Michael P. Manns

Markus CornbergMedizinische Hochschule Hannover

Dept. of Gastroenterology, Hepatology and Endocrinology

Germany

Hepatitis C:Hepatitis C:Therapeutic optionsTherapeutic options

PUBLIC HEALTH CHALLENGES FOR PUBLIC HEALTH CHALLENGES FOR CONTROLLING HCV INFECTIONCONTROLLING HCV INFECTION

VHPB Meeting, Ferney Voltaire, FranceVHPB Meeting, Ferney Voltaire, FranceMay 13 - 14, 2002May 13 - 14, 2002

PEG-IFN & Ribavirin 48 weeks

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996 1998

IFN 24 weeks

IFN 48 weeks

2002

IFN & Ribavirin 48 weeks

PEG-IFN 48 weeks

Su

s ta

ined

re

sp

on

se

(%)

Future therapies ?

Therapy of chronic hepatitis CTherapy of chronic hepatitis C

The PEG MoleculeThe PEG Molecule

IFN- conjugated to a

40kD (PEG-2a) or

12kD (PEG-2b)

polyethylenglycol polymer

HCVRNA

IFN

Mo. Di. Mi. Do. Fr. Sa. So.

HCVRNA

PEG-IFN

Mo. Di. Mi. Do. Fr. Sa. So.

Comparison of Pharmacokinetic Profiles:Comparison of Pharmacokinetic Profiles:PEG-IFN alfa vs. IFN alfaPEG-IFN alfa vs. IFN alfa

47% 47%

54%

0%

20%

40%

60%

IFN + RBV 0,5 PEG-IFN + RBV 1,5 PEG-IFN + RBV

45%

30%

56%

0%

20%

40%

60%

IFN + RBV PEG-IFN + P PEG-IFN + RBV

Fried et al., DDW 2001

Manns et al., Lancet 2001

Sustained ResponseSustained ResponsePEG-IFN alfa-2b/RBVPEG-IFN alfa-2b/RBV

Sustained ResponseSustained ResponsePEG-IFN alfa-2a/RBVPEG-IFN alfa-2a/RBV

0.8 g RBV1/1.2 g RBV

n = 224

n = 514 n = 511 n = 505

n = 444 n = 453

33%

42%

0%

20%

40%

60%

IFN + RBV 1,5 µg PEG-IFN + RBV

37%

46%

0%

20%

40%

60%

IFN + RBV 180 µg PEG-IFN + RBV

Fried et al., DDW 2001

Manns et al., Lancet 2001

Sustained ResponseSustained ResponsePEG-IFN alfa-2b/RBVPEG-IFN alfa-2b/RBV

Sustained ResponseSustained ResponsePEG-IFN alfa-2a/RBVPEG-IFN alfa-2a/RBV

Genotype 1

Genotype 1

+ 9%

+ 9%

Optimizing Response RatesOptimizing Response Rates

• Body weight adjusted dosing

• Treatment duration

• 80/80/80

• New adjuncts (amantadine)

Sustained Virologic ResponseSustained Virologic ResponseOptimal ribavirin Dosing (retrospective) Optimal ribavirin Dosing (retrospective)

88%80%Genotype 2/3

48%34%Genotype 1

IFN alfa-2b 3MU Peg IFN alfa-2b 1.5

61%47%Overall

Optimal ribavirin >10.6 mg/kg

Manns et al., Lancet 2001

ConclusionConclusionOptimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kgOptimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kg

<65 kg 800 mg/day

65-85 kg 1000 mg/day

>85 kg 1200 mg/day

Patient Weight ribavirin Dose

Prospective analyses are needed

Optimizing Response RatesOptimizing Response Rates

• Body weight adjusted dosing

• Treatment duration

• 80/80/80

• New adjuncts (amantadine)

HCV- Genotype 1/4 HCV- Genotype 2/3

HCV-RNA < 0.8 x 106 IE/ml

HCV-RNA < 0.8 x 106 IE/ml

HCV-RNA > 0.8 x 106 IE/ml

HCV-RNA > 0.8 x 106 IE/ml

24 weeks 48 weeks 24 weeks 24 weeks

EASL Consensus EASL Consensus 19991999

180 µg PEG-IFN alfa-2a + 800 mg RBV

180 µg PEG-IFN alfa-2a + 1000/1200 mg RBV

180 µg PEG-IFN alfa-2a + 800 mg RBV

180 µg PEG-IFN alfa-2a + 1000/1200 mg RBV

PEG-IFN alfa-2a and Ribavirin (n=1284)PEG-IFN alfa-2a and Ribavirin (n=1284)

Hadziyannis et al., EASL 2002

24 weeks

24 weeks

48 weeks

48 weeks

N=207

N=280

N=361

N=436

29%

41% 40%

51%

0%

20%

40%

60%

PEG+0,8RBV

PEG+0,8RBV

PEG+1/1,2RBV

PEG+1/1,2RBV

24 weeks 48 weeks

Hadziyannis et al., EASL 2002

PEG-IFN alfa-2a and Ribavirin PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype 1SVR Results HCV-Genotype 1

41%

51% 53%

61%

0%

20%

40%

60%

80%

PEG+0,8RBV

PEG+0,8RBV

PEG+1/1,2RBV

PEG+1/1,2RBV

24 weeks 48 weeks

Hadziyannis et al., EASL 2002

PEG-IFN alfa-2a and Ribavirin PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype 1 and low viral SVR Results HCV-Genotype 1 and low viral

loadload

78% 78%73%

77%

0%

20%

40%

60%

80%

100%

PEG+0,8RBV

PEG+0,8RBV

PEG+1/1,2RBV

PEG+1/1,2RBV

24 weeks 48 weeks

PEG-IFN alfa-2a and Ribavirin PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype NON-SVR Results HCV-Genotype NON-

11Hadziyannis et al., EASL 2002

Conclusion Conclusion (Ribavirin dosing / Treatment duration)(Ribavirin dosing / Treatment duration)

• Patients with HCV-Genotype-1:48 weeks therapy with optimal (high) ribavirin dosing independent of viral load

• Patients with HCV-Genotype-2/3: 24 weeks therapyhigh ribavirin dosing seems not to be necessary

What is the impact of What is the impact of adherence to therapy adherence to therapy

on SVR?on SVR?

Patient CategoriesPatient Categories

80/80/80 Group• > 80% interferon• > 80% ribavirin• > 80% expected duration therapy

< 80 ± < 80 + > 80 Group• < 80% interferon and/or• < 80% ribavirin and/or• > 80% expected duration therapy • Early discontinuations excluded

All Patients - PEG IFN 1.5 µg/kg + ribavirinAll Patients - PEG IFN 1.5 µg/kg + ribavirin

Su

sta

ined

vir

olo

gic

re

spo

ns

e (%

)

p = 0.04

0

20

40

60

80

100

ITT 80/80/80(305)

<80±80+>80(118)

54%54%

63%63%

52%52%

N=511 N=305 N=118

Manns et al., Lancet 2001McHutchison et al, EASL 2001

Conclusions 80/80/80Conclusions 80/80/80

• Patients who can be maintained on > 80% of PEG interferon and ribavirin for the proposed duration of therapy may have an enhanced sustained response rate

• Every effort should be made to continue the maximum tolerable doses of therapy for the duration of treatment

Optimizing Response RatesOptimizing Response Rates

• Body weight adjusted dosing

• Treatment duration

• 80/80/80

• New adjuncts (amantadine)

Other Combination AdjunctsOther Combination Adjuncts

Ribavirin Amantadine Rimantadine NSAIDs N-acetyl-cysteine Vitamin E Antibiotics

Corticosteroid priming Ursodeoxycholic acid Pentoxifylline Thymosin alpha Phlebotomy Extra-corporeal

photophoresis Mycophenolate Maxamine

0

20

40

60

Italian nonresponder pilot study: Italian nonresponder pilot study: IFN & Ribavirin & amantadine: IFN & Ribavirin & amantadine:

Brillanti et al., Hepatology 2000

pat

ien

ts (

%)

5 MU IFN tiw800-1000mg Riba

200mg Amantadine

5 MU IFN tiw800-1000mg Riba

n=40n=20

10%5%

HCV-RNA negative

ALT normal57%

48%

Berg et al., AASLD 2001, GASL 2002, EASL 2002

German multicenter study (400 naive patients)German multicenter study (400 naive patients)

9 MU IFN alfa-2a qd

2 weeks

1000/1200 mg Ribavirin

200 mg Amantadine / Placebo

6 MU IFN alfa-2a qd

6 weeks

6 MU IFN alfa-2a tiw

16 weeks

3 MU IFN alfa-2a tiw

24 weeks

Su

sta

ined

Re

sp

on

se

P=0,05552%

43%

0%

20%

40%

60%

IFN, RBV, Amantadine IFN, RBV, Placebo

N=200 N=200

Optimize treatment algorithmOptimize treatment algorithm

• Optimum duration to determine

treatment response

PEG-IFN PEG-IFN -2a -2a in Combination Therapy: in Combination Therapy: Predictability / Compliance AnalysisPredictability / Compliance Analysis

n = 390 (86%)

n = 63(14%)

2 log10 dropor neg HCV RNA

Yes

No

Week 12 (N = 453)n = 253(65%)

SVR

n = 137 (35%)

No SVR

n = 2(3%)

SVR

n = 61 (97%)

No SVR

Fried MW et al. DDW 2001

Week *12 HCVRNA not available in 14 patients McHutchison et al, EASL, 2002

discontinueRNA (+) < 2 log drop

n=31

Assess fibrosis F2/F3/F4: consider maintenance

n=188*

12 wks RNA (-)

n=120

Continue for 48 wksSVR = 90%

108/120

PCR (+) SVR = 0%0/17RNA (+) 2 log drop

n=23

Loss of SVR =26%

24wks

PCR (-)

Continue to 48 wks

SVR =100%6/6

Proposed treatment algorithm Proposed treatment algorithm

PEG-IFN alfa-2b study

Other patient groupsOther patient groups

• Patients with acute HCV Infection

• Nonresponder patients

• Patients after liver transplantation

Acute HCV-Infection

Recovery Chronic infection

(PEG)-Interferon alfaRibavirin

10-50% 50-90%

Is a prevention of the chronic course possible ?

NEJM November 15, 2001; 345: 1452-1457

Treatment of Acute Hepatitis C with Interferon Alfa-2b

Elmar Jaeckel, M.D., Markus Cornberg, M.D., Heiner Wedemeyer, M.D., Teresa Santantonio, M.D., Julika Mayer, M.D., Myrga Zankel, D.V.M., Giuseppe Pastore, M.D., Manfred Dietrich, M.D., Christian Trautwein,

M.D., Michael P. Manns, M.D., and the German Acute Hepatitis C Therapy Group

Schedule Schedule

Induction Therapy Follow-up

Week 1-4 Week 5-24 Week 25-48

5 MU daily Interferon alfa-2b

5 MU tiw Interferon alfa-2b

Jaeckel, et al., NEJM 2001

Therapy within 4 months after infection

44 Patienten in24 Behandlungszentren

Patients

Virological Response during therapyVirological Response during therapy

Jaeckel, Cornberg, Wedemeyer et al., NEJM 2001

0%

20%

40%

60%

80%

100%

0 4 8 12 16 20 24weeks

HC

V-R

NA

neg

ati

ve

48=F24

98%

therapy n=44

Santantonio et al. (Bari, Italy)

natural course n=40

30%

Wedemeyer et al., 1998

Summary of 23 publications34,5%

7,4%

0

10

20

30

40

50

ETR SRSus

tain

ed R

espo

nse

(%

)

Re-therapy in IFN - nonresponder patients Re-therapy in IFN - nonresponder patients with IFN/Ribavirinwith IFN/Ribavirin

HCV therapies - new strategiesHCV therapies - new strategies

• Daily dosing

• Induction dosing

• New adjuncts (amantadine)

• New interferons (CIFN, PEG-IFN)

Hannover-Study: SCHEDULEHannover-Study: SCHEDULE

Follow-up 24 weeks

0 weeks 8 weeks 24 weeks 48 weeks

18 µg Inferax daily1. – 8. wk

B

A

9 µg Consensus Interferon (Inferax) daily1. – 48. weeks

1.000/1.200 mg Ribavirin Meduna daily

9 µg Inferax daily9. – 48. weeks

1.000/1.200 mg Ribavirin weeks

71,4%

57,9%

0%

20%

40%

60%

80%

ETR SR

Group A (n=21)

Group B (n=19)

VIROLOGICAL response (intent to treat)VIROLOGICAL response (intent to treat)40 Nonreponder patients (>90% HCV-G-1)40 Nonreponder patients (>90% HCV-G-1)

65%

Chronic Hepatitis C - Nonreponder Patients:Chronic Hepatitis C - Nonreponder Patients:Therapeutic goalsTherapeutic goals

• Viral clearance

• Histological response

• Prevention of HCC

Nishiguchi, Lancet 1995, 2001

Incidence of HCC in patients with chronic Incidence of HCC in patients with chronic hepatitis C: Relevance of IFNhepatitis C: Relevance of IFN

Follow up [years]

Cu

mu

lati

ve In

cid

enc

e o

f H

CC

[%

]

1 2 3 4 5 6 7

10

20

30

40

50

Interferon alpha

Control

0 1 2 3 4 5

3

6

9

12

15NR (6 mo IFN)

Untreated

PR (12 mo IFN)

PR (24 mo IFN)

SR

Years after inclusion

% Cumulative Incidence of HCC% Cumulative Incidence of HCC

NR = Non Responders

PR = Partial Responders (ALT < x 2.5 n.v.)

SR = Sustained Response

882 patients with F3 / F4

Alberti, 2000

PEG-IFN PEG-IFN 2a therapy: naive patients2a therapy: naive patients

histological response (HAI-Score reduction >2)

Peg-IFN 180µg 1x/week 48 week (n=228)

IFN 3MU 3x/week 48 week (n=202)

Heathcote et al., 2000

0%

20%

40%

60%

80%

all PatientsPatients with SR

Partially Responder Nonresponder

Pa

tie

nts

57%

41%

83%79%

44% 43%47%

30%

p=0.06

p=0.001

PEG-IFN & Ribavirin in Nonresponder PEG-IFN & Ribavirin in Nonresponder HALT-C-Study (NIH)HALT-C-Study (NIH)

146 Nonresponder

59/138 Response (ITT 40,1%)

79 Nonresponder

20 weeks Peg-IFN alfa-2a + Ribavirin

8 drop outs

PEG-IFN Mono (HALT-C)

PEG-IFN + RBV48 Wochen

AASLD 2001: Shiffman et al.

Anti-fibrotic effect of IFN alfa Inhibition of collagen synthesis in cell culture and in vivo

Clinical Experience• Histological improvement with IFN-based therapy

in responders and non responders• Fibrosis regression in subjects on maintenance

IFN compared with subjects who stop IFN• Decrease in development of HCC and/or decrease

in mortality rate in all studies

Prevention of Progression of FibrosisPrevention of Progression of Fibrosis

Liver transplantationLiver transplantation

• Ribavirin leads to anemia and accumulation of iron

• Significant side effects of IFN/RBV

• Reported sustained response rates differ between different centers

• No data on long-term benefit are available

multicenter trials

Problems of the combination therapyProblems of the combination therapy

Therapy of HCV-Reinfection with Therapy of HCV-Reinfection with Interferon with or without RibavirinInterferon with or without Ribavirin

IFN IFN+RibaPatients n=43 n=21Biochemical Response ca. 20% 100%Viral elimination (PCR-neg. ETR) 0% 48%Histological Response ca. 5% 100%Rejection episodes ca. 15% 0%

Wright et al 1992, 1994, Feray et al 1995, Bizollon et al 1997

Liver transplantationLiver transplantation

• Deciding the best immunosuppression regimen

More importantMore important

rejectionrejectionDisease Disease

progressionprogression

SummarySummary

Naive patientswith elevated ALT and fibrosisHCV-Genotype-1

HCV-Genotype-2/3

PEG-IFN 48 weeks and high ribavirin (>10,6mg ribavirin/kg)PEG-IFN 24 weeks and (800mg) ribavirin

Acute Hepatitis C 5MU IFN qd 4 wk, 5MU IFN tiw 20 wkor PEG-IFN oiw 24 wk (ongoing study)

NonresponderNo fibrosisfibrosisadvanced fibrosis/cirrhosis

no treatmentStudies (PEG-IFN, CIFN, etc.)Studies (long-term IFN)

Liver transplantation Multicenter trials