Management of non responders khi

MANAGEMENT OF NON MANAGEMENT OF NON RESPONDERSRESPONDERS

Dr Nasir Khokhar MD FACP FACGDr Nasir Khokhar MD FACP FACGProfessor of Medicine and Professor of Medicine and

Director, Division of Director, Division of GastroenterologyGastroenterology

Shifa International Hospital, Shifa International Hospital, IslamabadIslamabad

CHALLENGECHALLENGE

Nonresponse to standard Nonresponse to standard IFN IFN ribavirin ribavirin

Nonresponse to PEG-IFN + Nonresponse to PEG-IFN + ribavirinribavirin

TREATMENT WITH TREATMENT WITH PEGYLATED INTERFERONPEGYLATED INTERFERON

Nonresponders to InterferonNonresponders to Interferon

IFN TIW + ribavirinIFN TIW + ribavirin SVR 12%-15% SVR 12%-15%PEG-IFN + ribavirin PEG-IFN + ribavirin SVR 25%-30% SVR 25%-30%No improvement withNo improvement with

Higher than standard doses of IFNHigher than standard doses of IFN 4-12 week “induction” with daily IFN4-12 week “induction” with daily IFN

Daily IFN + ribavirin x 1 yr may achieve Daily IFN + ribavirin x 1 yr may achieve rates similar to PEG-IFN + ribavirinrates similar to PEG-IFN + ribavirin

Shiffman ML. Hepatology. 2002;36:S128.Shiffman ML et al. Gastroenterology. 2004;126:1015.

Kaiser S et al. Hepatology. 2003;38:276A (Abstract 248).IFN, interferon; TIW, 3 times weekly

Nonresponders to IFN + Nonresponders to IFN + RibavirinRibavirin

HALT-C Trial: Retreatment with PEG HALT-C Trial: Retreatment with PEG + RBV+ RBV

Shiffman ML et al. Gastroenterology. 2004;126:1015.

0

10

20

30

40

50

Overall IFNNonresponders

IFN/RNonresponders

18

28

12

% S

VR

P0.0001

RENEW Trial: High-Dose RetreatmentRENEW Trial: High-Dose Retreatmentwith PEG-IFNwith PEG-IFN

Interim Analysis of 650 PatientsInterim Analysis of 650 Patients

0

10

20

30

40

50

24 Weeks 48 Weeks 72 Weeks

0.5 g/kg

1.5 g/kg

3.0 g/kg

On TreatmentOn Treatment SVRSVR

16

30

39

10

19 20

4 711

% H

CV

RN

A N

egat

ive

Gross JB et al. Presented at AASLD 2003. October 24-28, 2003. Boston, MA. (Abstract 321).

Nonresponders to IFN + Nonresponders to IFN + RibavirinRibavirin

NYC Trial: Retreatment withNYC Trial: Retreatment withPEG + RBVPEG + RBV

0

10

20

30

40

50

24 Weeks 48 Weeks SVR

Time on Treatment

PEG -2b 1.0 g/kg +Ribavirin 1000 mg

PEG -2b 1.5 g/kg +Ribavirin 800 mg

18

30

116

22

10

Jacobson IM et al. Gastroenterology. 2003;124:A714.

% H

CV

RN

A N

egat

ive

P0.05

72-wk Peg-IFN + RBV for HCV 72-wk Peg-IFN + RBV for HCV Genotype 1Genotype 1

Similar SVRSimilar SVR rates in unselected cohort of rates in unselected cohort of HCV infected ptsHCV infected pts

↑↑ SVR, SVR, ↓↓ relapse rate in pts without rapid relapse rate in pts without rapid virologic response virologic response

1. Berg T, et al. AASLD 2004. Abstract 169.2. Sanchez-Tapias JM, et al. AASLD 2004. Abstract 126.

100

50

0

Pat

ien

ts (

%)

100

50

0

Pat

ien

ts (

%)

3245

61

Unselected Population [1]

HCV RNA positive pts at Wk 4 [2]

EOT SVR

5352

72

52

48 wks

72 wks

67

EOT SVR

Nonresponders to PEG + Nonresponders to PEG + Ribavirin:Ribavirin:

Reasons for Lack of ResponseReasons for Lack of ResponseResistant virusResistant virusHost factorsHost factorsUnder-dosingUnder-dosingLack of adherenceLack of adherence

Inadequate treatment of side effectsInadequate treatment of side effects Lack of support at homeLack of support at home Sub-optimal medical staff supportSub-optimal medical staff support

CONCENSUS INTERFERONCONCENSUS INTERFERON

Nonresponders to IFN + Nonresponders to IFN + RibavirinRibavirin

Retreatment with Daily CIFNRetreatment with Daily CIFN120 nonresponders to IFN + Riba120 nonresponders to IFN + Riba

91% genotype 191% genotype 128% F3-F428% F3-F4

CIFN 9 CIFN 9 g/day + WB Riba 36 wksg/day + WB Riba 36 wks

SVR: 39%-44%SVR: 39%-44%

Kaiser S et al. AASLD 2004. Abstract 173.CIFN, consensus interferon; WB, weight-based

CIFN 18-27 CIFN 18-27 g/day + WB Riba 12 wksg/day + WB Riba 12 wks

MAINTAINANCE INTERFERON MAINTAINANCE INTERFERON THERAPYTHERAPY

Maintenance IFN for Maintenance IFN for Histologic RespondersHistologic Responders

0

0.5

1

1.5

2

2.5

3

Baseline 30 Months

Sta

ge

of

Fib

rosi

s

Maintained IFN(N=20)

Stopped at 6 mo(N=23)

Shiffman ML et al. Gastroenterology. 1999;117:1164.

2.52.2

1.7

2.4

4

3.5

Cirrhosis May Be ReversibleCirrhosis May Be ReversibleBiopsies After 48 Weeks of Antiviral Biopsies After 48 Weeks of Antiviral

TherapyTherapy

44

33

22

11

00

StageStageBeforeBefore

Patients, nPatients, nAfterAfter

Patients, n (%)Patients, n (%)

153 78 (51%)

23 (15%)

26 (17%)

23 (15%)

3 ( 2%)

Poynard T et al. Gastroenterology. 2002;122:1303.

Maintenance IFN TherapyInterim Efficacy Results from COPILOT

Afdhal NH, et al. Presented at: AASLD. 2002. Abstract 595.Afdhal NH, et al. Hepatology. 2004;40:239A. Abstract 171.

PEG-IFN -2b 0.5 g/kg/wk vs Colchicine 0.6 mg BID

OutcomeOutcome PEG-IFNPEG-IFN ColchicineColchicine PP value value

ALTALT 40 IU drop40 IU drop 42 IU drop42 IU drop NSNS

AFPAFP No changeNo change No changeNo change NSNS

HCV RNAHCV RNA 1 log fall (90%)1 log fall (90%) No changeNo change NSNS

EndpointEndpoint PEG-IFNPEG-IFN ColchicineColchicine

DeathDeath 11 22

OLTOLT 00 22

HCCHCC 77 88

CPT > 2 pointsCPT > 2 points 1111 1818

Variceal bleedVariceal bleed 11 99

Year 1 Analysis(N = 250)

Year 2 Analysis (N = 534)

A benefit in favor of PEG was found for cirrhosis (CPT 5–7),

albumin < 3.5, and portal hypertension (P < 0.05)

CPT = Child-Pugh-Turcotte Score

Low-dose Peg IFN Decreases Low-dose Peg IFN Decreases Risk of Variceal BleedingRisk of Variceal Bleeding

Afdhal N, et al. AASLD 2004. Abstract 171.

COPILOT (Colchicine vs PEG-IFN Long COPILOT (Colchicine vs PEG-IFN Long Term) StudyTerm) Study Randomized, controlled, multicenter, 2-year Randomized, controlled, multicenter, 2-year

interim analysisinterim analysis Patients with advanced fibrosis or cirrhosis Patients with advanced fibrosis or cirrhosis

who who had failed interferon-based therapyhad failed interferon-based therapy Clinical outcome at 2 years 1 bleed in Clinical outcome at 2 years 1 bleed in

26 patients in PEG group and 26 patients in PEG group and 11 in 42 11 in 42 patients in colchicine grouppatients in colchicine group

Rincon D, et al. AASLD 2004. Abstract 189.

Prospective study of 18 chronic HCV patients treated with Prospective study of 18 chronic HCV patients treated with PegIFN alfa-2b (1.5 PegIFN alfa-2b (1.5 g/kg/wk) + RBV (800-1200 mg/day)g/kg/wk) + RBV (800-1200 mg/day) Stage 3/4 fibrosis (METAVIR)Stage 3/4 fibrosis (METAVIR) Hepatic venous pressure gradient (HVPG) > 5 mm HgHepatic venous pressure gradient (HVPG) > 5 mm Hg Clinically compensated diseaseClinically compensated disease

Compared with 30 untreated controlsCompared with 30 untreated controls Mean % HVPG changeMean % HVPG change

Treated -21 ± 27% vs untreated +33 ± 12%Treated -21 ± 27% vs untreated +33 ± 12%

Absolute HVPG reduction in treatedAbsolute HVPG reduction in treated HVPG improvement seen in responders and HVPG improvement seen in responders and

nonresponders patientsnonresponders patients 3.6 ± 3.5 mm Hg (3.6 ± 3.5 mm Hg (PP < .001) < .001)

Antiviral Therapy Improves Portal Antiviral Therapy Improves Portal Vein PressureVein Pressure

WATCH AND WEIGHT FOR WATCH AND WEIGHT FOR DEVELOPMENT OF NEWER DEVELOPMENT OF NEWER

AGENTSAGENTS

21%21%

32%

71%

100%

0

20

40

60

80

100

Preclinical Phase I -Phase II

Phase II -Phase III

Phase III -Market

FDAApproval

Ad

van

cin

g t

o N

ext

Ph

ase

(%)

1 Year 3 Years 3 Years 1 Year

DiMasi JA, et al. J Health Econ. 2003;22:151-185.

Timeline for FDANew Drug Approval

A new drug takes approximately 7–8 years to reach the

market

Directions in HCV TherapeuticsDirections in HCV TherapeuticsImmunotherapiesImmunotherapies

McHutchison JG, et al. Hepatology. 2002;36:S245-S252. Papatheodoridis GV, et al. J Viral Hepat. 2004:11:287-296. Pearlman BL. Am J Med. 2004;117:344-352.

CompanyCompany ProductProduct StatusStatus DescriptionDescription

Human GenomeHuman Genome AlbuferonAlbuferon Ph. IPh. I Fusion albumin + IFNFusion albumin + IFN

IDEAIDEA TransfersomeTransfersome®® IFN IFN Ph. IPh. I Transfersome + IFNTransfersome + IFN

Roche/RibapharmRoche/Ribapharm LevovirinLevovirin Ph. IPh. I L-isomer of RBV L-isomer of RBV DiscontinuedDiscontinued

AmarilloAmarillo IFN alphaIFN alpha Ph. IIPh. II Oral formulationOral formulation

BioMedicinesBioMedicines Omega IFNOmega IFN Ph. IIPh. II IFN omegaIFN omega

InterMuneInterMune ActimmuneActimmune®® Ph. IIPh. II Antiviral/immune modulatorAntiviral/immune modulator

MaximMaxim CepleneCeplene Ph. IIPh. II Histamine immune modulator Histamine immune modulator FailedFailed

ViragenViragen MultiferonMultiferon Ph. IIPh. II Multisubtype human IFNMultisubtype human IFN

VertexVertex MetroMetro Ph. IIPh. II IMPDH inhibitorIMPDH inhibitor

InterMuneInterMune InfergenInfergen®® Ph. IIIPh. III IFN (daily dose)IFN (daily dose)

ValeantValeant ViramidineViramidine Ph. IIIPh. III RBV prodrugRBV prodrug

SciCloneSciClone ZadaxinZadaxin®® Ph. IIIPh. III Thymosin alpha immune modulatorThymosin alpha immune modulator

IndevusIndevus IP 501IP 501 Ph. IIIPh. III Antifibrotic Antifibrotic DiscontinuedDiscontinued

Directions in HCV TherapeuticsDirections in HCV TherapeuticsAntiviral TherapiesAntiviral Therapies

McHutchison JG, et al. Hepatology. 2002;36:S245-S252. Papatheodoridis GV, et al. J Viral Hepat. 2004:11:287-296. Pearlman BL. Am J Med. 2004;117:344-352.

CompanyCompany ProductProduct StatusStatus DescriptionDescription

VertexVertex VX 950VX 950 Ph. IPh. I NS3/NS4 Protease inhibitorNS3/NS4 Protease inhibitor

AnadysAnadys ANA245ANA245 Ph. IPh. I NucleosideNucleoside

AkrosAkros JTK 003JTK 003 Ph. IPh. I Polymerase inhibitorPolymerase inhibitor

BoehringerBoehringer BILN 2061BILN 2061 Ph. IPh. I Protease inhibitor Protease inhibitor DiscontinuedDiscontinued

Chiron/CSLChiron/CSL HCV vaccineHCV vaccine Ph. IPh. I VaccineVaccine

IdenixIdenix NM 283NM 283 Ph. I/IIPh. I/II Polymerase inhibitorPolymerase inhibitor

InnogeneticsInnogenetics HCV E1 vaccineHCV E1 vaccine Ph. IIPh. II HCV E1 proteinHCV E1 protein

IsisIsis ISIS 14803ISIS 14803 Ph. IIPh. II Antisense targeting IRESAntisense targeting IRES

RPIRPI HeptazymeHeptazymeTMTM Ph. IIIPh. III Ribozyme Ribozyme DiscontinuedDiscontinued

Proposed AlgorithmProposed Algorithm for Treatment Failures for Treatment Failures

12 weeks

Adapted from: Davis GL, et al. Hepatology. 2003;38:645-652.

Retest quantitative HCV RNA

HCV RNA decreased > 2 logs vs baseline

HCV RNA not decreased 2 logs

HCV RNA undetectable

HCV RNA detectable

Repeat HCV RNA

Change to PEG-IFN + RBV

Change toCIFN + RBV

Change to Maintenance IFN

Stop Rx Watch and Wait

End of Treatment

6 Month Follow-up

24 weeks

48 weeks

72 weeks

Nonresponders: SummaryNonresponders: Summary

1.1. Nonresponders to standard IFN Nonresponders to standard IFN ribavirin ribavirin: : consider treatment with PEG + ribavirinconsider treatment with PEG + ribavirin

2.2. Nonresponders to PEG + ribavirin: Nonresponders to PEG + ribavirin: consider same treatment if there was consider same treatment if there was inadequate dosing, adherence, or inadequate dosing, adherence, or monitoringmonitoring

3.3. Further attempts to cure HCV are most Further attempts to cure HCV are most appropriate for patients who hadappropriate for patients who had Relapse after initial clearanceRelapse after initial clearance Good reduction in viremia (eg, 2 logs)Good reduction in viremia (eg, 2 logs)

Nonresponders: SummaryNonresponders: Summary

4.4. Nonresponders with minimal Nonresponders with minimal fibrosis: observe without fibrosis: observe without treatment while waiting for new treatment while waiting for new antiviral drugsantiviral drugs

5.5. Nonresponders with advanced Nonresponders with advanced fibrosis: considerfibrosis: consider Low-dose maintenance PEG-IFNLow-dose maintenance PEG-IFN Experimental treatments that might Experimental treatments that might

suppress virus or inhibit fibrosissuppress virus or inhibit fibrosis

• Nonresponders to initial therapy represent a significant clinical challenge

• Achieving an SVR remains the primary goal in the nonresponder patient population

• Retreatment with PEG-IFN and ribavirin results in an SVR in 4%–12% of patients

• Recent data suggest that retreatment with CIFN and ribavirin results in an SVR in 27%–43% of patients

Take Home Messages

• Maintenance therapy may reduce the risk of HCV-related complications in patients who fail to achieve an SVR

• Additional data from HALT-C and COPILOT may help define role, benefit, side effects, and tolerance of maintenance therapy

• Early research on new agents to treat HCV is promising, but these agents remain far from reaching the clinic

Take Home Messages (cont.)

THANK YOU FOR YOUR THANK YOU FOR YOUR ATTENTIONATTENTION