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