Terapia dell’Epatite cronica HCV correlata:

Peg-IFN/ribavirina e che altro?

L’infettivologia del terzo millennio: non solo AIDSPaestum 18-20 maggio 2006

T. Santantonio

Malattie Infettive Università degli Studi di Bari

Milestones in Therapy of Chronic Hepatitis C

Strader et al Hepatology 2004

0

10

20

30

40

50

60

6

16

34

4239

54-56

1986 1998 2001 2002

IFN6m

IFN12m

IFN/RBV6m

IFN/RBV12m

PEG12m

PEG/RBV12m

Su

stai

ned

Vir

olo

gic

Res

po

nse

Sustained Virologica Response according to genotype

0

20

40

60

80

100

PegIFNa2b + RBV PegIFNa2a + RBV

42%

82%

46%

76%

Manns et al Lancet 2001, Fried et al NEJM 2002

Genotype 1 Genotypes 2/3

% S

VR

Virological determinants of treatment outcomeS

ust

ain

ed V

iro

log

ic R

esp

on

se

Difficult to treat

Easy to treat

0

10

20

30

40

50

60

70

80

90

100

HCV-2HCV-1

High viremia

HCV-3

High viremia

HCV-4HCV-1

Low viremia

HCV-3

Low viremia

30%

50%

60%70%

80%

90%

Therapy of HCV - 2006

Whom to treat

All patients are potential candidates

Priority should be for:

• Progressive/advanced disease• Highly motivated patients• Young patients• Easy-to-treat

Exclusions are:• Major contraindications• Decompensated liver disease

Therapy of HCV - 2006

How to treat

HCV-2/3 Peg-IFN/RBV 800-1000 mg x 6 mo

HCV-1/4 Peg-IFN/RBV 1000-1200 mg x 12 mo

Stopping rule for HCV-1 at 12-24 weeks

80/80/80 adherence rule important (particularly for HCV-1)

Attempts to optimize therapy

Some patients might be OVERTREATEDSome patients might be UNDERTREATED

Better Tailoring the Current Therapy

Development of New Therapies

DIFFICULT-TO-TREAT SUBGROUPS

Genotype 2 & 3

Shorter duration ?

• increase tolerability

• lower costs

Better Tailoring the Current Therapy

SVR in Patients HCV-2/3, 14 vs. 24 Weeks PEG-IFN -2b 1.5 g/kg QW + ribavirin 800-1,400 mg/day, N=122

82% 90%

56%

0%

20%

40%

60%

80%

100%

% o

f P

ati

en

ts

Overall, (N=122) PCR Negative at week 4/8,14 weeks Tx., (n=95)

PCR Positive at week 4/8,24 weeks Tx., (n=27)

Dalgard O. et al. Hepatology 2004;40:1260 –1265.

78% of Patients were PCR Negative at Week 4/8.

SVR in HCV-2/3 Patients PCR neg at week 4/8 14 Week Tx.

PEG-IFN -2b 1.5 g/kg QW + ribavirin 800-1,400 mg/day

92%88%

98%

79%

0%

20%

40%

60%

80%

100%

% o

f P

ati

en

ts

HCV 2 < 600 000 IU,

(n=13)

HCV 2 ≥ 600 000 IU,

(n=8)

HCV 3 < 600 000 IU,

(n=40)

HCV 3 ≥ 600 000 IU,

(n=33)

*

* p=0.019, G3a LVL vs HVL.Dalgard O. et al. Hepatology 2004;40:1260 –1265.

PEG-IFN 2b 1.0 g/Kg/week + RIBA 1000-1200 mg/day

STANDARD REGIMEN (70 pts)

VARIABLE REGIMEN (213 pts)

Week 4 HCV-RNA (Amplicor)

neg pos

12 wks 24 wks

week 4 neg 89% 87% HCV-2 76%

week 4 pos 50% 72%

week 4 neg 100% 77% HCV-3 76%

week 4 pos 43% 41%

24 wks

Mangia et al. NEJM 2005

S V R

Relapse Rates

-2%

-8%

-10%*

-6%

-20%

-10%

0%

% o

f P

ati

en

ts

PCR Neg. at week 4,24 weeks Tx., (n=42)

PCR Pos. at week 4,24 weeks Tx., (n=13)

PCR Neg. at week 4,12 weeks Tx., (n=126)

PCR Pos. at week 4,24 weeks Tx., (n=54)

*P=0.19, In patients PCR negative at week 4, 12 vs. 24 weeks Tx.

Mangia A. N Engl J Med 2005;352:2609-17.

Standard duration Variable duration

PEG-IFN 2a 180 g + RIBA 800-1200 mg/day (n=153)

Week 4 HCV-RNA (Monitor)

< 600 IU/mL (n=142)

16 wks (71) 24 wks (71)

> 600 IU/mL (n=11)

randomized

HCV-2 All 95% 95%HVL 93% 93% 1/1 100%

LVL 100% 100%

HCV-3 All 76% 75%HVL 54% 67% 3/9 33%LVL 93% 84%

24 wks

S V R

Von Wagner et al, Gastroenterology 2005

- 20%

- 10% - 7% - 5%

- 12% - 9%

(12 vs 24 wks) (16 vs 24 wks)

AE requiring dose reduction

Withdrawal

Mangia 2005(PEG-IFN 2b)

Von Wagner 2005(PEG-IFN 2a)

Overall Safety / Tolerability

ACCELERATE: study design

PEG-IFN -2a 180 g/wk plus RBV 800 mg/day

Follow-up

Study week

0 32168 24 40 48

n=1469

PEG-IFN -2a 180 g/wk plus RBV 800 mg/day

Follow-up

Randomisation. Treatment duration blinded until week 16

Shiffman M, et al. 41st EASL 2006; Abstract 734

732

731

THE ACCELERATE TRIAL

MAIN CONCLUSIONS

PEG-IFN Alfa-2a plus 800 mg Ribavirin• 24 wks better than 16 wks for HCV-2 and

HCV-3 due to higher relapse rates with shorter therapy

Shiffman et al EASL 2006

New Schedule of Treatment for Rapid Responders

HCV-2

Week 4 – HCV-RNA

Neg Pos

Treat for 12-16 wks Treat for 24 wks

Solid with full WBD ribavirin

Same for HCV-3 ?

Same for advanced disease ?

Genotype 1 & Rapid Virologic Response

Shorter duration ?

• increase tolerability

• lower costs

Better Tailoring the Current Therapy

Virologic Response Rates in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks

PEG-IFN -2b 1.5 g/kg QW + ribavirin 800-1400 mg/day

81%

50%

0%

20%

40%

60%

80%

100%

% o

f P

ati

en

ts

EOT SVR

74% 71%

0%

20%

40%

60%

80%

100%

% o

f P

ati

en

ts

EOT SVR

1. Zeuzem et al, J Hepatol 20062. Manns et al, Lancet 2001

24 Weeks Tx.1, N=235 48 Weeks Historical Control48 Weeks Historical Control2, 2, N=38N=38

SVR Rates by First Time to PCR Negativity in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx.

PEG-IFN -2b 1.5 g/kg QW + ribavirin

89%

25%17%

0%

20%

40%

60%

80%

100%

% o

f P

ati

en

ts

4, (n=110) 12, (n=61) 24, (n=24)

85%93%

67%

0%

20%

40%

60%

80%

100%

% o

f Patients

4, (n=13) 12, (n=15) 24, (n=3)

24 Weeks Tx.1, N=235 48 Weeks Historical Control48 Weeks Historical Control2, 2, N=38N=38

1. Zeuzem et al, J Hepatol 20062. Manns et al, Lancet 2001

Discontinuation and Dose Reductions for Adverse Events HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx.

PEG-IFN -2b 1.5 g/kg QW + ribavirin

24 Weeks Tx., N=2351

48 Weeks Historical control, N=382

Discontinuation 3% 25%

Dose reductions 14% 49%

1. Zeuzem et al, J Hepatol 20062. Manns et al, Lancet 2001

89

16

73

35

0

20

40

60

SV

R (

%)

Patients with an RVR at week 4

88 91

80

23

44

100

Patients without an RVR at week 4

n= 18 33 40 55 81 84 208 210

24-LD

24-SD

48-LD

48-SD

LD = RBV 800 mg/day; SD = RBV 1000–1200 mg/day; RVR = HCV RNA <50 IU/mL at week 4 Jensen D, et al. AASLD 2005

PEG IFN 2a + RBV: comparison of SVRs in Genotype 1 patients with and without RVR

(n=729)

Week 4 - qualitative HCV-RNA

Week 12 - quantitative HCV-RNA Week 12 - quantitative HCV-RNA

Negative PositivePositive

Treat for 24 wks

> 2 log

Treat for 48 wks

< 2 log

Stop(or shift to

suppressive therapy)

New Schedule for Rapid RespondersHCV-1

Applicable only to patients with LVL

and without cirrhosis

WHAT ABOUT SLOW RESPONDERS ?

0 12 24 48 72

HC

V R

NA

Fast RespondersSlow responders

Time HCV RNA negative

Level of detection

End of Treatment

Adapted from Bekkering F. et al, Hepatology, 2001, Buti M. et al, Hepatology, Vol. 35, No. 4, 2002

Time HCV RNA negative

Genotype 1 & Slow Virologic Response

Longer duration ?

• increase response rate

• decreased tolerability

• higher costs

Better Tailoring the Current Therapy

Extended treatment duration for HCV type 1: comparing 48 vs 72 weeks of PEG-IFN α-2a plus Ribavirin

Berg et al Gastroenterology 2006

Extended treatment duration for HCV type 1: comparing 48 vs 72 weeks of PEG-IFN α-2a plus Ribavirin

Berg et al Gastroenterology 2006

Follow-up

Follow-up

A prospective, randomised clinical trial in genotype 1 or 4 patients

Randomisation

0 72Week 4; RVR 24 48 96

No RVR AND EVR: Peg-iFN -2a 180 g/wk + RBV 1000-1200 mg/day

No RVR AND EVR: Peg-IFN -2a 180 g/wk (48wks) then 135 g/wk (24wks) + RBV 1000-1200mg/day

RVR: Peg-IFN -2a 180 g/wk +RBV1000-1200

Follow-up

Follow-up

Week 12; EVR

No RVR AND No EVR: Peg-IFN -2a 180 g/wk +RBV 1000-1200mg/day

n=26

7

n=104

Ferenci P, et al. EASL 2006

RVR = HCV RNA <50 IU/mL at week 4, EVR = HCV RNA <600 IU/ml or >2-log10 drop at week 12

Attempts to optimize therapy

Some patients might be OVERTREATEDSome patients might be UNDERTREATED

Better Tailoring the Current Therapy

Development of New Therapies

DIFFICULT-TO-TREAT SUBGROUPS

Potential targets and approaches in the next 5 years

Treatment of chronic hepatitis C

New IFNs

• Albumin-linked IFN alfa• Peg-Consensus IFN• Gene-shuffled IFN• “oral IFN inducers”

Potential targets and approaches in the next 5 years

Potential antiviral targets and approaches

New IFNs Ribavirin analogues

• Viramidine

Potential targets and approaches in the next 5 years

Potential antiviral targets and approaches

New IFNs Alternative “ribavirin-like” drugs

Specific HCV Inhibitors

• NS3 Protease Inhibitors

• NS5B RNA Polymerase Inhibitors

• IRES inhibitors (antisense oligonucleotides, ribozymes, siRNAs)

• Other HCV inhibitors

Potential targets and approaches in the next 5 years

Treatment of chronic hepatitis C

New IFNs Immune Therapies

Alternative “ribavirin-like” drugs

Specific HCV Inhibitors

• Thymosin alfa-1• IL-10• Histamine• HC Ig• Therapeutic vaccine

Therapies in Development for HCV

LevovirinLevovirin

Dev

elo

pm

ent

Sta

ge

Dev

elo

pm

ent

Sta

ge

Phase IIPhase II

On MarketOn Market

Phase IIIPhase III

Phase IPhase I

ResearchResearch

PreclinicalPreclinical

ThymosinThymosin

HCV VaccinesHCV Vaccines

Other IFNsOther IFNs

Many others includingAntisense

AntifibroticsImmune stimulants

Gene therapy

Many others includingAntisense

AntifibroticsImmune stimulants

Gene therapy

Ribozymes Ribozymes

E2 VaccineE2 Vaccine

RibavirinRibavirin

AntisenseAntisense

HCV ImmunotherapyHCV Immunotherapy

LevovirinLevovirin

ViramidineViramidine

Gamma IFNGamma IFN Histamine HClHistamine HCl

IL 10 & IL 12others

IL 10 & IL 12others

IMPDH inhibitorsIMPDH inhibitors

Apoptosis Inhibitors

Apoptosis Inhibitors

siRNAsiRNA

IFN & PEG IFNIFN & PEG IFN

Polymerase inhibitors

Polymerase inhibitors

Protease InhibitorsProtease Inhibitors