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