History of Alpha Interferon Therapy of Chronic Hepatitis C Paris Hepatitis Conference: 2012 Jay H....
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Transcript of History of Alpha Interferon Therapy of Chronic Hepatitis C Paris Hepatitis Conference: 2012 Jay H....
History of Alpha Interferon Therapy of Chronic Hepatitis C
Paris Hepatitis Conference: 2012
Jay H. Hoofnagle, M.D.Director,
Liver Disease Research BranchNational Institutes of HealthBethesda, Maryland, USA
Hepatitis C 1980s
• 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
• 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
• 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
050
100150200250300350400450500
-6 -3 0 1 2 3 4 5 6 7 8 9 10 11 12 18 24
AL
T (
U/L
)
Time After Starting Therapy
Interferon 5 → 1 MU/day
Normal
Interferon alfa for Chronic Non-A, Non-B Hepatitis
Months
Interferon 5 MU/d
HAI/Fibrosis
Pre = 10/1
Yr 1 = 3/0
Interferon for Hepatitis C
• First use of interferon alfa in chronic 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
0%
20%
40%
60%
80%
100%
Davis et al Di Bisceglie et al
Nor
mal
AL
T o
n T
her
apy
48%
n = 166 n = 51
46%
28%
10%8%
3 MU
1 MU
2 MU
PlaceboControl
1 to 3 mu three times weekly for 6 months
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 20th century
050
100150200250300350400450500
-6 -3 0 1 2 3 4 5 6 7 8 10 12 18 24 36
AL
T (
U/L
)
HCV RNA
Time After Starting Therapy
Interferon-α
+ + - - -- -
Normal
Interferon alfa for Chronic Non-A, Non-B Hepatitis
Months
-Interferon-α
HAI/Fibrosis
Pre = 10/1
Yr 1 = 3/0
Genotype 1a
-
Shindo et al 1991
Interferon-alfa 2b Approved for use in the United States: 1991
• 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 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
HCV RNA
Time After Starting Therapy
Interferon
+ + - - -- -
Normal
Interferon alfa for Chronic Non-A, Non-B Hepatitis
Months Years
-Interferon
HAI/Fibrosis
Pre = 10/1
Yr 1 = 3/0
Yr 10 = 3/0
Genotype 1a
-
050
100150200250300350400450500
-6 -3 0 1 2 3 4 5 6 7 8 10 12 18 2 3 4 6 11 20
AL
T (
U/L
)
-
Long Term Outcome after SVR
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
At 7.2 years, the relapse free rate was 96%
103 81 44 9 7 3
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
0%
10%
20%
30%
40%
50%
6 months 12 months
Per
cen
t S
ust
ain
ed R
esp
onse
End-TreatmentSustained
24%
6%
13%
n = 231 n = 225
29%
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
0%
10%
20%
30%
40%
50%
60%
70%
80%
McHutchison Poynard
SV
R R
ate 43%
n = 912 n = 832
38%31%
13%
35%
IFN & Rbv
12 mo
IFN12 mo
IFN & Rbv
12 mo
IFN 12 mo
NEJM 1998 Lancet 1998
19%IFN & Rbv6 mo
IFN & Rbv6 mo
Peginterferon Further Increases the Response Rate in Chronic Hepatitis C
0%
10%
20%
30%
40%
50%
60%
70%
80%
Fried Manns
SV
R
54%
n = 1121 n = 1530
56%
44%
13%
47%
Peg & Rbv
12 mo IFN & Rbv
12 mo
Peg & Rbv
12 mo IFN & Rbv
12 mo
NEJM 2002 Lancet 2001
alfa-2a alfa-2b
0%
20%
40%
60%
80%
100%
IFN IFN IFN/R IFN/R PegIFN/R
Su
stai
ned
Res
pon
se
16%
55%
6%
Progress in Therapy of Hepatitis C: 1991-2002
34%42%
6 mo 12 mo 6 mo 12 mo 12 mo
1991
1995
1998
2002
0%
20%
40%
60%
80%
100%
IFN IFN IFN/R IFN/R PegIFN/R PegIFN/R
Su
stai
ned
Res
pon
se
16%
55%
6%
Lack of Progress in Therapy of Hepatitis C2002-2010
34%42%
6 mo 12 mo 6 mo 12 mo 12 mo
1991
1995
1998
2002
55%
2010
6-12 mo
Therapy of Hepatitis CFactors 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
0%
20%
40%
60%
80%
100%
Peg alfa-2a & Rbv Peg alfa-2b & Rbv
SV
R R
ate
Genotype 1 Genotype 2-3
82%
46% 42%
n = 453 n = 511
76%
Manns et al
2001
Fried et al
2002
Chronic Hepatitis C:Sustained Response Rates by Race
28%
52%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
AfricanAmericans
CaucasianAmericans
ETR
SVR
Res
po
nse
Rat
e
n = 196 205
40%
70%
Virahep-C: Conjeevaram
2006
Genotype 1 only
HCV Advance of the Year: 2009
• “Genetic variation in IL28B predicts hepatitis C 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
Genome wide view of p values of SNPsassociated with a sustained virological response
to peginterferon and ribarivin treatment of chronic hepatitis C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 20 X 15 17 19 21 Y
-30
-15
0
Ge et al Nature 2009
SVR rates by rs12979860 genotype
42%
19%24%
17%
81%
53%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
European-American African-American
C/C
C/T
T/T
Res
po
nse
Rat
e
Ge Nature: 2009
Thomas Nature : 2009
C allele: 68% C allele: 36%
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 (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
Two HCV Protease Inhibitors Efficacy in Chronic Hepatitis C, genotype 1
0%
20%
40%
60%
80%
100%
Poordad Jacobson
SV
R
75%
n = 938 n = 1088
68% 67%
40%
69%
44%
T12 wk Peg & Rbv
T8 wk Peg & Rbv
Peg & Rbv
12 mo
Boc Peg & Rbv
Boc Peg & Rbv[TG] Peg &
Rbv12 mo
Boceprevir NEJM 2011
TelaprevirNEJM 2011
2012 and A Vision of the Future
• The combination of two Direct Acting Agents with 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
0%
20%
40%
60%
80%
100%
IFN IFN IFN/R PegIFN/R P/R/PI P/R/DAAs
Su
stai
ned
Res
pon
se R
ate
16%
55%
6%
Progress in Therapy of Hepatitis C
42%
6 mo 12 mo 6-12 mo 6-12 mo 3-6 mo
1991
1995
1998
2002
2011
2014 ?
6-12 mo
75%
>95%
New Therapy for a Chronic Liver Disease
0
50
100
150
200
250
0 2 4 8 12 16 24 40 48 56 64 72 80 88 96 120
AL
T/A
ST (U
/L)
Weeks after Start of Therapy
AST
ALT
Drug
Histology ScorePre: 6 / 0 96 wks: 2 / 0
199
22
60
2426
5927
140
Vitamin E for NASH: PIVENS
0
50
100
150
200
250
0 2 4 8 12 16 24 40 48 56 64 72 80 88 96 120
AL
T/A
ST (U
/L)
or W
eigh
t (k
g)
Weeks after Start of Therapy
ALT
AST
Weight
Vitamin E (800 IU/day)
Patient 6098NAS ScorePre: 6 / 0 96 wks: 2 / 0
199
22
60
24
[3 wk]
26
5927
140
1 kg weight loss
Sanyal et al NEJM 2010
Lessons from the History of Interferon Therapy of Hepatitis C?
• 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