PUBLIC HEALTH CHALLENGES FOR CONTROLLING HCV INFECTION
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Michael P. Manns Markus Cornberg Medizinische Hochschule Hannover Dept. of Gastroenterology, Hepatology and Endocrinology Germany PowerPoint PPT Presentation


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PUBLIC HEALTH CHALLENGES FOR CONTROLLING HCV INFECTION. Hepatitis C: Therapeutic options. Michael P. Manns Markus Cornberg Medizinische Hochschule Hannover Dept. of Gastroenterology, Hepatology and Endocrinology Germany. VHPB Meeting, Ferney Voltaire, France May 13 - 14, 2002.

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Michael P. Manns Markus Cornberg Medizinische Hochschule Hannover Dept. of Gastroenterology, Hepatology and Endocrinology Germany

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Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

PUBLIC HEALTH CHALLENGES FOR CONTROLLING HCV INFECTION

Hepatitis C:

Therapeutic options

Michael P. Manns

Markus Cornberg

Medizinische Hochschule Hannover

Dept. of Gastroenterology, Hepatology and Endocrinology

Germany

VHPB Meeting, Ferney Voltaire, France

May 13 - 14, 2002


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Therapy of chronic hepatitis C

Future therapies ?

80%

60%

PEG-IFN & Ribavirin 48 weeks

IFN & Ribavirin 48 weeks

40%

Sustained response (%)

PEG-IFN 48 weeks

IFN 48 weeks

20%

IFN 24 weeks

0%

1988

1990

1992

1994

1996

1998

2002


The peg molecule

The PEG Molecule

IFN- conjugated to a40kD (PEG-2a) or12kD (PEG-2b)polyethylenglycol polymer


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

HCVRNA

HCVRNA

IFN 

PEG-IFN 

Mo.

Di.

Mi.

Do.

Fr.

Sa.

So.

Mo.

Di.

Mi.

Do.

Fr.

Sa.

So.

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


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Sustained Response

PEG-IFN alfa-2b/RBV

Manns et al., Lancet 2001

n = 511

n = 505

n = 514

1/1.2 g RBV

0.8 g RBV

Sustained Response

PEG-IFN alfa-2a/RBV

Fried et al., DDW 2001

n = 444

n = 224

n = 453


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Sustained Response

PEG-IFN alfa-2b/RBV

Genotype 1

+ 9%

Manns et al., Lancet 2001

Sustained Response

PEG-IFN alfa-2a/RBV

Genotype 1

+ 9%

Fried et al., DDW 2001


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Optimizing Response Rates

  • Body weight adjusted dosing

  • Treatment duration

  • 80/80/80

  • New adjuncts (amantadine)


Sustained virologic response optimal ribavirin dosing retrospective

Sustained Virologic ResponseOptimal ribavirin Dosing (retrospective)

Optimal ribavirin >10.6 mg/kg

IFN alfa-2b 3MU

Peg IFN alfa-2b 1.5

Overall

47%

61%

Genotype 1

34%

48%

Genotype 2/3

80%

88%

Manns et al., Lancet 2001


Conclusion optimum ribavirin dosing with peg ifn alfa2b 1 5 g kg

ConclusionOptimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kg

ribavirin Dose

Patient Weight

<65 kg800 mg/day

65-85 kg1000 mg/day

>85 kg1200 mg/day

Prospective analyses are needed


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Optimizing Response Rates

  • Body weight adjusted dosing

  • Treatment duration

  • 80/80/80

  • New adjuncts (amantadine)


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

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 1999


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

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

Hadziyannis et al., EASL 2002

180 µg PEG-IFN alfa-2a + 800 mg RBV

24 weeks

N=207

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

N=280

24 weeks

180 µg PEG-IFN alfa-2a + 800 mg RBV

N=361

48 weeks

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

48 weeks

N=436


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

PEG-IFN alfa-2a and Ribavirin

SVR Results HCV-Genotype 1

Hadziyannis et al., EASL 2002

48 weeks

24 weeks

PEG+0,8RBV

PEG+1/1,2RBV

PEG+0,8RBV

PEG+1/1,2RBV


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

PEG-IFN alfa-2a and Ribavirin

SVR Results HCV-Genotype 1 and low viral load

Hadziyannis et al., EASL 2002

48 weeks

24 weeks

PEG+0,8RBV

PEG+1/1,2RBV

PEG+0,8RBV

PEG+1/1,2RBV


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

PEG-IFN alfa-2a and Ribavirin

SVR Results HCV-Genotype NON-1

Hadziyannis et al., EASL 2002

48 weeks

24 weeks

PEG+0,8RBV

PEG+1/1,2RBV

PEG+0,8RBV

PEG+1/1,2RBV


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Conclusion (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


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

What is the impact of adherence to therapy on SVR?


Patient categories

Patient 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 g kg ribavirin

p = 0.04

63%

54%

52%

N=305

N=118

N=511

All Patients - PEG IFN 1.5 µg/kg + ribavirin

Manns et al., Lancet 2001

McHutchison et al, EASL 2001

Sustained virologic response (%)


Conclusions 80 80 80

Conclusions 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


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Optimizing Response Rates

  • Body weight adjusted dosing

  • Treatment duration

  • 80/80/80

  • New adjuncts (amantadine)


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Other Combination Adjuncts

  • Corticosteroid priming

  • Ursodeoxycholic acid

  • Pentoxifylline

  • Thymosin alpha

  • Phlebotomy

  • Extra-corporeal photophoresis

  • Mycophenolate

  • Maxamine

  • Ribavirin

  • Amantadine

  • Rimantadine

  • NSAIDs

  • N-acetyl-cysteine

  • Vitamin E

  • Antibiotics


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

60

ALT normal

HCV-RNA negative

40

20

0

Italian nonresponder pilot study: IFN & Ribavirin & amantadine:

57%

48%

n=20

patients (%)

n=40

10%

5%

5 MU IFN tiw800-1000mg Riba200mg Amantadine

5 MU IFN tiw800-1000mg Riba

Brillanti et al., Hepatology 2000


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

60%

52%

P=0,055

43%

40%

Sustained Response

20%

N=200

N=200

0%

IFN, RBV, Amantadine

IFN, RBV, Placebo

German multicenter study (400 naive patients)

9 MU IFN alfa-2a qd

2 weeks

6 MU IFN alfa-2a qd

6 weeks

6 MU IFN alfa-2a tiw

16 weeks

3 MU IFN alfa-2a tiw

24 weeks

1000/1200 mg Ribavirin

200 mg Amantadine / Placebo

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


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Optimize treatment algorithm

  • Optimum duration to determine treatment response


Peg ifn 2a in combination therapy predictability compliance analysis

n = 390 (86%)

n = 63(14%)

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

Week 12 (N = 453)

SVR

n = 253(65%)

Yes

No SVR

n = 137 (35%)

2 log10 dropor neg HCV RNA

SVR

n = 2(3%)

No SVR

No

n = 61 (97%)

Fried MW et al. DDW 2001


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

24wks

Assess fibrosis F2/F3/F4:

consider maintenance

  • RNA (+) < 2 log drop

  • discontinue

  • n=31

SVR = 90%

108/120

12 wks

  • RNA (-)

Continue for 48 wks

  • n=120

  • n=188*

SVR = 0%

0/17

  • PCR (+)

  • RNA (+)  2 log drop

  • PCR (-)

  • n=23

Loss of SVR =26%

SVR =100%

6/6

Continue to 48 wks

Proposed treatment algorithm

PEG-IFN alfa-2b study

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


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Other patient groups

  • Patients with acute HCV Infection

  • Nonresponder patients

  • Patients after liver transplantation


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Is a prevention of the chronic course possible ?

Acute HCV-Infection

10-50%

50-90%

Recovery

Chronic infection

(PEG)-Interferon alfa

Ribavirin


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

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

NEJM November 15, 2001; 345: 1452-1457


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Jaeckel, et al., NEJM 2001

Therapy within 4 months after infection

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

Schedule


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Patients

44 Patienten in

24 Behandlungszentren


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Virological Response during therapy

100%

98%

80%

therapy n=44

60%

natural course n=40

HCV-RNA negative

40%

30%

20%

Santantonio et al. (Bari, Italy)

0%

48=F24

0

4

8

12

16

20

24

weeks

Jaeckel, Cornberg, Wedemeyer et al., NEJM 2001


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

50

Summary of 23 publications

40

34,5%

30

Sustained Response (%)

20

7,4%

10

0

ETR

SR

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

Wedemeyer et al., 1998


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

HCV therapies - new strategies

  • Daily dosing

  • Induction dosing

  • New adjuncts (amantadine)

  • New interferons (CIFN, PEG-IFN)


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

0 weeks

8 weeks

24 weeks

48 weeks

A

9 µg Consensus Interferon (Inferax) daily

1. – 48. weeks

1.000/1.200 mg Ribavirin Meduna daily

B

18 µg Inferax daily

1. – 8. wk

9 µg Inferax daily

9. – 48. weeks

1.000/1.200 mg Ribavirin weeks

Hannover-Study: SCHEDULE

Follow-up 24 weeks


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

VIROLOGICAL response (intent to treat)

40 Nonreponder patients (>90% HCV-G-1)

80%

Group A (n=21)

71,4%

Group B (n=19)

57,9%

60%

40%

65%

20%

0%

ETR

SR


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Chronic Hepatitis C - Nonreponder Patients:

Therapeutic goals

  • Viral clearance

  • Histological response

  • Prevention of HCC


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

50

Control

40

30

Cumulative Incidence of HCC [%]

Interferon alpha

20

10

1

2

3

4

5

6

7

Follow up [years]

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

Nishiguchi, Lancet 1995, 2001


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

% Cumulative Incidence of HCC

882 patients with F3 / F4

NR (6 mo IFN)

NR = Non Responders

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

SR = Sustained Response

15

Untreated

12

9

PR (12 mo IFN)

6

PR (24 mo IFN)

3

SR

0

1

2

3

4

5

Years after inclusion

Alberti, 2000


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

PEG-IFN 2a therapy: naive patients

histological response (HAI-Score reduction >2)

Peg-IFN 180µg 1x/week 48 week (n=228)

83%

79%

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

80%

p=0.001

57%

60%

p=0.06

47%

44%

43%

41%

Patients

40%

30%

20%

0%

Patients with SR

Partially Responder

all Patients

Nonresponder

Heathcote et al., 2000


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

PEG-IFN & Ribavirin in Nonresponder

HALT-C-Study (NIH)

AASLD 2001: Shiffman et al.

146 Nonresponder

20 weeks

Peg-IFN alfa-2a + Ribavirin

8 drop outs

59/138 Response

(ITT 40,1%)

79 Nonresponder

PEG-IFN + RBV

48 Wochen

PEG-IFN Mono (HALT-C)


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Prevention of Progression of Fibrosis

  • 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


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Liver transplantation

Problems of the combination therapy

  • 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


Therapy of hcv reinfection with interferon with or without ribavirin

Therapy of HCV-Reinfection with Interferon with or without Ribavirin

IFNIFN+Riba

Patientsn=43n=21

Biochemical Responseca. 20% 100%

Viral elimination (PCR-neg. ETR)0% 48%

Histological Response ca. 5%100%

Rejection episodesca. 15% 0%

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


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Liver transplantation

More important

  • Deciding the best immunosuppression regimen

rejection

Disease progression


Michael p manns markus cornberg medizinische hochschule hannover dept of gastroenterology hepatology and endocrinolog

Summary


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