Transcript Virahep-C Design Issues

History of Alpha Interferon Therapy of
Chronic Hepatitis C
Paris Hepatitis Conference: 2012
Jay H. Hoofnagle, M.D.
Director,
Liver Disease Research Branch
National Institutes of Health
Bethesda, Maryland, USA
Hepatitis C 1980s
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A disease with no name: non-A, non-B hepatitis
Virus was unknown and no serological markers
Diagnosis based on serum ALT levels, liver
biopsy and compatible history (risk factors)
Despite this, trials of therapy were done
Corticosteroids: 1980-82: harmful (ISVHLD 1983)
Acyclovir: 1982-84: no effect (J Med Virol 1985)
Recombinant interferon alfa developed and
evaluated as cancer chemotherapy
Paris: January 2012
Rationale for Alpha Interferon
Therapy of Chronic Hepatitis C
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Broad spectrum of antiviral activity
Activity in vitro against almost all viruses, both
DNA and RNA
Activity in humans against both HBV and HDV
4 month course induced remissions in disease in
30-40% of patients with chronic hepatitis B
Side effects, effective dose and duration of
therapy reasonably established in hepatitis B
Pilot Trial of interferon alfa-2b in
Chronic Non-A, Non-B Hepatitis
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IRB approved protocol to treat 10 patients: 1982
Well defined non-A, non-B hepatitis with
• Clear risk factors for infection
• ALT levels persistently > 200 U/L
• Liver biopsy showing chronic hepatitis
Planned Regimen: 5 MU daily for 4 months
End points: Change in ALT levels, liver histology
Sought industry sponsorship from 3 companies
receiving approval from Schering-Plough: 1984
ALT (U/L)
Interferon alfa for Chronic Non-A, Non-B Hepatitis
500
450
400
350
300
250
200
150
100
50
0
Interferon 5 → 1 MU/day
Interferon 5 MU/d
HAI/Fibrosis
Pre = 10/1
Yr 1 = 3/0
Normal
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-3
0
1
2
3
4
5
6
7
8
9
10 11 12
Months
Time After Starting Therapy
18 24
Interferon for Hepatitis C
• First use of interferon alfa in chronic
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non-A, non-B hepatitis: 1984-86
Ten patients with clear epidemiological
evidence for non-A, non-B hepatitis
All had stable and persistent elevations
in serum ALT for 6 months or more
ALT levels fell to normal in 8 and
remained normal after therapy in 5.
Two Randomized Controlled Trials of Alpha
Interferon for Chronic Non-A, Non-B Hepatitis
Normal ALT on Therapy
100%
1 to 3 mu three
times weekly
for 6 months
80%
60%
46%
48%
40%
3 MU 28%
20%
2 MU
1 MU 8%
Control
10%
Placebo
0%
Davis et al
n = 166
Di Bisceglie et al
n = 51
New England Journal of Medicine 1989
Hepatitis C Virus Discovered! 1989
• Identification of a small viral RNA sequence in
serum of chimpanzee with experimental non-A,
non-B hepatitis (Houghton et al 1989)
• Allowed for development of tests for anti-HCV
• Rapidly introduced into blood donor screening
• Allowed for accurate diagnosis
• Led to elucidation of the structure of HCV
• Tests for viral RNA in serum (PCR)
• A landmark medical advance of 20
th
century
Interferon alfa for Chronic Non-A, Non-B Hepatitis
ALT (U/L)
HCV 500
RNA 450
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- +
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Interferon-α
400
350
300
250
200
150
100
50
0
- - - - -
Interferon-α
HAI/Fibrosis
Pre = 10/1
Yr 1 = 3/0
Normal
-6
-3
0
1
2
3
4
5
6
7
8
10
Months
Genotype 1a
Time After Starting Therapy
12
18
24
36
Shindo et al 1991
Interferon-alfa 2b Approved for
use in the United States: 1991
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Based upon results of two registration trials
in the United States: 3 parts to response
• Biochemical: normalization ALT
• Histological: improvement in HAI
• Virological: loss of HCV RNA
Sustained (for how long and in how many?)
Interferon Therapy of Chronic
Hepatitis C: Long-term Outcome
• In long-term follow up, most patients with a
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sustained virological response demonstrate
resolution of disease and gradual improvement in
liver histology
Underlying liver disease does not progress
Fibrosis resolves in a proportion of patients
HCC can occur, but is rare
“Cure” of the infection and chronic liver disease
1985, Pre: HAI = 11
1996, Post: HAI = 3
1985, Pre: Fibrosis = 3+
1996, Post: Fibrosis = 0
Interferon alfa for Chronic Non-A, Non-B Hepatitis
ALT (U/L)
HCV 500
RNA 450
400
350
300
250
200
150
100
50
0
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-
+
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Interferon
- - - - - -
Interferon
HAI/Fibrosis
Pre = 10/1
Yr 1 = 3/0
Yr 10 = 3/0
Normal
-6 -3
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1
2
3
4
5
6
7
8 10 12 18 2
3
Months
Genotype 1a
Time After Starting Therapy
4
6 11 20
Years
Long Term Outcome after SVR
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Of the first 103 patients who achieved an SVR at
the Clinical Center, NIH:
 All except three remained HCV RNA negative
 No patient died of end-stage liver disease
 One patient (with cirrhosis) developed HCC
Patients had no symptoms/signs of liver disease
Laboratory results improved: [baseline vs last]
 ALT:
152 vs 27 U/L
 AST:
86 vs 24 U/L
 Platelets: 208,000 vs 239,000 /μL
 APRI:
1.31 vs 0.33
Koh et al: 2010
Life Table of Relapse
103
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44
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7
3
At 7.2 years, the relapse free rate was 96%
Outcomes of Therapy of
Hepatitis C
• Sustained Virological Response (SVR)
• Absence of HCV RNA from serum 24 weeks
after stopping therapy
• End-of-Treatment Virological Response
with Relapse (Relapse)
• Virological Non-Response (NR)
NIH Consensus Conference: 1997
Speakers: NIH Consensus Conference on Hepatitis C: 1997
Sustained Virological Response Rates Induced by Alpha
Interferon Alone (3 MU thrice weekly) Were Quite Poor
End-Treatment
Sustained
Percent Sustained Response
50%
40%
30%
29%
20%
10%
24%
13%
6%
0%
6 months
12 months
n = 231
n = 225
McHutchison et al 1998
Ribavirin for Chronic
Hepatitis C: Rationale
• A broad spectrum antiviral agent with activity
against flaviviruses (RSV, Hantavirus)
• HCV was found to be a flavivirus
• Pilot studies of monotherapy were initiated
• Improved ALT levels in ~50%
• Had little effect on HCV RNA levels
• Possibility that the combination of ribavirin
and interferon might be beneficial
Ribavirin Markedly Increases the Response
Rate to Alpha Interferon in Chronic Hepatitis C
80%
70%
SVR Rate
60%
NEJM 1998
Lancet 1998
50%
40%
30%
20%
43%
38%
31%
IFN &
Rbv
12 mo
IFN &
Rbv
6 mo
10%
IFN &
Rbv
12 mo
13%
35%
IFN &
Rbv
6 mo
19%
IFN
12 mo
IFN
12 mo
0%
McHutchison
Poynard
n = 912
n = 832
Peginterferon Further Increases the Response
Rate in Chronic Hepatitis C
80%
NEJM 2002
Lancet 2001
70%
60%
56%
SVR
50%
40%
30%
20%
54%
44%
Peg &
Rbv
12 mo
IFN &
Rbv
13%
12 mo
47%
Peg &
Rbv
12 mo
IFN &
Rbv
12 mo
10%
0%
Fried
Manns
n = 1121
n = 1530
alfa-2a
alfa-2b
Progress in Therapy of Hepatitis C:
1991-2002
100%
Sustained Response
80%
2002
55%
1998
60%
42%
1995
40%
1991
20%
34%
16%
6%
0%
IFN
IFN
IFN/R
IFN/R
6 mo
12 mo
6 mo
12 mo
PegIFN/R
12 mo
Lack of Progress in Therapy of Hepatitis C
2002-2010
100%
Sustained Response
80%
60%
1998
2002
55%
2010
55%
PegIFN/R
PegIFN/R
42%
40%
1995
1991
20%
34%
16%
6%
0%
IFN
IFN
IFN/R
IFN/R
6 mo
12 mo
6 mo
12 mo
12 mo
6-12 mo
Therapy of Hepatitis C
Factors that Correlate with Non-Response
• Genotype 1 vs 2 and 3
• African-American vs Caucasian race
• Higher Initial levels of HCV RNA
• Higher degrees of fibrosis
• Older age
• Other significant co-morbidities
Chronic Hepatitis C:
Sustained Response Rates by Genotype
Genotype 1
Genotype 2-3
100%
SVR Rate
80%
60%
82%
76%
46%
42%
40%
20%
Fried et al
Manns et al
2002
2001
Peg alfa-2a & Rbv
Peg alfa-2b & Rbv
0%
n = 453
n = 511
Chronic Hepatitis C:
Sustained Response Rates by Race
100%
Genotype 1 only
Response Rate
90%
80%
70%
70%
60%
50%
ETR
SVR
40%
40%
30%
52%
20%
28%
10%
0%
n=
African
Americans
Caucasian
Americans
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205
Virahep-C:
Conjeevaram
2006
HCV Advance of the Year: 2009
• “Genetic variation in IL28B predicts hepatitis C
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treatment-induced viral clearance” Nature 2009; 461:
399-401. David Goldstein and 12 colaborators.
GWAS on more than 1600 recipients of peginterferon/
ribavirin therapy of chronic hepatitis C, genotype 1.
Polymorphism on chromosome 19 [rs12979860] was
associated with SVR in all patient groups.
Variants: C/C, C/T, T/T:
Resides 3 kb upstream of IL28B gene [interferon λ-3]
Ge et al: Nature 2009
IL28b
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7 8 9 10 11 12 13 14
16 18 20
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17
X
19 21
-30
-15
0
Genome wide view of p values of SNPs
associated with a sustained virological response
to peginterferon and ribarivin treatment
of chronic hepatitis C
Ge et al Nature 2009
Y
SVR rates by
rs12979860 genotype
100%
Response Rate
90%
81%
80%
70%
60%
50%
C/C
C/T
T/T
53%
42%
40%
30%
24%
20%
19% 17%
10%
0%
European-American
African-American
C allele: 68%
C allele: 36%
Ge Nature: 2009
Thomas Nature : 2009
What is IL28B? Interferon λ-3
• Type III Interferons, discovered in 2003
• Unclear significance
• Separate receptor on cells
• Has similar activity and induces similar
genes as interferon α and β
• Slower, somewhat weaker but more
prolonged effect
• What is its relationship to hepatitis C?
IL28 in Response to HCV Infection
Thomas et al:
Gastroenterology
2012, in press
HCV Advance of the Year: 2010
• Development and licensure of first Direct Acting Agents
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(DAAs) with proven activity against hepatitis C
HCV NS3/4 Protease Inhibitors
Boceprevir
Telaprevir
Promise of other DAAs with activivity against other
HCV specific targets
HCV Polymerase inhibitors
HCV NS5A inhibitors
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Two HCV Protease Inhibitors
Efficacy in Chronic Hepatitis C, genotype 1
100%
SVR
80%
60%
40%
Boceprevir
NEJM 2011
Telaprevir
NEJM 2011
75%
68% 67%
Boc
Peg &
Rbv
Boc
Peg &
Rbv
[TG]
20%
40%
69%
T12 wk
Peg & T8 wk
Rbv Peg &
Rbv
44%
Peg &
Rbv
12 mo
Peg &
Rbv
12 mo
0%
Poordad
Jacobson
n = 938
n = 1088
2012 and A Vision of the Future
• The combination of two Direct Acting Agents with
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peginterferon and ribavirin for 24 weeks
In 10 patients with genotype 1 who had failed to respond
to peginterferon and ribavirin alone
100% SVR rate
The two DAAs alone yielded a 36% SVR rate in 9 similar
patients with genotype 1
Demonstration of success of an interferon-free regimen
Lok et al: NEJM 2012; 366: 216-24
Progress in Therapy of Hepatitis C
2014 ?
>95%
Sustained Response Rate
100%
2011
75%
80%
2002
60%
1998
55%
42%
40%
20%
1991
6%
1995
16%
0%
IFN
IFN
IFN/R
6 mo
12 mo
6-12 mo
PegIFN/R
6-12 mo
P/R/PI
6-12 mo
P/R/DAAs
3-6 mo
New Therapy for a Chronic Liver Disease
250
Drug
199
ALT/AST (U/L)
200
ALT
150
140
100
60
59
50
27
26
AST
0
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2
4
8
22
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12 16 24 40 48 56 64 72 80 88 96 120
Weeks after Start of Therapy
Histology Score
Pre:
6/0
96 wks: 2 / 0
Vitamin E for NASH: PIVENS
Vitamin E (800 IU/day)
ALT/AST (U/L) or Weight (kg)
250
200
199
ALT
150
140
1 kg weight loss
100
Weight
60
50
27
AST
26
0
0
2
[3 wk]
Patient
Sanyal
et al 6098
NEJM 2010
4
8
59
22
24
12 16 24 40 48 56 64 72 80 88 96 120
Weeks after Start of Therapy
NAS Score
Pre:
6/0
96 wks: 2 / 0
Lessons from the History of Interferon
Therapy of Hepatitis C?
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Clinical observation in a small number of
patients can lead to important advances
The interplay between basic and clinical
research ensures and speeds such advances
Ultimately, most liver diseases will be treatable
Some will be preventable
Some curable
Paris: January 2012
Liver Diseases Branch, NIH: 2011