Guidelines hep c  palestine may 2010
Upcoming SlideShare
Loading in...5
×
 

Guidelines hep c palestine may 2010

on

  • 526 views

Guidelines hep c palestine may 2010

Guidelines hep c palestine may 2010

Statistics

Views

Total Views
526
Views on SlideShare
505
Embed Views
21

Actions

Likes
0
Downloads
11
Comments
0

1 Embed 21

http://psgastro.ps 21

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Slide . Projection of Lifetime Outcomes in HCV Infection Efforts to portray the natural history of HCV infection are complicated by a number of factors, including the asymptomatic nature of the early disease process and the lack of awareness among the general population, especially in less developed nations. This slide depicts the natural history of HCV infection as proposed by Alter and Seeff in a review of long-term outcomes data. This projection of the lifetime outcomes in HCV infection is based on a composite of available data and the most accurate estimates of the frequency of events that enhance liver disease progression. Alter and Seeff have incorporated data from retrospective, prospective, and cohort studies in their examination of the outcomes in HCV infection.   Alter HF, Seeff LB. Semin Liver Dis. 2000;20:17 – 35.
  • Più frequenti criteri di esclusione adottai nei tials Petrtanto tutte le persone con tali criteri di esclusione non sono studiati nei trials E sulle persone con tali carrateristiche later funziona, funzionerebbe, funzionerà????
  • Goals of Therapy Clinically relevant goals for treatment of HCV are classified as primary or secondary. The primary goal is the eradication of the virus as evidenced by negative HCV RNA. The secondary goals include the histologic improvement of hepatic inflammation and fibrosis as evidenced by delayed fibrosis and progression to cirrhosis and prevention of hepatic decompensation and HCC. Reference Lindsay KL. Introduction to therapy of hepatitis C. Hepatology . 2002;36:S114-S120.
  • New Definitions of Early Virologic Response to Antiviral Therapy for Hepatitis C Patients who achieve an Early Virologic Response (EVR) can be further categorized as achieving a complete EVR (cEVR) or partial EVR (pEVR). Patients who achieve pEVR (detectable but ≥ 2 log 10 drop in HCV RNA at week 12), can be categorized as slow responders or partial responders. Slow responders are those patients who have ≥ 2 log 10 drop in HCV RNA at week 12 and are HCV RNA negative at week 24. Partial responders, on the other hand, remain HCV RNA positive at week 24. References Marcellin P, Jensen DM, Hadziyannis SJ, Ferenci P. Differentiation of early virologic response (EVR) into RVR, complete EVR (cEVR) and partial EVR (pEVR) allows for a more precise prediction of SVR in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (Pegasys) and ribavirin (Copegus). Presented at AASLD 2007. Oct. 2-6, 2007; Boston, MA. Poster #1308. Sánchez-Tapias JM, Ferenci P, Diago M, et al. How can we identify HCV genotype 1 patients who may benefit from an extended treatment duration with peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (Copegus)? Presented at EASL 2007. April 11-15, 2007; Barcelona, Spain. Poster #641. M10, S04
  • Slide . Quantitative HCV tests: dynamic ranges Results of viral load tests can be expressed in terms of copies per mL (which are not interchangeable between assays), and international units (IU) per mL (which can be used to make direct comparisons among assays). Assays to detect anti-HCV in patients on antiviral therapy include the COBAS AMPLICOR™ HCV MONITOR Test, v2.0 , a quantitative test used to determine the concentration of HCV RNA with a range of detection from 600 IU/mL to 500 000 IU/mL, and the AMPLICOR HCV MONITOR ® Test, v2.0 with a range of detection from 600 IU/mL to 850 000 IU/mL. 1 These tests have a qualitative lower limit of detection of approximately 50 IU/mL. 2 The COBAS TaqMan™ HCV Test has a lower limit of detection of 30 IU/mL and an upper limit of 200 million IU/mL. Another quantitative assay for monitoring viral concentrations of HCV is SuperQuant™, which has a quantitative range of 100 copies/mL to 100 million copies/mL of HCV RNA. 3 The Bayer Versant HCV RNA 3.0 Quantitation by bDNA (branched-chain DNA) assay has a quantitative range of 615 IU/mL to 7.7 million IU/mL. The Bayer Versant transcription mediated amplification (TMA) viral load test is a qualitative HCV assay that uses molecular diagnostics technology called TMA to detect the presence of HCV RNA. Its lower limit of detection is less than 50 IU/mL. 4 1. Roche Molecular Diagnostics. 2. Strader D, et al. Hepatology 2004; 39: 1147 3. National Genetics Institute. SuperQuant™ 4. Pawlotsky, J-M. Hepatology 2002; 36: S65
  • RVR Important Predictor of SVR: Results SVR rates were similar across genotypes in patients achieving an RVR. Multiple logistic regression analysis confirmed that RVR predicted SVR. In patients with an RVR, genotype was not a significant predictor of SVR. Reference Fried MW, Hadziyannis SJ, Shiffman M, Messinger D, Zeuzem S. Rapid virological response is a more important predictor of sustained virological response (SVR) than genotype in patients with chronic hepatitis C virus infection. Presented at EASL 2008. April 23-27, 2008; Milan, Italy. Abstract #7. F22
  • Predictors of Week 12 Response and SVR by Magnitude of Response at Week 4: Methods This retrospective analysis of 2 phase III studies in HCV genotype 1 patients treated with Pegasys plus RBV sought to determine whether magnitude of response at 4 weeks predicts response at 12 weeks and SVR in patients who do not achieve rapid virologic response. References Marcellin P, Reau N, Ferenci P, Jensen DM. Refined prediction of week 12 response and SVR based on the virological response at week 4 in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS). Presented at AASLD 2008. Nov 1-4, 2008; San Francisco, CA. Poster #1853. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med . 2002;347(13):975-982. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140(5):346-355. F25, H01, M14
  • Virologic Response Rates in G1 Patients With and Without an RVR A total of 90 patients (16%) had an RVR at week 4. When grouped according to RVR status (RVR vs no RVR) patients without an RVR were much less likely to be HCV RNA negative at week 12 and to attain SVR. Reference Marcellin P, Reau N, Ferenci P, Jensen DM. Refined prediction of week 12 response and SVR based on the virological response at week 4 in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS). Presented at AASLD 2008. Nov 1-4, 2008; San Francisco, CA. Poster #1853. M14
  • Predictors of Week 12 Response and SVR by Magnitude of Response at Week 4: Methods This retrospective analysis of 2 phase III studies in HCV genotype 1 patients treated with Pegasys plus RBV sought to determine whether magnitude of response at 4 weeks predicts response at 12 weeks and SVR in patients who do not achieve rapid virologic response. References Marcellin P, Reau N, Ferenci P, Jensen DM. Refined prediction of week 12 response and SVR based on the virological response at week 4 in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS). Presented at AASLD 2008. Nov 1-4, 2008; San Francisco, CA. Poster #1853. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med . 2002;347(13):975-982. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140(5):346-355. F25, H01, M14
  • Virologic Response Rates at Weeks 12 and 72 in Genotype 1 Patients When patients without RVR were subdivided according to the magnitude of reduction in HCV RNA levels between baseline and week 4, probability of SVR correlated with degree of response at week 4, with the highest likelihood of SVR occurring in those with unquantifiable (77%) or > 3 log 10 drop (61%) at week 4. There was a similar trend in the proportion of patients within each subgroup who were HCV RNA-negative at week 12. Reference Marcellin P, Reau N, Ferenci P, Jensen DM. Refined prediction of week 12 response and SVR based on the virological response at week 4 in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS). Presented at AASLD 2008. Nov 1-4, 2008; San Francisco, CA. Poster #1853. M14
  • Predictors of Week 12 Response and SVR by Magnitude of Response at Week 4: Conclusions Rapid virologic response is a good predictor of SVR in patients treated with peginterferon alfa-2a and ribavirin. Even in patients without RVR, degree of decline in HCV RNA levels between baseline and week 4 can be useful in predicting SVR. Unquantifiable ( ≥ 50, but < 600 IU/mL) HCV RNA or > 3 log 10 drop in HCV RNA levels are highly predictive of SVR. Reference Marcellin P, Reau N, Ferenci P, Jensen DM. Refined prediction of week 12 response and SVR based on the virological response at week 4 in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS). Presented at AASLD 2008. Nov 1-4, 2008; San Francisco, CA. Poster #1853. M14
  • Patients With a Durable SVR at Mean 4.1 (0.4 – 7) Years Follow-up The vast majority of patients who achieved an SVR had a durable response at a mean follow-up of 4 years irrespective of their disease status or treatment regimen. Reference Swain M, Lai MY, Shiffman ML, et al. Durable sustained virological response (SVR) after treatment with peginterferon alfa-2a (40KD) (Pegasys) alone or in combination with ribavirin (Copegus): 5-year follow-up and the criteria of a cure. Presented at EASL 2007. April 11-15, 2007; Barcelona, Spain. Abstract #1. S52
  • LOCF, last observation carry-forward.   The results showed that there was no change in platelet levels at Week 4 compared with baseline levels in placebo patients; however, for patients who received 30 mg/day, 50 mg/day, or 75 mg/day eltrombopag, there was a significant increase in platelet counts up to levels that enabled the majority of patients to complete HCV treatment.
  • AEs, adverse events; Hb, hemoglobin; IFN, interferon; pegIFN, peginterferon; PI, package insert; RBV, ribavirin; SC, subcutaneous; TIW, 3 times each week.   This slide lists some of the definitions related to hematologic adverse events as outlined in package inserts. In dealing with these events, growth factors are not used very often, with approximately 5% to 10% of patients receiving erythropoietin, and even fewer receiving filgrastim  
  • AEs, adverse events; Hb, hemoglobin; IFN, interferon; pegIFN, peginterferon; PI, package insert; RBV, ribavirin; SC, subcutaneous; TIW, 3 times each week.   This slide lists some of the definitions related to hematologic adverse events as outlined in package inserts. In dealing with these events, growth factors are not used very often, with approximately 5% to 10% of patients receiving erythropoietin, and even fewer receiving filgrastim  
  • Slide . Quantitative HCV tests: dynamic ranges Results of viral load tests can be expressed in terms of copies per mL (which are not interchangeable between assays), and international units (IU) per mL (which can be used to make direct comparisons among assays). Assays to detect anti-HCV in patients on antiviral therapy include the COBAS AMPLICOR™ HCV MONITOR Test, v2.0 , a quantitative test used to determine the concentration of HCV RNA with a range of detection from 600 IU/mL to 500 000 IU/mL, and the AMPLICOR HCV MONITOR ® Test, v2.0 with a range of detection from 600 IU/mL to 850 000 IU/mL. 1 These tests have a qualitative lower limit of detection of approximately 50 IU/mL. 2 The COBAS TaqMan ™ HCV Test has a lower limit of detection of 30 IU/mL and an upper limit of 200 million IU/mL. Another quantitative assay for monitoring viral concentrations of HCV is SuperQuant™, which has a quantitative range of 100 copies/mL to 100 million copies/mL of HCV RNA. 3 The Bayer Versant HCV RNA 3.0 Quantitation by bDNA (branched-chain DNA) assay has a quantitative range of 615 IU/mL to 7.7 million IU/mL. The Bayer Versant transcription mediated amplification (TMA) viral load test is a qualitative HCV assay that uses molecular diagnostics technology called TMA to detect the presence of HCV RNA. Its lower limit of detection is less than 50 IU/mL. 4 1. Roche Molecular Diagnostics. 2. Strader D, et al. Hepatology 2004; 39: 1147 3. National Genetics Institute. SuperQuant™ 4. Pawlotsky, J-M. Hepatology 2002; 36: S65

Guidelines hep c  palestine may 2010 Guidelines hep c palestine may 2010 Presentation Transcript

  • The First Congress of the Palestinian Society of Gastroenterology (20-22) May 2010 Recent guidelines/strategies in chronic hepatitis C therapy Antonio Ascione MD Consultant Hepatologist Center for liver diseases Fatebenefratelli Hospital Naples - ITALY
  • The overall prevalence, according to the WHO, is around 3% (range 1–10%). Hepatitis C virus (HCV) infection is aworldwide problem with at least 150–180 million of people chronically infected.
  • Outcomes of HCV Infection 100 acute HCV infections 20% recovery 80% persistent infections 20 patients 80 patients Alcohol 30% stable, chronic, 40% variable 30% severe HBV nonprogressive progression progressive hepatitis HIV Iron 24 patients 32 patients 24 patientsSteatosis Antiviral therapy 56 patients End-stage disease, HCC, Treatment Sustained liver transplantation, failure (~40%) response (~60%) death 13% LIVER RELATED 22 patients 34 patients DEATHS IN 20 YRS
  • Development of therapies for HCV chronic hepatitis (SVR) 66% Achille’s heel of guidelines: • Fixed dose of the drugs • Fixed lenght of treatment • Characteristics of host response not taken into consideration
  • Which Patients Should Be Treated ? XHCV carriers older than 65y NO / YESHCV carriers with normal ALT NO / YESHCV carriers with abnormal ALT • Mild histology NO / YES Decision should depend on: - Age < 40-45 yrs - ALT profile > x 3 - 4 - Histologic activity - HCV Genotype 2/3 • Moderate / severe YES
  • LONG-TERM OUTCOME AFTER ANTIVIRALTHERAPY OF DECOMPENSATED CIRRHOTICPATIENTS WITH HEPATITIS C VIRUS INFECTIONIACOBELLIS Angelo, et al.Division of Gastroenterology and Digestive Endoscopy,“Casa Sollievo della Sofferenza” Hospital, IRCCS, S. Giovanni RotondoResults. Among 75 treated patients, 24 individuals (32%) achieved an SVR. Conclusions. In cirrhotic patients secondary to HCV infection who have progressed to a stage of liver decompensation, attaining an SVR after antiviral therapy has a substantial positive impact on the long-term prognosis. Accepted as oral presentation, MASL First meeting, Napoli (ITALY), June 13-15,2010
  • Typical exclusion criteria in RCTs of therapy in chronic hepatitis C Age> 65 yrs Depression Low hemoglobin (<12 g/dl) Psychiatric disease Low WBC count (<3,000/mm3) Coronary artery dis Neutropenia (<1,500/mm3) Cerebrovascular dis Thrombocytopenia (< 100,000/ Neurologic illness mm3) Seizure disorders Decompensated liver disease Alcohol abuse Bilirubin >2.0 mg/dL IV drug use Albumin <3.5 g/dL Methadone treatment Prothr time >2 sec prolonged Hemophilia Creatinine >1.5 mg/dL Hemoglobinopathy Alphafetoprotein >50 mg/dL Autoimmunity HBsAg+ Thyroid diseases Any other known liver disease Institutionalization
  • Schedules for Naive Patients PEG-IFN α2a 180 μg/week orHCV - 1/4 Ribavirin 1000 (</=75 Kg) - 1.200 (>75 Kg) / dx 48 weeks TREATMENT MUST BE PEG-IFN α2b 1.5 µg/Kg/wk PERSONALIZED AND Ribavirin 800/1400 according body weight GUIDED BY THEHCV - 2/3 RESPONSE TO THERAPY PEGs same dosages, less ribavirinx 24 weeks DURATION: shorter ? Longer ?
  • FIRST OF ALLAnalyse carefully THE PATIENTAnd try and modify negative factors
  • PATIENT DISEASE THERAPY
  • Which patient must be treated?All those who show signs of progressive liver disease and have no contraindications to the treatment (Consensus NIH, EASL, APASLD, AISF)All patients HCV-RNA positive should be evaluated for therapy because of the natural history of HCV chronic infection
  • HIPPOCRATES (Kos ~460 - Larissa~ 377 B.C.) PRIMUM NON NOCEREA fundamental medical precept: first do not harm
  • CONTRAINDICATIONSPEG-IFNAutoimmune liver diseases IN decompensation in patients with cirrhosisHepatic FEMALE UNDER THERAPYNeonates and infants CHECK MONTLYHypersensitivity THE PREGNANCY TESTPEG-IFN PLUS RIBAVIRINPregnant womenMen whose partners are pregnantHemoglobinopathies (thalassemia)Hypersensitivity
  • WARNINGSPEGINTERFERON CAN CAUSEMay cause or aggravate fatal or life-threatening neuropsychiatric,autoimmune, ischemic, and infectious disorders. Monitor closely withperiodic clinical and laboratory evaluations and withdraw therapy inpatients with persistently severe or worsening signs or symptoms of theseconditionsRIBAVIRIN CAN CAUSEHemolytic anemia. The anemia associated with ribavirin therapy mayresult in a worsening of cardiac diseaseRibavirin is genotoxic and mutagenic and should be considered a potentialcarcinogenRibavirin may cause birth defects and/or death of the fetus. Extreme caremust be taken to avoid pregnancy in female patients and in femalepartners of male patients Ribavirin is not effective as monotherapy
  • Side effectsNearly all patients experience one or more AEMost common are: flu like syndrome, fatigue, The patientarthralgias, insommia,pyrexia, myalgia, headache, should know everythinganorexia, ansiety, depression, irritability,psychiatric reactions since the beginningOther common symptoms are: anorexia, nausea,vomiting, diarrea, pruritus, alopecia, injection sitereactions
  • Goals of Therapy in HCV hepatitis• Primary goal – Eradicate HCV infection  SVR• Secondary goals – Slow disease progression – Improve histology – Reduce risk of hepatocellular carcinoma – Improve health-related quality of life Lindsay et al. Hepatology. 2002;36:S114-S120.
  • Sustained virological response to interferon-alpha is associated with improved outcome in HCV- related cirrhosis: a retrospective study. S. Bruno, T. Stroffolini, S. Bollani, A. Ascione,G. Mazzella, L. Benvegnù, A. Mangia, P Andreone,M. Persico, G. F. Gaeta, P. Almasio on behalf of the AISF Group HEPATOLOGY 2007;45:579-87.
  • Kaplan Meier curves of liver-related mortality according to the achievement of SVR 1,0 SVR ,8 No SVR p<0.001 by Log Rank test ,6 ,4 ,2 0,0 0 24 48 72 96 120 144 168 Patients at risk months SVR 199 194 185 173 118 73 23
  • Kaplan Meier curves of HCC development according to the achievement of SVR 1,0 Surveillance is ,8 mandatory for these subjects ,6 p<0.001 by Log Rank test ,4 No SVR ,2 SVR 0,0 0 24 48 72 96 120 144 168Patients at risk monthsSVR 199 194 185 173 117 72 21
  • Survival Sustained virological responders p=0.02 log rank testSurvival probability (%) Treatment failure MONTHSPicciotto FP et al, J Hepatol. 2007;46:459-65.
  • Effects of IFN Treatment on HRQOL Baseline to 48-week mean changes3025 Virologic Responders (41) Virologic Non Responders (396)201510 5 0 Phys. Role-ph. Bodily Gen. Vitality Soc. Role emot. Mental Funct. pain Health Funct. Health (Multicenter Italian Study, 2004)
  • Histological Response AmongSustained Virological Responders 100 83% Histological Response (%) 79% 80 62 / 75 Patients With 19 / 24 P = 0.76 60 40 20 0 IFN α-2a PEG (40kDa) IFN α-2a 3 MIU 180 µg J. Heathcote et al, NEJM, 2000
  • The effect of peginterferon α-2a on liver histology in chronic hepatitis C: a meta analysis of individual patients data Subgroup analysis of patients with cirrhosis (n=198) 66.1% 4 4Before 3 24.2% 3 3 After 1 9.6 % 1 1 0 0% 0 0 SVR the only predictor for staging improvement Cammà et al, Hepatology, 2004
  • Poynard et al ., Gastroenterology 2004
  • FULL REVERSAL OF CIRRHOSIS REMAINS: A VIRTUAL REALITYOF STATISTICAL ILLUSIONS Valeer Desmet, J hepatol, 2005
  • Patterns of Virological Response Baseline Treatment Nonresponder Breakthrough HCV RNA Partial responder Relapser Detection limit Sustained HCV RNA responder (cure)Undetectable 6 months Time
  • Short term reponse of HCV-RNA to IFN Direct antiviral Immune action Clearance Null-responderSerum HCV RNA 1st phase Flat partial responder Slow partial responder 2nd phase detection limit 0 1 2 3 7 14 21 28 Days Rapid virological responder or SUPERESPONDERS
  • Patterns of Virological Response Initial Response to Post treatment observation response treatment HCV RNA “Nonresponse” Based on EVR Complete EVR (cEVR)RVR EVR LLD Partial EVR (pEVR) SVRWEEKS 0 1 4 12 18 24 4872 Modified from Pawlotsky JM, Hepatology vol. 32, #5, 2000
  • New Definitions of Response to TreatmentRapid Virologic HCV RNA undetectable by Week 4Response (RVR)Early Virologic ≥ 2 log decline in HCV RNA by Week 12Response (EVR)End of Treatment Undetectable HCV RNA at end of treatment(EOT) ResponsePartial Virologic ≥ 2 log decline in HCV RNA by Week 12, but HCVResponse RNA detectable at Week 24SustainedVirologic HCV RNA negativity 12-24 weeks after treatment endResponse (SVR)
  • Quantitative HCV-RNA (IU/mL) Tests Dynamic Ranges of AssaysSuperQuant™ 100 copies/mL 100 million copies/mL ROCHE COBAS TaqMan™ 15 IU/mL 100 million IU/mL HCV TestRoche COBAS AMPLICOR™HCV MONITOR Test, v2.0 600 IU/mL 500 000 IU/mLRoche AMPLICOR HCVMONITOR® Test, v2.0 600 IU/mL 850 000 IU/mLBayer bDNA 3.0 615 IU/mL 7.7 million IU/mLDisclaimer: Information on this slide represents my opinions, not those of Roche
  • RVR is an Important Predictor of SVR • Methods − Subanalysis of 3 phase III trials: ACCELERATE, Fried, Hadziyannis − 1.383 patients treated for 24 (G2/3) or 48 (G1/4) weeks with Pegasys 180 mcg/wk plus ribavirin 800 mg/d (G2/3) or 1.000/1.2000 mg/d (G1/4)Fried WW et al, presented at EASL 2008, April 23-27, 2008, Milan, Italy, Abstract #7
  • STOPPING RULES TELL YOUTO STOP TREATMENT IF AT W12HCV-RNA IS STILL POSITIVE
  • Why an RVR/EVR-guided Approach Makes Sense● Simplification of treatment in pts with a good prognostic profile (=RVR)● Intensification of treatment in pts with a poor prognostic profile (non-RVR + EVR)● Motivation of patients achieving early responses
  • HOW CAN WE OBTAIN BETTER RESULTS?• PAY ATTENTION TO THE BAD FRIENDS• ADHERENCE TO PRESCRIBED THERAPY• RIBAVIRIN ANEMIA AND LEUKOPENIA• TREAT SIDE EFFECTS!
  • BAD FRIENDS • ALCOHOL • OVERWEIGHT • IRON • STEATOSIS• METABOLIC DISORDERS
  • ADHERENCE TO PRESCRIBED THERAPY
  • Side efffects must be treated Granulocyte-Col Stimulating Factor
  • How can we improve treatment outcomes? Identify and Genotype is the most importantmanage predictorsof poor response baseline predictor of responseUse on-treatment 1. Response-guided therapy (RGT) predictors of 2. Optimisation of ribavirin dosing response andoptimise ribavirin Treatment options for New strategies non-respondersFuture strategies New molecules
  • Swain et al EASL Meeting, 2007,
  • CONCLUSIONS• Safety comes first! Check contraindications.• Follow carefully the patient for side effects: don’t reduce/stop therapy too early: don’t run away. Compliance is crucial.• Follow the on-treatment virological response in order to decide the duration of therapy• RVR is highly predictive of success.• Use an appropriate test for HCV-RNA quantification.• Optimize the treatment with the drugs now available (PEG+RIBA).
  • Island of Procida (Napoli - ITALY)CorricellaFisherman’s Port at sunrise Materiale per Roma Grazie
  • BACK UP SLIDES
  • PEGINTERFERON PLUS RIBAVIRIN IS THE STANDARD OF CARE FOR HCV CRHONIC INFECTIONMany side effects:Anemia caused by Ribavirin and PEG-IFNNeutropenia caused by PEG-IFNThrombocytopenia caused by PEG-IFN
  • SYMPTOMS ASSOCIATED WITH:• Anemia – Fatigue, impaired QoL, and reduced adherence – Can increase risk of myocardial ischemia, other cardiovascular abnormalities • Higher risk in patients with chronic obstructive pulmonary disease• Neutropenia – Can predispose to infection (very rare in immunocompetent)• Thrombocytopenia – Can predispose to bleeding (very rare)
  • SIDE EFFECTS - 1 GENOTYPE 1/4 GENOTYPE 2/3 PEG-IFN PEG-IFN PEG-IFN PEG-IFN ALPHA-2a PLUS ALPHA-2b PLUS ALPHA-2a PLUS ALPHA-2b PLUS TOTAL RIBAVIRIN (N=93) RIBAVIRIN (N=93) RIBAVIRIN (N=67) RIBAVIRIN(N=67) Number (%) Number (%) Number (%) Number (%) Number (%)DISCONTINUATION 3 (3.2) 13 (14) 1 (1.5) 9 (13.4) 26 (8.1) Laboratory 0 5 (5.4) 0 0 5 (1.6) abnormalities* Adverse Events 3 (3.2) 8 (8.6) 1 (1.5) 9 (13.4) 21 (6.6) DOSE 33 (35.5) 33 (35.5) 19 (28.4) 23 (34.3) 108 MODIFICATION ** (33.7) LABORATORY ABNORMALITIES* Anemia 17 (18.3) 20 (21.5) 13 (19.4) 10 (14.9) 60 (18.7) Neutropenia 3 (3.2) 3 (3.2) 1 (1.5) 1 (1.5) 8 (2.5)Thrombocytopenia 4 (4.3) 3 (3.2) 3 (4.5) 3 (4.5) 13 (4.1)NO ADVERSE EVENT 9 (9.7) 7 (7.5) 7 (10.4) 7 (10.4) 30 (9.4)* Laboratory abnormalities included anemia, neutropenia, thrombocytopenia** > 20% PEGINTERFERON or RIBAVIRIN dose modification
  • General Guidelines for RBV Dose Reduction or Discontinuation Laboratory Manufacturer Package Insert values RecommendationsHemoglobin No change in RBV dose if patient has minimal symptoms< 11.0 but> 10 g/dL In a symptomatic anemic patient, consider RBV dose reduction by 200 mg/day and/or starting an erythropoietic growth factor Decrease RBV by 200 mg/day and/or consider starting an erythropoietic< 10.0 but growth factor> 8.5 g/dL Recheck hemoglobin levels at least every 2 wks or more frequently if indicated< 8.5 g/dL Discontinue until resolutionIn patients with stable underlying cardiac disease, reduceribavirin by 200 mg/day if ≥ 2 g/dL drop in hemoglobin occursover a 4-week period. If the hemoglobin level is < 12 g/dLafter 4 weeks of dose reduction, discontinue RBV untilresolution and reevaluation.
  • Laboratory Values Manufacturer Package Insert RecommendationsLABORATORY MANUFACTURER PACKAGE INSERT VALUES RECOMMENDATIONSWhite blood cell count< 1.5 x 109/L PegIFN alfa-2b: reduce dose by 50% and re-evaluate< 1.0 x 109/L PegIFN alfa-2b: discontinue until resolutionAbsolute neutrophil count PegIFN alfa-2a: reduce dose to 135 µg/wk and re-evaluate< 0.75 x 109/L PegIFN alfa-2b: reduce dose by 50% and re-evaluate< 0.50 x 109/L PegIFN alfa or cIFN: discontinue until resolutionPlatelet count< 80,000/mm3 PegIFN alfa-2b: reduce dose by 50% and re-evaluate PegIFN alfa-2a: reduce dose to 90 µg/wk and re-evaluate< 50,000/mm3 PegIFN alfa-2b or cIFN: discontinue until resolution< 25,000/mm3 PegIFN alfa-2a: discontinue until resolution
  • HOW TO MANAGE ANEMIA IN CLINICAL PRACTICE ? Full blood count at week 2 Hb >11 Hb <10 Check in 2 weeks Reduce dose of RBV And check weekly If Hb>10follow up every 2 w Accurate evaluation of the patient (age, heart problems, SVR?
  • HOW TO MANAGE NEUTROPENIA IN CLINICAL PRACTICE ? Full blood count at week 2 Neutrophils >750 mm3 Neutrophils <750 mm3 Reduce dose and check Check in 2 weekly weeks If N between 750 and If N still < 750 giveIf N >750 follow-up 1000 Continue same dose for 2 w every 2 weeks If N > 1000 go back With weekly check If N >750 increase dose to initial dose and check weekly
  • Granulocyte colony-stimulatingfactor ( G-CSF): FILGRASTIM ,LENOGRASTIM,PEGFILGRASTIM300 µg SC TIW Cost: 183,26 EuroShould not be given as primarytherapy to prevent pegIFN alfa dosereductions
  • Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment 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 by LOCF analysis in all eltrombopag dose groups compared with placebo (P ≤ .001) Median Platelet Count, x 103/µL (Range) Treatment Week Eltrombopag Eltrombopag Eltrombopag Placebo 30 mg/day 50 mg/day 75 mg/day Baseline, N = 74 55 (27-75) 59 (34-94) 52 (26-66) 54 (28-75) Week 4 53 (34-74) 137 (40-528) 214 (47-499) 209 (78-527)  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 therapyMcHutchison JG, et al. N Engl J Med. 2007;357:2227-2236. clinicaloptions.com/hep
  • Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment Hematologic AEs Associated With HCV Therapy Anemia Neutropenia Thrombocytopenia Definition  Hemoglobin < 12 g/dL  Absolute neutrophil count  Platelets < 75,000/mL  > 3 g/dL decrease in Hb < 750 cells/mL Etiology  RBV: hemolysis  Interferon: bone marrow  Interferon: bone marrow  IFN: bone marrow suppression suppression suppression Monitor  Monitor labs closely first  Monitor labs closely first  Monitor platelet counts closely weeks weeks during the first weeks  Assess severity of symptoms  Assess severity of symptoms  Assess for gum bleeding, bruising, nose bleeds Dose Adjust  Adjust ribavirin dose  Adjust interferon dose  Adjust interferon dose Consider  Epoetin alfa 40,000 units SC  Granulocyte colony-stimulating  Administration of oprelvekin is Pharmacologic weekly or darbepoetin alfa 3 factor 300 µg SC TIW associated with edema in the Intervention* µgKg SC every other week  Should not be given as lower extremities and cannot primary therapy to prevent be recommended pegIFN alfa dose reductions  Phase II studies of 75 mg/day eltrombopag shows promise *Off-label use.PEG-Intron [package insert]. Kenilworth, NJ: Schering Corp; March 2008. Pegasys [package insert].Nutley, NJ: Roche Pharmaceuticals; January 2008. Soza A, et al. Hepatology. 2002;36:1273-1279. McHutchison JG, et al. N Engl J Med. 2007;357:2227-2236. clinicaloptions.com/hep
  • Maintaining Patients on HCV Treatment: Strategies for Successful Retreatment Hematologic AEs Associated With HCV Therapy Anemia Neutropenia Thrombocytopenia Definition  Hemoglobin < 12 g/dL  Absolute neutrophil count  Platelets < 75,000/mL  > 3 g/dL decrease in Hb < 750 cells/mL Etiology  RBV: hemolysis  Interferon: bone marrow  Interferon: bone marrow  IFN: bone marrow suppression suppression suppression Monitor  Monitor labs closely first  Monitor labs closely first  Monitor platelet counts closely weeks weeks during the first weeks  Assess severity of symptoms  Assess severity of symptoms  Assess for gum bleeding, bruising, nose bleeds Dose Adjust  Adjust ribavirin dose  Adjust interferon dose  Adjust interferon dose Consider  Epoetin alfa 40,000 units SC  Granulocyte colony-stimulating  Administration of oprelvekin is Pharmacologic weekly or darbepoetin alfa 3 factor 300 µg SC TIW associated with edema in the Intervention* µgKg SC every other week  Should not be given as lower extremities and cannot primary therapy to prevent be recommended pegIFN alfa dose reductions  Phase II studies of 75 mg/day eltrombopag shows promise *Off-label use.PEG-Intron [package insert]. Kenilworth, NJ: Schering Corp; March 2008. Pegasys [package insert].Nutley, NJ: Roche Pharmaceuticals; January 2008. Soza A, et al. Hepatology. 2002;36:1273-1279. McHutchison JG, et al. N Engl J Med. 2007;357:2227-2236. clinicaloptions.com/hep
  • Virological Response: NEW definitions Rapid virological response HCV-RNA undetectable at week 4 SHORTER IFN/RIBA REGIMEN (?) Early virological response HCV-RNA undetectable at week 12 12 WEEKS RULE FOR STOPPING THERAPY
  • Quantitative HCV Tests Dynamic Ranges of AssaysSuperQuant™ 100 copies/mL 100 million copies/mL ROCHE COBAS TaqMan™ 15 IU/mL 100 million IU/mL HCV TestRoche COBAS AMPLICOR™HCV MONITOR Test, v2.0 600 IU/mL 500 000 IU/mLRoche AMPLICOR HCVMONITOR® Test, v2.0 600 IU/mL 850 000 IU/mLBayer bDNA 3.0 615 IU/mL 7.7 million IU/mL HCV RNA IU/mL
  • Importance of Highly Sensitive HCV-RNA Assays for IFN-treatment: 48 vs. 72 Weeks of Treatment W 12: < 2 log HCV RNA Reduction W 24: 24% HCV RNA negative (< 50 IU/ml) 48 Weeks of Therapy 72 Weeks of Therapy Relapse: 87% Relapse: 46% Berg et al. Gastroenterology 2006
  • SUSTAINED VIROLOGICAL RESPONSE ** Manns * Fried * Hadzyiannis * DITTO• ALL NON RESPONDERS 54% 56% 63% 66% ~45%• Gen 1 42% 46% 52% 60% AF ALL TREATED• G1 HVL 30% 41% 47% PATIENTS• >800.000 UI/ml HVL 42% 53% 66% *Pegasys 180 mcg + 1000-1200 mg x 48 weeks **Pegintron 1.5 mcg/Kg + 800 mg x 48 weeks
  • Why does HCV treatment fail?Host factors Virus• Race ? • Genotype• Age • Viral load (patient/infection)• Gender• High estrogens levels Reasons for• Body weight treatment failure• Fibrosis• Siderosis• Steatosis• Diabetes• Active drug abuse• Concomitant Treatment disease • Poor adherence to therapy• COINFECTIONS • Discontinuation for side effects• ALCOHOL • Use of a less than effective regimen (dose/duration)