hepatite crônica c€¦ · hepatite crônica c novos tratamentos prof. henrique sergio moraes...

Hepatite crônica CHepatite crônica C

Novos tratamentosNovos tratamentos

Prof. Henrique Sergio Moraes CoelhoProf. Henrique Sergio Moraes Coelho

III Workshop Internacional de AtualizaIII Workshop Internacional de Atualizaçção em Hepatologiaão em Hepatologia

Abril de 2008 CuritibaAbril de 2008 Curitiba--ParanParanáá

HepatologyHepatology 20042004

56-61

“Real-World” SVR ResultsCanadian Expanded-Access Program

Yoshida E, et al., DDW; May 14-19, 2005. Abstract S1572.

N=863, treated with PEG IFN alfa-2b QW + RBV 800 mg/d

Naive, No Cirrhosis

Naive, Cirrhosis

0102030405060708090

100

Relapsers Nonresponders

SVR

(%) 56

41

77

4134

58

4035

51

23 20

35

All GenotypesGenotype 1Genotype 2-3

PEG IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response

Requer injeções repetidas;

Tempo de tratamento prolongado

Efeitos colaterais são freqüentes e difíceis de aceitar em pacientes assintomáticos;

Contra-indicações são freqüentes (20–30% dos candidatos);

Metade dos pacientes não responde;

Necessidade de novas drogas para hepatite C

Problemas com a terapia antiviral Peg/RBVl

a) Pacientes com cirrose hepática ;

b) Pacientes co-infectados (C + HIV);

c) No pós-transplante hepático;

d) Nos recidivantes, após tratamento com PegINF/RBV;

e) Não respondedores a PegInf/RBV(avaliar fatores preditivos)

f) Pacientes com genótipo 1 com fatores preditivos de má resposta

Quem serão os candidatos às novas terapias antivirais?

6

Potenciais alvos das novas moléculas

InibidoresInibidores de de ProteaseProtease

InibidoresInibidores dada PolimerasePolimerase

Kwong A, et al. Beyond interferon and ribavirin: Antiviral therapies for hepatitis C virus. Drug Discovery Today: Therapeutic Strategies. 2006;3:211-220.

Protease Inhibitor Telaprevir for Treatment of Hepatitis C

Telaprevir(VX 950)

• Selective, specific peptidomimetic inhibitor• 14 days • Most sustained viral suppression

with 750 mg q8h ; highest trough levels• Mean log drop 4.4 with 750 mg dosing• Leveling off or rebound associated with

identifiable “mutations”• Even more profound viral suppression reported

with PEG IFN (median 5.5 log) - Vertex press releaseJan 8, 2006

Reesink HW, et al. Hepatology. 2005;42:234A.

Placebo VX-950 450 mg q8h VX-950 750 mg q8h VX-950 1250 mg q12h

11

22

33

44

55

66

77

00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414

Study Time (Days)Study Time (Days)

Med

ian

HC

V R

NA

(Log

10IU

/mL)

TelaprevirMedian HCV RNA Over Time

Reesink HW, et al. DDW; May 14-19, 2005. Abstract 527.

Resistance profiles established

clinicaloptions.com/hep

Update on Investigational Agents in HCV: 2007

PROVE 1: Telaprevir + PegIFN/RBV in Treatment-Naive HCV GT 1 Patients

Jacobson I, et al. AASLD 2007. Abstract 177.

45

6561

35

0

20

40

60

80

10012 wks TVR/pegIFN/RBV;12 wks pegIFN/RBV 12 wks TVR/pegIFN/RBV

SVR Rates in12 and 24-Week Arms

Patie

nts

(%)

48 wks pegIFN/RBV12 wks TVR/pegIFN/RBV; 36 wks pegIFN/RBV

End-of-Treatment Response in 48-Week Arms

0

20

40

60

80

100

Intent-to-treat Interim Analysis

(n = 79) (n = 17) (n = 75) (n = 79)



Treatment-naive patients

infected with HCV

genotype 1*

(n = 323)

Telaprevir 750 mg every 8 hrs + PegIFN alfa-2a + RBV

(n = 81)Telaprevir 750 mg every 8 hrs

+ PegIFN alfa-2a + RBV(n = 82)

Telaprevir 750 mg every 8 hrs+ PegIFN alfa-2a

(n = 78)

Hezode C, et al. AASLD 2007. Abstract 80.

Wk 12

*Patients received telaprevir 1250-mg loading dose or placebo based on the arm to which they were randomized. Patients received 12 or 24 weeks regardless of whether RVR occurred.

Wk 24 Wk 48


Placebo + PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg QD(n = 82)

PegIFN alfa-2a + RBV(n = 81)

Interim AnalysisWk 36

Follow-up

Follow-up

Follow-up





2421Viral breakthrough‡

295965OngoingSVR†

51*62*

80*79*

69*73*

1341

Undetectable HCV RNA

Wk 4Wk 12

TVR + PegIFN for

12 Wks(n = 78)

TVR + PegIFN + RBV for

12 Wks(n = 82)

TVR + PegIFN + RBV for

24 Wks(n = 81)

Placebo +PegIFN + RBV

(n = 82)

Outcome, %

*P < .001 vs pegIFN/RBV/placebo arm.†SVR at 12 wks posttreatment for 24-week arm; SVR at 24 wks posttreatment for 12-week and no-RBV arms.‡HCV RNA increase of > 1 log above the nadir, or increase to > 100 IU/mL in patients with previously undetectable HCV RNA.




51

202

122

AnemiaGrade 3

90

231

110

DyspneaGrade 3

152615Insomnia

404

476

260

Rash, all typesGrade 3

280

48< 1

320

NauseaGrade 3

581

561

240

PruritusGrade 3

•TVR + PegIFN•for 12 Wks

•(n = 78)

TVR + PegIFN + RBVfor 12/24 Wks

(n = 163)

Placebo + PegIFN + RBV

(n = 81)

Adverse Event, %


Total adverse events leading to discontinuation during Weeks 1-12– Control: 5% – 24-week arm: 15% – 12-week arm: 13% – No RBV arm: 10%

Boceprevir (SCH 503034)

N

HN NH2

OO

HN

HN

O

O

MeMeO

Me

Me

Me

Me Me

Me

Dados In vitro• Ki* =14 nM • elastase/HCV = 2000• Replicon IC50 = 200 nM• Replicon IC90 = 400 nM

(200 ng/mL)• No inhibition of CYP

Dados Farmacocinéticos• Biodisponibilidade oral• Distribuição Fígado/Plasma: ~30• Nenhum problema naestabilidade plasmática

Zeuzem et al. AASLD 2005

Farmacodinâmica Boceprevir – EstudoMonoterapia em Não Respondedores

-2

-1,5

-1

-0,5

0

0,5

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Dias Após Início Tratamento

Méd

ias

de R

eduç

ão e

mLo

g 10 H

CV

RN

A

Placebo100 mg BID200 mg BID400 mg BID400 mg TID

Tratamento Follow-up

SCH 503034 Plus PEG IFNAntiviral Activity in Genotype 1

NonrespondersPEG IFN alfa-2bAlone (n = 22)PEG IFN alfa-2b+SCH503034200 mg TID(n = 12)PEG IFN alfa-2b+SCH503034400 mg TID(n = 12)

-3

-2.5

-2

-1.5

-1

-0.5

0

Mean

HCV

RNA

Cha

nge (

Log

Mean

HCV

RNA

Cha

nge (

Log 1010

))

Treatment DayTreatment Day0 5 10 15

Zeuzem S, et al. Hepatology. 2005;42:233A.

SPRINT -1 Study

•• N= 595 pacientes N= 595 pacientes -- Naive e GenNaive e Genóótipo 1tipo 1

•• Estados Unidos, CanadEstados Unidos, Canadáá e Europae Europa

•• 77% americanos77% americanos

•• 16% Afro16% Afro--americanosamericanos

•• 7% cirr7% cirróóticosticos

Scre

enin

g

HCV SPRINT-1 Study - Fase II – Pacientes Naïve G1

Arm 2

Arm 1

Arm 3

Boceprevir 800 mg TID + PegIntron (1,5mcg/kg/sem) +

low dose Rebetol (400+1000mg/dia)

48 Semanas

Follow-up

24 Weeks

PegIntron (1,5mcg/kg/sem) + Rebetol (800-1400mg/dia)

48 SemanasArm 4

Follow-up

24 Weeks

Boceprevir 800mg TID + PegIntron + Rebetol

28 Weeks

Follow-up

24 Weeks

Follow-up

24 Weeks

Boceprevir 800mg TID + PegIntron (1,5mcg/kg/sem) + Rebetol (800 + 1400mg/dia)

48 Weeks

Boceprevir 800mg TID + PegIntron +

Rebetol

24 Weeks

Follow-up

24 Weeks

Follow-up

24 WeeksBoceprevir 800mg TID +PegIntron +

Rebetol

44 WeeksPegIntron + Ribavirin

4 Semanas

Resultados – RVPc Semana 12

70%79%

54%

34%

0%

20%

40%

60%

80%

100%

Grupo 1 Grupo 2 Grupo 3 Grupo 4

RVPc - PCRnegativo nasemana 12(<15UI/ml)

Polymerase Inhibitors for Hepatitis C



Treatment-naive patients

with HCV genotype 1

infection

(N = 104)

R1626 1500 mg BID+ PegIFN(n = 21)

R1626 3000 mg BID + PegIFN(n = 32)

R1626 1500 mg BID + PegIFN + RBV

(n = 31)

Wk 48Wk 4

interim analysis

PegIFN alfa-2a 180 µg/wk +RBV 1000-1200 mg QD

(n = 20)

PegIFN + RBV

PegIFN + RBV

PegIFN + RBV

24-week follow-up

Polymerase Inhibitor R1626 in Treatment-Naive Genotype 1 Patients

Pockros PJ, et al. AASLD 2007. Abstract 167.

Interim results of multicenter, randomized, active-controlled, double-blind, phase IIa trial



Polymerase Inhibitor R1626 for Treatment-Naive Genotype 1 Patients


-2.4

-3.6-4.5

-5.2-6

-5

-4

-3

-2

-1

0

PegIFN/RBV R1626 1500/pegIFN R1626 3000/pegIFN R1626 1500/pegIFN/RBV

Mean HCV RNA Reduction at Wk 4

Log 1

0IU

/mL

HC

V R

NA

0

20

40

60

80

100

5

33

6981

Patie

nts

(%)

Undetectable HCV RNA at Wk 4



Polymerase Inhibitor R1626 for Treatment-Naive Genotype 1 Patients

No emergence of R1626 resistance detectedGastrointestinal adverse effects common with R1626, particularly in 3000 mg dosing armCytopenias, especially neutropenia, commonly associated with R1626

– Neutropenia not associated with increased incidence of infection


1 (5)0 (0)

10 (32)3 (10)

3 (9)0 (0)

0 (0)0 (0)

AnemiaGrade 1/2Grade 3/4

0 (0)4 (13)15 (47)2 (10)ThrombocytopeniaGrade 3/4

6 (30)2 (10)

16 (52)12 (39)

5 (16)25 (78)

8 (38)10 (48)

NeutropeniaGrade 3Grade 4

PegIFN/RBV(n = 20)

R1626 1500 mg

+ PegIFN/RBV(n = 31)

R1626 3000 mg

+ PegIFN(n = 32)

R1626 1500 mg

+ PegIFN(n = 21)

Week 4 Cumulative LaboratoryAbnormalities, n (%)

Treatment With Nitazoxanide for Hepatitis C



HCV GT 4 patients from

2 sites in Egypt

(N = 120)

Nitazoxanide 500 mg BID

(n = 40)*

Nitazoxanide500 mg BID

(n = 40)*

Wk 48

*n = 28 interferon-based regimen naive; 12 interferon-based regimen experienced.

PegIFN alfa-2a 180 μg/wk+ RBV 1000-1200 mg QD

(n = 40 [all interferon naive])

Nitazoxanide 500 mg BID+ PegIFN alfa-2a 180 μg/wk

Nitazoxanide 500 mg BID+ PegIFN alfa-2a 180 μg/wk

+ RBV 1000-1200 mg QD

Wk 12SVR12Wk 60

Follow-up

Follow-up

Follow-up

Nitazoxanide-Based Therapy for HCV Genotype 4-Infected Patients

Rossignol JF, et al. AASLD 2007. Abstract 178.

STEALTH C-1: phase II, randomized, controlled trial of nitazoxanide in HCV– Nitazoxanide: a thiazolide with in vitro activity against HBV and HCV– Approved for treatment of diarrhea caused by Giardia and Cryptosporidium



Nitazoxanide-Based Therapy for HCV Genotype 4-Infected Patients (cont’d)

SVR12 in treatment-experienced patients

– Nitazoxanide + pegIFN + RBV: 25%

– Nitazoxanide + pegIFN: 8%

Discontinuations during therapy in treatment-naive patients

– Nitazoxanide + pegIFN: 18%

– Nitazoxanide + pegIFN + RBV: 14%

– PegIFN + RBV: 18%

Nitazoxanide generally welltolerated

– Grade 3 neutropenia more common in nitazoxanide-containing arms

Rossignol JF, et al. AASLD 2007. Abstract 178.

54

71 71 6864

8679 79

38

73

58

43

0

20

40

60

80

100

Wk 4 Wk 12 ETR SVR 12

Nitazoxanide/pegIFN

Nitazoxanide/pegIFN/RBV

PegIFN/RBV

ITT Analysis in Interferon-Naive Patients: HCV RNA Negative* During Combination Therapy

*HCV RNA < 10 IU/mL.

P = .006

Patie

nts

(%)


HCV Treatment Update

Phase II Study: Eltrombopag Increased Platelet Counts at All Doses Evaluated

Significantly more patients with HCV-associated thrombocytopenia achieved ≥ 100,000 cells/μL at Week 4 in all eltrombopag dose groups compared with placebo (P ≤ .0003)

Best responses with eltrombopag 75 mg/day– 91% of this group able to initiate HCV therapy

– 65% of this group able to complete 12 weeks of therapy

209 (78-527)214 (47-499)137 (40-528)53 (34-74)Week 454 (28-75)52 (26-66)59 (34-94)55 (27-75)Baseline

Eltrombopag75 mg/day

Eltrombopag50 mg/day

Eltrombopag30 mg/dayPlacebo

Median Platelet Count, x 103/µL (Range)Treatment Week

McHutchinson JG, et al. AASLD 2006. Abstract LB3.

New Interferon Formulationsfor Hepatitis C



Among adherent patients weighing ≥ 75 kg, albIFN 900 μg every 2 wks + RBV achieved a higher rate of SVR vs pegIFN + RBV: 74.2% vs 53.3%

Significant predictors of SVR (pooled all groups)– ≥ 80% adherence to therapy vs < 80% adherence: 67% vs 39% (P < .001)

– Baseline ALT > 3 x ULN vs < 3 x ULN: 66% vs 54% (P < .001)

– HCV RNA < 400,000 IU/mL vs > 400,000 IU/mL: 76% vs 48% (P < .001)

– Gamma glutamyltransferase < ULN vs ≥ ULN: 62% vs 42% (P < .001)

Albinterferon alfa-2b in Treatment-Naive Genotype 1 Patients (cont’d)

Zeuzem S, et al. AASLD 2007. Abstract 180.

51555858SVR70807379Wk 4853756966Wk 1218342526Wk 4

AlbIFN 1200 µg Every 4 Wks + RBV

(n = 116)


(n = 110)


(n = 118)

PegIFN+ RBV

(n = 114)

HCV RNA Negative, %

STAT-CLikely Picture - Near Future

Viral enzymeinhibitors

Immunemodulation

RBV orrelated drugs± ±

Interferon as a platform for future combinations

Duration of treatment?Dosis?Other combinations?

hepatite crônica c€¦ · hepatite crônica c novos tratamentos prof. henrique sergio moraes...

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