment of
Chronic Hepatitis B

• Once carrier state has developed serious sequelae
  are common
• patients who are HBsAg and HBeAg
• annual rate of progression to cirrhosis is 12.1
• progression to HCC occurs in 0.5 annually
• Alpha interferon is the only licenced treatment
  for HBV
• new therapies include lamivudine, famciclovir
  and penciclovir, as well as new nucleotide
  analogues combined with interferon

Seef, L ULDH 1997
34
Reports of Acute Hepatitis B in Canada, 1992-1995
Rate (per 100,000 population)
Gully, Paul ULDH 1997
35
The Problem of Precore Mutants

• Chronic hepatitis B patient who is HBeAg-,
  HBV-DNA
• Patients are more resistant to therapy with
  antiviral agents such as IFN
• Tend to be older, with a longer duration of
  disease, and a higher rate of cirrhosis
• Aggressive regimen of IFN recommended
• start with 5-6 MU tiw for 6 months
• stop therapy in non-responders
• continue 6 more months in responders
• Treatment might be improved with IFN lamivudine

Alberti, ULDH 1997
36
Update on Hepatocellular Carcinoma

• Often multifocal and incurable at presentation
• Large symptomatic tumours give life expectancy of
  less than 1 year
• Among cirrhotic patients 20 will develop HCC
  over 5 years
• 1 million new cases arise worldwide each year
• Screening programs are not recommended
• no program has been shown to reduce mortality
• screening tests are neither sensitive nor
  specific
• target population is not clearly defined