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MANAGEMENT OF NONMANAGEMENT OF NON
RESPONDERSRESPONDERS
Dr Nasir Khokhar MD FACP FACGDr Nasir Khokhar MD FACP FACG
Profess...
CHALLENGECHALLENGE
Nonresponse to standardNonresponse to standard
IFNIFN ±± ribavirinribavirin
Nonresponse to PEG-IFN +N...
TREATMENT WITHTREATMENT WITH
PEGYLATED INTERFERONPEGYLATED INTERFERON
Nonresponders to InterferonNonresponders to Interferon
IFN TIW + ribavirinIFN TIW + ribavirin SVR 12%-15%SVR 12%-15%
PEG...
Nonresponders to IFN + RibavirinNonresponders to IFN + Ribavirin
HALT-C Trial: Retreatment with PEG +HALT-C Trial: Retreat...
RENEW Trial: High-Dose RetreatmentRENEW Trial: High-Dose Retreatment
with PEG-IFNwith PEG-IFN
Interim Analysis of 650 Pati...
Nonresponders to IFN + RibavirinNonresponders to IFN + Ribavirin
NYC Trial: Retreatment withNYC Trial: Retreatment with
PE...
72-wk Peg-IFN + RBV for HCV Genotype 172-wk Peg-IFN + RBV for HCV Genotype 1
Similar SVRSimilar SVR rates in unselected c...
Nonresponders to PEG + Ribavirin:Nonresponders to PEG + Ribavirin:
Reasons for Lack of ResponseReasons for Lack of Respons...
CONCENSUS INTERFERONCONCENSUS INTERFERON
Nonresponders to IFN + RibavirinNonresponders to IFN + Ribavirin
Retreatment with Daily CIFNRetreatment with Daily CIFN
12...
MAINTAINANCE INTERFERONMAINTAINANCE INTERFERON
THERAPYTHERAPY
Maintenance IFN for HistologicMaintenance IFN for Histologic
RespondersResponders
0
0.5
1
1.5
2
2.5
3
Baseline 30 Months
S...
Cirrhosis May Be ReversibleCirrhosis May Be Reversible
Biopsies After 48 Weeks of AntiviralBiopsies After 48 Weeks of Anti...
Maintenance IFN Therapy
Interim Efficacy Results from COPILOT
Afdhal NH, et al. Presented at: AASLD. 2002. Abstract 595.
A...
Low-dose Peg IFN DecreasesLow-dose Peg IFN Decreases
Risk of Variceal BleedingRisk of Variceal Bleeding
Afdhal N, et al. A...
Rincon D, et al. AASLD 2004. Abstract 189.
 Prospective study of 18 chronic HCV patients treated with PegIFNProspective s...
WATCH AND WEIGHT FORWATCH AND WEIGHT FOR
DEVELOPMENT OF NEWERDEVELOPMENT 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
FDA
Approval
...
Directions in HCV TherapeuticsDirections in HCV Therapeutics
ImmunotherapiesImmunotherapies
McHutchison JG, et al. Hepatol...
Directions in HCV TherapeuticsDirections in HCV Therapeutics
Antiviral TherapiesAntiviral Therapies
McHutchison JG, et al....
Proposed AlgorithmProposed Algorithm
for Treatment Failuresfor Treatment Failures
12 weeks
Adapted from: Davis GL, et al. ...
Nonresponders: SummaryNonresponders: Summary
1.1. Nonresponders to standard IFNNonresponders to standard IFN ±± ribavirinr...
Nonresponders: SummaryNonresponders: Summary
4.4. Nonresponders with minimal fibrosis:Nonresponders with minimal fibrosis:...
• Nonresponders to initial therapy represent a
significant clinical challenge
• Achieving an SVR remains the primary goal ...
• Maintenance therapy may reduce the risk of
HCV-related complications in patients who fail to
achieve an SVR
• Additional...
THANK YOU FOR YOURTHANK YOU FOR YOUR
ATTENTIONATTENTION
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Management of non responders khi

  1. 1. MANAGEMENT OF NONMANAGEMENT OF NON RESPONDERSRESPONDERS Dr Nasir Khokhar MD FACP FACGDr Nasir Khokhar MD FACP FACG Professor of Medicine and Director,Professor of Medicine and Director, Division of GastroenterologyDivision of Gastroenterology Shifa International Hospital, IslamabadShifa International Hospital, Islamabad
  2. 2. CHALLENGECHALLENGE Nonresponse to standardNonresponse to standard IFNIFN ±± ribavirinribavirin Nonresponse to PEG-IFN +Nonresponse to PEG-IFN + ribavirinribavirin
  3. 3. TREATMENT WITHTREATMENT WITH PEGYLATED INTERFERONPEGYLATED INTERFERON
  4. 4. Nonresponders to InterferonNonresponders to Interferon IFN TIW + ribavirinIFN TIW + ribavirin SVR 12%-15%SVR 12%-15% PEG-IFN + ribavirinPEG-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 achieveDaily 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
  5. 5. Nonresponders to IFN + RibavirinNonresponders to IFN + Ribavirin HALT-C Trial: Retreatment with PEG +HALT-C Trial: Retreatment with PEG + RBVRBV Shiffman ML et al. Gastroenterology. 2004;126:1015. 0 10 20 30 40 50 Overall IFN Nonresponders IFN/R Nonresponders 18 28 12 %SVR P<0.0001
  6. 6. RENEW Trial: High-Dose RetreatmentRENEW Trial: High-Dose Retreatment with 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 µg/kg 1.5 µg/kg 3.0 µg/kg On TreatmentOn Treatment SVRSVR 16 30 39 10 19 20 4 7 11 %HCVRNANegative Gross JB et al. Presented at AASLD 2003. October 24-28, 2003. Boston, MA. (Abstract 321).
  7. 7. Nonresponders to IFN + RibavirinNonresponders to IFN + Ribavirin NYC Trial: Retreatment withNYC Trial: Retreatment with PEG + RBVPEG + RBV 0 10 20 30 40 50 24 Weeks 48 Weeks SVR Time on Treatment PEG α-2b 1.0 µg/kg + Ribavirin 1000 mg PEG α-2b 1.5 µg/kg + Ribavirin 800 mg 18 30 11 6 22 10 Jacobson IM et al. Gastroenterology. 2003;124:A714. %HCVRNANegative P>0.05
  8. 8. 72-wk Peg-IFN + RBV for HCV Genotype 172-wk Peg-IFN + RBV for HCV Genotype 1 Similar SVRSimilar SVR rates in unselected cohort ofrates in unselected cohort of HCV infected ptsHCV infected pts ↑↑ SVR,SVR, ↓↓ relapse rate in pts without rapidrelapse rate in pts without rapid virologic responsevirologic response 1. Berg T, et al. AASLD 2004. Abstract 169. 2. Sanchez-Tapias JM, et al. AASLD 2004. Abstract 126. 100 50 0 Patients(%) 100 50 0 Patients(%) 32 45 61 Unselected Population [1] HCV RNA positive pts at Wk 4 [2] EOT SVR 5352 72 52 48 wks 72 wks 67 EOT SVR
  9. 9. Nonresponders to PEG + Ribavirin:Nonresponders to PEG + Ribavirin: Reasons for Lack of ResponseReasons for Lack of Response Resistant virusResistant virus Host factorsHost factors Under-dosingUnder-dosing Lack 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
  10. 10. CONCENSUS INTERFERONCONCENSUS INTERFERON
  11. 11. Nonresponders to IFN + RibavirinNonresponders to IFN + Ribavirin Retreatment with Daily CIFNRetreatment with Daily CIFN 120 nonresponders to IFN + Riba120 nonresponders to IFN + Riba 91% genotype 191% genotype 1 28% F3-F428% F3-F4 CIFN 9CIFN 9 µµg/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 18-27CIFN 18-27 µµg/day + WB Riba 12 wksg/day + WB Riba 12 wks
  12. 12. MAINTAINANCE INTERFERONMAINTAINANCE INTERFERON THERAPYTHERAPY
  13. 13. Maintenance IFN for HistologicMaintenance IFN for Histologic RespondersResponders 0 0.5 1 1.5 2 2.5 3 Baseline 30 Months StageofFibrosis Maintained IFN (N=20) Stopped at 6 mo (N=23) Shiffman ML et al. Gastroenterology. 1999;117:1164. 2.5 2.2 1.7 2.4 4 3.5
  14. 14. Cirrhosis May Be ReversibleCirrhosis May Be Reversible Biopsies After 48 Weeks of AntiviralBiopsies After 48 Weeks of Antiviral TherapyTherapy 44 33 22 11 00 StageStage BeforeBefore Patients, nPatients, n AfterAfter Patients, n (%)Patients, n (%) 153 78 (51%) 23 (15%) 26 (17%) 23 (15%) 3 ( 2%) Poynard T et al. Gastroenterology. 2002;122:1303.
  15. 15. Maintenance IFN Therapy Interim 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 α-2b 0.5 µg/kg/wk vs Colchicine 0.6 mg BID OutcomeOutcome PEG-IFNPEG-IFN ColchicineColchicine PP valuevalue 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
  16. 16. Low-dose Peg IFN DecreasesLow-dose Peg IFN Decreases Risk of Variceal BleedingRisk of Variceal Bleeding Afdhal N, et al. AASLD 2004. Abstract 171.  COPILOT (Colchicine vs PEG-IFN LongCOPILOT (Colchicine vs PEG-IFN Long Term) StudyTerm) Study  Randomized, controlled, multicenter, 2-yearRandomized, controlled, multicenter, 2-year interim analysisinterim analysis  Patients with advanced fibrosis or cirrhosis whoPatients with advanced fibrosis or cirrhosis who had failed interferon-based therapyhad failed interferon-based therapy  Clinical outcome at 2 years 1 bleed in 26Clinical outcome at 2 years 1 bleed in 26 patients in PEG group andpatients in PEG group and 11 in 42 patients11 in 42 patients in colchicine groupin colchicine group
  17. 17. Rincon D, et al. AASLD 2004. Abstract 189.  Prospective study of 18 chronic HCV patients treated with PegIFNProspective study of 18 chronic HCV patients treated with PegIFN alfa-2b (1.5alfa-2b (1.5 µµg/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 andHVPG 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 VeinAntiviral Therapy Improves Portal Vein PressurePressure
  18. 18. WATCH AND WEIGHT FORWATCH AND WEIGHT FOR DEVELOPMENT OF NEWERDEVELOPMENT OF NEWER AGENTSAGENTS
  19. 19. 21%21% 32% 71% 100% 0 20 40 60 80 100 Preclinical Phase I - Phase II Phase II - Phase III Phase III - Market FDA Approval AdvancingtoNextPhase(%) 1 Year 3 Years 3 Years 1 Year DiMasi JA, et al. J Health Econ. 2003;22:151-185. Timeline for FDA New Drug Approval A new drug takes approximately 7–8 years to reach the market
  20. 20. Directions in HCV TherapeuticsDirections in HCV Therapeutics ImmunotherapiesImmunotherapies 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®® IFNIFN Ph. IPh. I Transfersome + IFNTransfersome + IFN Roche/RibapharmRoche/Ribapharm LevovirinLevovirin Ph. IPh. I L-isomer of RBVL-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 modulatorHistamine 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 AntifibroticAntifibrotic DiscontinuedDiscontinued
  21. 21. Directions in HCV TherapeuticsDirections in HCV Therapeutics Antiviral 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 inhibitorProtease 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 RibozymeRibozyme DiscontinuedDiscontinued
  22. 22. Proposed AlgorithmProposed Algorithm for Treatment Failuresfor 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 to CIFN + RBV Change to Maintenance IFN Stop Rx Watch and Wait End of Treatment 6 Month Follow-up 24 weeks 48 weeks 72 weeks
  23. 23. Nonresponders: SummaryNonresponders: Summary 1.1. Nonresponders to standard IFNNonresponders to standard IFN ±± ribavirinribavirin:: consider treatment with PEG + ribavirinconsider treatment with PEG + ribavirin 2.2. Nonresponders to PEG + ribavirin: considerNonresponders to PEG + ribavirin: consider same treatment if there was inadequate dosing,same treatment if there was inadequate dosing, adherence, or monitoringadherence, or monitoring 3.3. Further attempts to cure HCV are mostFurther 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)
  24. 24. Nonresponders: SummaryNonresponders: Summary 4.4. Nonresponders with minimal fibrosis:Nonresponders with minimal fibrosis: observe without treatment while waitingobserve without treatment while waiting for new antiviral drugsfor new antiviral drugs 5.5. Nonresponders with advanced fibrosis:Nonresponders with advanced fibrosis: considerconsider  Low-dose maintenance PEG-IFNLow-dose maintenance PEG-IFN  Experimental treatments that might suppress virusExperimental treatments that might suppress virus or inhibit fibrosisor inhibit fibrosis
  25. 25. • 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
  26. 26. • 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.)
  27. 27. THANK YOU FOR YOURTHANK YOU FOR YOUR ATTENTIONATTENTION

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