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Tp Traitement Hcv Du 2010
 

Tp Traitement Hcv Du 2010

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    Tp Traitement Hcv Du 2010 Tp Traitement Hcv Du 2010 Presentation Transcript

    • 25 janv. 2010 VHC Traitement des cas simples Traitement des cas compliqués Thierry Poynard Vlad Ratziu, Yves Benhamou LiverCenter lundi 25 janvier 2010 1
    • 25 janv. 2010 Treatment of Acute Hepatitis C: A la carte from 0 to 1 year LiverCenter lundi 25 janvier 2010 2
    • 25 janv. 2010 The Definition of Acute Hepatitis C • Exposure to HCV • Within 4 months • Anti-HCV seroconversion • Raised ALTs • HCVRNA positivity 3 lundi 25 janvier 2010 3
    • 25 janv. 2010 Rationale for Treating Acute HCV • High risk of chronicity • Risk of spreading the virus • Chances for better cure (no fibrosis, recovery of immune response) 4 lundi 25 janvier 2010 4
    • 25 janv. 2010 Anti-Viral Treatment of Acute HCV • Randomized controlled trials • Meta-analysis • Uncontrolled trials 5 lundi 25 janvier 2010 5
    • 25 janv. 2010 RCTs of IFNα in Acute HCV 4 trials; n=141 All IFN α-2b alone All patients transfused 12 weeks of treatment Age 51yrs, 62% males 9-15 months fw-up • VILLADOMIU n=28 Hepatology 1992 • LI n=32 China J Int Med 1993 • LAMPERTICO n=48 Hepatology 1994 • HWANG n=23 J Hepatol 1994 6 lundi 25 janvier 2010 6
    • 25 janv. 2010 Meta-Analysis of IFN α-2b RCTs in Acute HCV Sustained Response (12mo) Control % Response Interferon 60 45 P < 0.0001 30 15 0 Normal ALT Negative HCVRNA Myers R, Cochrane Database Syst Rev 2003 7 lundi 25 janvier 2010 7
    • 25 janv. 2010 Meta-Analysis of IFN α-2b RCTs in Acute HCV Sustained Viral Response Hwang 1994 (n=33) OR (95% CI) Lampertico 1994 (n=48) Li 1993 (n=32) 4.8 (1.1-22) TOTAL (n=113) 7.7 (1.6-38) 9.9 (1.5-65) 6.8 (2.6-17.5) * 0.1 1.0 10 100 Favours Control Favours IFN *P<0.0001 Myers R, Cochrane Database Syst Rev 2003 8 lundi 25 janvier 2010 8
    • 25 janv. 2010 IFN-α2b Treatment of Acute Hepatitis C Uncontrolled Trial (N=44) • Characteristics: Interferon a-2b for 6 months: • Young 36 yrs Induction dose: 5MU daily for 4 wks • Females (57%) Regular dose: 3MU tiw for 20 wks • Symptomatic (jaundice 68%) Follow-up 24 wks post Rx for viral end-point • Genotype 1 (68%) 89 days (30-112) 54 days (15-105) CONTAMINATION SYMPTOMS TREATMENT Jackel, N Engl J Med 2001 9 lundi 25 janvier 2010 9
    • 25 janv. 2010 Acute Hepatitis C : 43 patients followed 42 sustained responders normal ALT 1 lost follow up Tolerance: 1 stop 12 weeks adverse events IFN 5 M/day % HCV RNA+ IFN 5 M TIW 100 75 50 25 0 Inclusion 12w 24w 48w Jaeckel E et al. N Engl J Med 2001 lundi 25 janvier 2010 10
    • 25 janv. 2010 Anti-Viral Treatment of Acute HCV STRATEGIES 11 lundi 25 janvier 2010 11
    • 25 janv. 2010 Hypothesis: Early control of viral replication prevents chronicity • Treat all patients ? • Treat early ? • Doses of IFN ? • Ribavirin ? • Duration of treatment ? 12 lundi 25 janvier 2010 12
    • 25 janv. 2010 Spontaneous Viral Clearance After Acute HCV Infection % VIRAL TIME PERIOD AUTHOR (N) CLEARANCE 1985-1991 Alter (n=106) 38* 1993-2000 Gerlach (n=54) 44 1988-1996 Villano (n=43) 14 2000-2001 Hofer (n=12) 67 * No PCR, ALT data only 13 lundi 25 janvier 2010 13
    • 25 janv. 2010 Prevalence of Symptoms According to Outcome Self limited Chronic 100 87 % 87 % P=0.02 P=0.002 75 59 % 47 % 50 25 0 JAUNDICE FLU-LIKE SYMPTOMS OR 4.9 (1.3-19) OR 7.8 (2.2-29) Gerlach, Gastroenterology 2003 14 lundi 25 janvier 2010 14
    • 25 janv. 2010 Predictors of Spontaneous Viral Clearance ... • Younger age (?) • Females (?) • White vs. Blacks (?) • Rare Quasispecies • Genotype non-1 • ALT useless • Can normalize despite viral persistence (50%) 15 lundi 25 janvier 2010 15
    • 25 janv. 2010 Early Prediction of HCV Clearance After Acute Infection ? Self Limited Chronic Days after onset of symptoms Hofer, Hepatology 2003 16 lundi 25 janvier 2010 16
    • 25 janv. 2010 Acute hepatitis C and HIV coinfection • «People coinfected with HIV and hepatitis C might progress to chronic liver disease more quickly. • Several recent reports have documented acute hepatitis C among men who have sex with men who engage in high risk sexual practices and often have concomitant genital ulcer disease.» Jodie Dionne-Odom, Lancet Infect Dis 2009 17 lundi 25 janvier 2010 17
    • 25 janv. 2010 Proposal: Treatment Restricted to Patients that Fail to Clear the Virus • Asymptomatic or • HCVRNA still detectable 3-4 months after onset of symptoms • PEG IFN (± ribavirin) treatment, at least 24 weeks ?? 18 lundi 25 janvier 2010 18
    • 25 janv. 2010 Treatment of Chronic Hepatitis C: A la carte from 0 to 5 years LiverCenter lundi 25 janvier 2010 19
    • 25 janv. 2010 Prise en charge de l’Hépatite C en 2010 • Améliorer le dépistage • Simplifier le bilan • Améliorer le traitement • A la carte • Ne pas baisser les bras 20 lundi 25 janvier 2010 20
    • 25 janv. 2010 Chronic Hepatitis B or C FibroTest ActiTest Fibroscan if FibroTest not applicable Advanced Fibrosis No Advanced Fibrosis Severe Activity No Severe Activity FibroTest Hepatologist every 2-4 years HAS for HCV Dec 2007 lundi 25 janvier 2010 21
    • 25 janv. 2010 Approval of HCV treatments Date Endpoint Treatment Approval Reference 1991 ALT Interferon Davis NEJM Poynard Lancet 1998 SVR Interferon Ribavirin McHutchison NEJM Manns NEJM, 2001 SVR PEG Interferon Ribavirin Fried NEJM PEG Interferon Ribavirin, 2011 ? SVR ?? Boceprevir, Telaprevir ?? 2015 ? SVR Xprevir+Yprevir ?? lundi 25 janvier 2010 22
    • 25 janv. 2010 HCV Treatment: % Sustained Virological Response 99 100 88 80 80 73 60 48 40 35 40 20 15 20 5 1 1 0 ol ir w w -R -R v 24 48 tr G re N on PE -P IF N N C IF IF R P- G 1-4-5-6 G 2-3 lundi 25 janvier 2010 23
    • 25 janv. 2010 Factors associated with SVR in HCV • Genotype • Viral load • Fibrosis stage • Age (Duration) • HIV • Male • BMI,Steatosis,Diabetes • Ethnicity, IL-28 Poynard et al Lancet 2003, Gastroenterology 2009 24 lundi 25 janvier 2010 24
    • 25 janv. 2010 Facteur prédictifs «indépendants» de réponse virologique Facteur Naïf 2ème Chance Baseline 12 Weeks Baseline 12 weeks Genotype x x x x Fibrosis stage x x x x Viral load x x x x Age (Duration) x HIV x ? ? ? Male x Stéatose, Diabète x ? ? Ethnicity/IL28 x ? ? ? Previous treatment X Poynard Lancet 2007, Poynard Gastroenterology 2009, Ge Nature 2009, 25 lundi 25 janvier 2010 25
    • 25 janv. 2010 IL28B CC génotype vs non-CC: réponse au traitement 1,628 HCV Genotype 1 IDEAL study ! Ge et al Nature 2009, Thomson et al, submitted lundi 25 janvier 2010 26
    • 25 janv. 2010 Facteurs associès à la réponse au traitement (Genotype 1) Odds Ratio (All <0.0004) IL28B CC genotype vs non-CC 5.2 Charge virale ≤ 600,000 vs > 600,000 IU/mL 3.1 Caucasien vs Afro-Américain 2.8 Fibrose METAVIR F012 vs F34 2.7 Hispanique vs Afro-Américain 2.1 Glycémie < 5.6 vs > 5.6 mmol/L 1.7 Ge et al Nature 2009, Thomson et al, submitted lundi 25 janvier 2010 27
    • 25 janv. 2010 Traitement à la carte avec PEG-Riba? • Attention aux faux amis • G2 et G3 mais • F2F3F4 • Attention au gras et au sucre Poynard et al Hepatology 2000, Lancet 2003, Hepatology 2003 28 lundi 25 janvier 2010 28
    • 25 janv. 2010 Results: SVR Genotype 2 and 3 PEG-IFN α-2b 1.5 μg/kg QW α-2b + ribavirin 800-1,400 mg/day 100 75 50 25 0 HCV 2 (n=42) HCV 3 (n=182) Zeuzem et al, J Hepatol, 2004 29 lundi 25 janvier 2010 29
    • 25 janv. 2010 Results: SVR Genotype 2 and 3 ≤ or > 600,000 IU PEG-IFN α-2b 1.5 μg/kg QW α-2b + ribavirin 800-1,400 mg/day 100 75 50 25 0 G2 ≤ 6 (n=20) G2 > 6 (n=22) G3 ≤ 6 (n=99) G3 > 6 (n=83) Zeuzem et al, J Hepatol, 2004 30 lundi 25 janvier 2010 30
    • 25 janv. 2010 A la carte regimen with PEG-Riba? • Longer duration for Genotype 2 and 3 if • Advanced fibrosis F2F3F4 • Steatosis in genotype 2 • HIV Poynard et al Hepatology 2000, Lancet 2003, Hepatology 2003 31 lundi 25 janvier 2010 31
    • 25 janv. 2010 Genotype 2 and 3 patients F2F3F4 treated PEG IFN alfa 2b and ribavirin flat dose SVR % 78,0 58,5 39,0 19,5 0 PEG IFN-R 48w n=54 32 Zeuzem et al, J Hepatol, 2004 lundi 25 janvier 2010 32
    • 25 janv. 2010 Genotype 2 and 3 patients with bridging fibrosis treated PEG IFN alfa 2a and ribavirin weight based dose SVR 100% 75% 50% 25% 0% PEG IFN-R 24w n=20 Hadziyannis et al Ann Inter Med, 2004 33 lundi 25 janvier 2010 33
    • 25 janv. 2010 Genotype 2 and 3 patients with bridging fibrosis treated PEG IFN alfa 2a and ribavirin weight based dose SVR 100% 75% 50% 25% 0% PEG IFN-R 24w n=20 PEG IFN-R 48w n=33 Hadziyannis et al Ann Inter Med, 2004 34 lundi 25 janvier 2010 34
    • 25 janv. 2010 Genotype 2 and 3 patients with bridging fibrosis treated PEG IFN alfa 2a and ribavirin weight based dose SVR 74 56 37 19 0 PEG IFN-R 24w n=20 PEG IFN-R 48w n=33 Hadziyannis et al Ann Inter Med, 2004 35 lundi 25 janvier 2010 35
    • 25 janv. 2010 Genotype 2 and 3 patients with bridging fibrosis treated PEG IFN alfa 2b and ribavirin weight based dose 14 weeks for VEVR*, 24 weeks for NVEVR EOT SVR 100 75 50 25 0 EVR PEG IFN-R 14w n=14 NEVR PEG IFN-R 24w n=14 *Undetectable 4,8 W Dalgart et al Hepatology, 2004 36 lundi 25 janvier 2010 36
    • 25 janv. 2010 A la carte regimen with PEG-Riba? • Shorter duration (2-4 months) • For Genotype 2 and 3, if no relapse factors Poynard et al Hepatology 2000, Lancet 2003, Hepatology 2003 37 lundi 25 janvier 2010 37
    • 25 janv. 2010 Genotype 2 and 3 patients treated PEG IFN alfa 2b 1.0 ug/Kg and ribavirin weight based dose 12 weeks for VEVR*, 24 weeks for NVEVR Standard Variable 80 60 40 20 0 VEVR SVR *Undetectable 4 W Mangia et al NEJM, 2005 38 lundi 25 janvier 2010 38
    • 25 janv. 2010 Traitement à la carte avec PEG-Riba? N=96 patients naïfs consécutifs: facteurs de risque de rechute • Plus d’un facteur de risque 84% • Génotype 1,4,5,6 58% • Charge virale >= 800,000 IU/ml 38% • Age >40 ans 66% • Sexe masculin 60% • Fibrose avancée: F2, F3, F4 34% Poynard et al Hepatology 2000, D’Arondel JVH 2006 39 lundi 25 janvier 2010 39
    • 25 janv. 2010 Traitement à la carte PEG-Riba D’Arondel JVH 2006 40 lundi 25 janvier 2010 40
    • Background 41 lundi 25 janvier 2010 41
    • 25 janv. 2010 Impact of Steatosis on SVR (uni and multivariate) No Steatosis Steatosis 100 75 50 25 G3 G1,4,5,6 0 Fibrosis G1,4,5,6 HVL+fibrosis Poynard Hepatology 2003 lundi 25 janvier 2010 42
    • 25 janv. 2010 A la carte suisse, ou à l’américaine ? 43 lundi 25 janvier 2010 43
    • 25 janv. 2010 IDEAL Study Design HCV 1 Naive to Previous Therapy PEG-IFN α-2b + ribavirin 800-1400mg/daily 1.5 µg/kg QW (48 wks) N=960 Screening PEG-IFN α-2b + ribavirin 800-1400mg/daily 1.0 µg/kg QW (48 wks) N=960 S* PEG-IFN α-2a + ribavirin 1000-1200mg/daily 180 µg QW (48 weeks) N=960 Endpoint 48 weeks 24 weeks Follow-up S* Stratification: Baseline HCV < vs ≥ 600,000 IU & African American vs non AA Primary Endpoint: Loss of serum HCV RNA 24 weeks posttreatment 44 lundi 25 janvier 2010 44
    • 25 janv. 2010 IDEAL results n=3,070 PEG 2b 1.5 PEG 2b 1.0 PEG 2a 50 40 30 20 10 0 SVR Relapse Discontinuation AE 82% >= 600.000 IU/mL, 11% F3F4, 19% African American lundi 25 janvier 2010 45
    • 25 janv. 2010 Prediction of Sustained Response based on Week 12 HCV-RNA 174 patients treated PEG2b 1.5 Riba 90 90 60 30 26 0 0 PCR+ <2log drop n=31 PCR+ >=2 log n=23 PCR- n=120 lundi 25 janvier 2010 46
    • 25 janv. 2010 Treatment à la Carte 2009 RBV >10.6 mg/kg/d PEG IFN 1.5 µg/kg QW Quantitative viral load at 4/12 weeks Negative or >2-log decrease <2-log decrease PCR at 12/24 weeks Negative Positive Count favorable factors: Stop at 12 weeks ? genotype 2/3, viral load <1 MIU mL Discuss slow responder F0–F1 (FibroTest), BMI <27 PEG IFN for fibrosis prevention if progression is rapid <3 3 or 4 favorable factors favorable factors IL28 in 2010 ?? Stop at 48 weeks Stop at 12/24 weeks lundi 25 janvier 2010 47
    • 25 janv. 2010 Prise en charge de l’Hépatite C en 2010 • Améliorer le dépistage • Simplifier le bilan • Améliorer le traitement • A la carte, surtout si cas compliqués • Ne pas baisser les bras 48 lundi 25 janvier 2010 48
    • 25 janv. 2010 Traitement à la carte avec PEG-Riba? • Ne pas baisser les bras : maladie virale et fibrosante • Traitement anti-fibrosant • On peut vivre avec le virus • On peut mourir sans le virus Poynard et al, Lancet 2003 49 lundi 25 janvier 2010 49
    • 25 janv. 2010 Progression de la fibrose chez les patients VHC avec doubles biopsies, traités ou non par IFN 24-48 semaines F METAVIR 102 contrôles 4 3 91 “non répondeurs” ALT 3 mo 2 1 94 “répondeurs” ALT 3mo 0 0 10 20 30 40 Années Sobesky et al, Gastroenterology 1999 lundi 25 janvier 2010 50
    • 25 janv. 2010 Incidence (per year) of Cirrhosis in patients with Chronic hepatitis C: 2 Randomized trials Reinforced 3MU TIW 6 mo 15 10 p=0.14 p=0.004 5 0 Poynard Degos Poynard T, N Engl J Med 1995 Degos F, J Hepatol 1998 lundi 25 janvier 2010 51
    • 25 janv. 2010 Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy • 593 patients 2 biopsies • 106 Untreated patients 4.8 years • 304 IFN virologic non-responders 3.2 years • 183 IFN virologic responders 3.2 years Y Shiratori, Ann Int Med 2000 52 lundi 25 janvier 2010 52
    • 25 janv. 2010 Fibrosis progression rate per year in patients with Hepatitis C 10 0 -10 -20 -30 IFN-SR IFN-NR Untreated lundi 25 janvier 2010 53
    • 25 janv. 2010 Four pivotal International RCTs SPRI Poynard et al, McHutchison et al, Lindsay et al, Manns et al 4,493 Patients 4 Trials Naive HCV patients 3,010 Patients with paired biopsies One pathologist One virologist Poynard et al Gastroenterology, 2002 lundi 25 janvier 2010 54
    • 25 janv. 2010 Fibrosis progression rate per year in F2-F3-F4 with paired biopsies and duration of infection Before After 0,2 0,1 0,14 0,14 0 0,00 -0,59 -0,1 -0,2 -0,3 P<0.001 -0,4 -0,5 NR (n=679) SVRs (n=210) Titre de catégorie Poynard et al Gastroenterology, 2002 lundi 25 janvier 2010 55
    • 25 janv. 2010 FibroTest: Estimates anti-fibrotic impact Baseline EOF FibroTest 1,0 -10% -31% 0,8 0,71 0,64 0,68 0,6 0,47 0,4 0,2 0 F234 NR n=110 F234 SVR n=65 Poynard et al Hepatology, 2003 56 lundi 25 janvier 2010 56
    • 25 janv. 2010 Reversal of cirrhosis in 75 (49%) of patients F0 F1 153 F2 F3 78 F4 First Second Poynard et al Gastroenterology 2002, Pol et al Hum Pathol 2004, Camma et al Hepatology 2004 57 lundi 25 janvier 2010 57
    • Impact of treatment on FibroTest n=817 1.00 F METAVIR difference 0.75 -3 -2 Fibrotest 0.50 -1 0 1 2 0.25 3 Baseline Follow-up 0.00 Poynard et al Hepatology, 2003 lundi 25 janvier 2010 58
    • 25 janv. 2010 Disappearance of cirrhosis: significant factors No more cirrhosis n=75 Persistent cirrhosis n=78 100 89 100 80 45 47 60 33 45 15 40 Reinforced regimen 23 20 Sustained response Age 0 Activity grade A0A1 after Multivariate analysis P=0.02 Poynard et al Gastroenterology, 2002 lundi 25 janvier 2010 59
    • 25 janv. 2010 Reversibility of Cirrhosis F3 Regression Pararameters (Repair Complex) Delicate perforated septa Isolated thick collagen fibers Delicate periportal fibrosis spikes Portal tracts, Hepatic Vein remnants Prolapsed Hepatocytes, Inside Portal tracts or splitting septa, minute regenerative nodules, aberrant parenchymal veins. F4 Wanless, Arch Pathol Lab Med 2000 lundi 25 janvier 2010 60
    • lundi 25 janvier 2010 61
    • 10 Years Later, Right Lobe lundi 25 janvier 2010 62
    • 25 janv. 2010 Beware of hepatocellular carcinoma in sustained virological responders previously F3 or F4 lundi 25 janvier 2010 63
    • 25 janv. 2010 Maintenance therapy trials HALT-C COPILOT EPIC3 Patients Ishak 4-6 Ishak 3 – 6 Metavir 2 –4 N 1000 800 2200 (3 studies) End-point Fibrosis/Clinical Fibrosis /Clinical Fibrosis/Clinical PEG-IFN α−2a PegIntron® Initial Tx. None +riba 800 mg + Rebetol® WBD PEG-IFN α−2a PegIntron® PegIntron® Maintenance Tx. 90 μg 0.5 μg/kg 0.5 μg/kg Maintenance Control Placebo Colchicine Observation Treatment 3.5 4 3-5 Duration (years) Recruitment Complete Mid-point Analysis Complete Status 64 lundi 25 janvier 2010 64
    • lundi 25 janvier 2010 65
    • 25 janv. 2010 HALT-C: Peg 2a 90 mcg/w 3.5 years Compliance: • 53% still on treatment, • 10% lower dose, • 37% stopped therapy lundi 25 janvier 2010 66
    • 25 janv. 2010 Poynard, Ratziu, NEJM 2009: Lack of power ? • The results only show that, as anticipated in the power calculations, therapy cannot halve the progression rate. • The number of patients correctly treated with paired biopsies at 3.5 years, needs to be given and compared to the number needed to demonstrate a reduction by two of progression with 18 mm biopsies. • The risk of false negative conclusion seems even higher, as a significant impact on necrosis and inflammation has been observed. • Biomarkers to increase the power should have been considered. • The impact on necroinflammatory lesions and transaminases is good news, as these endpoints led to approval of interferon in the first place. • Mortality related to HCV is still growing and the agencies should wait for more trials before reaching such a conclusion. 67 lundi 25 janvier 2010 67
    • 25 janv. 2010 Maintenance therapy trials HALT-C COPILOT EPIC3 Patients Ishak 4-6 Ishak 3 – 6 Metavir 2 –4 N 1000 800 2200 (3 studies) End-point Fibrosis/Clinical Fibrosis /Clinical Fibrosis/Clinical PEG-IFN α−2a PegIntron® Initial Tx. None +riba 800 mg + Rebetol® WBD PEG-IFN α−2a PegIntron® PegIntron® Maintenance Tx. 90 μg 0.5 μg/kg 0.5 μg/kg Maintenance Control Placebo Colchicine Observation Treatment 3.5 4 3-5 Duration (years) Recruitment Complete Mid-point Analysis Complete Status 68 lundi 25 janvier 2010 68
    • 25 janv. 2010 COPILOT – Study Design PEG-IFN-α2b 0.5 µg/kg/wk Interferon / Rebetron / PEG + RIB Non-responders F2-F4 Colchicine 0.6 mg bid Clinical US LB, US, q 24 Endoscopy, Endoscopy, Evaluation endoscopy q 12 Weeks Weeks LB LB Baseline 12 weeks 24 weeks 2 years 5 4 years Jahre  557 patients enrolled  Ishak Fibrosis Stage > 3 69 lundi 25 janvier 2010 69
    • 25 janv. 2010 PEG-IFN alfa-2b: effective maintenance for patients with portal hypertension (PHTN) No. PHTN PHTN Colchicine 134 126 Events 8 (6%) 34 (27%)* PEG-IFN alfa-2b 155 111 Events 12 (7%) 14 (11%)* *Fishers test, P<0.004: PEG-IFN alfa-2b vs. Colchicine 70 lundi 25 janvier 2010 70
    • 25 janv. 2010 Development of PHTN at year 2 Among patients without PHTN at baseline Colchicine PEG-IFN alfa 2b • 92 patients at risk • 95 patients at risk • 8 varices • 20 varices • 4 gastropathy • 4 gastropathy • Overall 12%* • 2 patients developed new varices with bleeding within initial 2 years • Overall 28%* * p = 0.03 71 lundi 25 janvier 2010 71
    • 25 janv. 2010 Portal pressure Studies on Peg-IFN alfa 2b 0.5mcg/kg mm Hg 30 Mean 15mmHg 25 20 Mean 8mmHg 15 10 5 0 Baseline 24 weeks 72 lundi 25 janvier 2010 72
    • EPIC 3 Program Design Non-Responder Trial: N=2200 CHC with fibrosis (F2, F3 or F4 METAVIR) who failed to respond any IFN alfa/alpha + Ribavirin PEG-Intron 1.5 μg/kg/wk + Rebetol 800-1400mg/d N=3136 screened*, 1843 treated* 1369 analyzed for EVR * HCV RNA negative at week 12 METAVIR F4 CHC subjects Subject continue 36 weeks trt Non-responder to any + 24 weeks follow-up IFN alfa/alpha + Ribavirin 978 analyzed for SVR* DIRECT ENROLLERS 570 EVR: 341 neg 229 pos 346 non EVR 2 na Chronic Suppression for Chronic Suppression Non-Cirrhotics, n=700 for Cirrhotics, n=1000 HCV RNA positive at week 12 HCV RNA positive at week 12 METAVIR F2 or F3 subjects METAVIR F4 subjects PEG-Intron 0.5μg/kg/wk vs. control PEG-Intron 0.5μg/kg/wk vs. control Duration: 3 years Max duration: 5 years 385 Randomized* 404 Randomized* 73 lundi 25 janvier 2010 73
    • 25 janv. 2010 Multivariate Regression Analysis Predictors of Response • HCV genotype • G2/3 vs. G1, OR = 4.9; P < 0.0001 • Previous treatment response • Relapser vs. non-responder, OR = 3.8, P <0.0001 • Baseline METAVIR fibrosis score • F2 vs. F4, OR = 2.2; P = <.0001 / F3 vs F4, OR = 1.4; P = 0.0183 • Previous treatment • IFN α + RBV vs. PEG-IFN α + RBV, OR = 2.0, P <0 .0001 • Baseline viral load • ≤600,000 IU/mL vs. > 600,000 IU/mL, OR = 1.9, P < 0.0001 74 lundi 25 janvier 2010 74
    • 25 janv. 2010 SVR in Prior Non-Responders to Peg-Riba Peg-IFN α-2 a + b/R, n = 476 All Patients 0,04 G1 F4 0,04 G1 F3 0,04 G1 F2 0,06 G2/3 F4 0,18 G2/3 F3 0,38 G2/3 F2 0,56 75 lundi 25 janvier 2010 75
    • 25 janv. 2010 SVR in Prior Relapsers to Peg-Riba Peg-IFN α-2 a + b/R, n = 344 All Patients 0,32 G1 F4 0,18 G1 F3 0,21 G1 F2 0,32 G2/3 F4 0,51 G2/3 F3 0,62 G2/3 F2 0,61 76 lundi 25 janvier 2010 76
    • Prognostic value of FibroTest in 1,459 HCV virological non responders EPIC-3 Trial 2009 F0 F1 F2 F3 F4 80 75 60 63 65 61 60 57 SVR % 52 48 40 40 27 29 27 20 24 20 16 15 0 All Biopsy n=1459 EVR Biopsy n=506 All FibroTest n=1459 EVR FibroTest n=506 Poynard Gastroenterology 2009, AASLD 2009 lundi 25 janvier 2010 77
    • 25 janv. 2010 Maintenance therapy with Ribavirin alone Interferon Follow-up Ribavirin Tx 120 P=0.06 n=32 100 80 Sustained R ALT Ribavirin IU/L 60 Placebo 40 20 0 Baseline EOT 12 months 18 months Hoofnagle et al Hepatology, 2003 78 lundi 25 janvier 2010 78
    • 25 janv. 2010 Improvement of Activity Grade (HAI) with Ribavirin 16 Ribavirin 1.0-1.2 vs 16 patients placebo non viral responders Activity Grade Ribavirin Placebo 10 P=0.02 8 6 4 2 0 M0 M18 Hoofnagle et al, Hepatology 2003 lundi 25 janvier 2010 79
    • 25 janv. 2010 Attention: optimiste mais pas trop: nouvelles molécules, Molécules en Développement bénéfice/risque attente ? toujours besoin PEG-Riba • ITMN-191 (Intermune/Roche) • TMC435350 (Medivir/ • Telaprevir (Vertex) Protease •! MK-7009 (Merck) Tibotec) • Boceprevir •! BI 201335 (Schering Plough) Inhibitors (Boehringer Ingelheim) • GS-9190 (Gilead) • R7128 (Pharmasset/Roche) • BMS-790052 (BMS) Polymerase •! PF-00868554 (Pfizer) Inhibitors •! ANA598 (Anadys) •! BILB 1941 (Boehringer Ingelheim) • Bavituximab (Peregrine) • DEBIO-025 (Debiopharm) Novel • NIM811 (Novartis) Mechanisms • Nitazoxanide (Romark) of Action • Celgosivir (Migenix) Phase 1 Phase 2 Phase 3 4 lundi 25 janvier 2010 80
    • 25 janv. 2010 Difficult to treat patients • Adverse events • Cirrhotic • Coinfected HIV • Aged patients • Anemic • IV drug user • Uremic • Neutropenic • Hemophiliac • Thrombopenic • Thalassemic 81 lundi 25 janvier 2010 81
    • 25 janv. 2010 Difficult physician ? • Adverse events • Anemic • Coinfected HIV • Uremic • Neutropenic • IV drug user • Cirrhotic • Thrombopenic • Aged patients Hepatitis C virus-infected patients report communication problems with physicians 82 lundi 25 janvier 2010 82
    • 322 Outpatients 131 (41%) of patients report poor communication with physicians 28% 23% 9% Physician incompetence Feelings of Misdiagnosis Stigmatized by Physician Dx and Tx Abandoned (n=29) (n=91) (n=74) Zickmund S, Hepatology 2004 83 lundi 25 janvier 2010 83
    • 25 janv. 2010 Time course of side effects Hematologic side effects Severity Flu-like Fatigue symptoms Depressive/anxiety symptoms 0 1 2 3 4 5 6 7 8 9 10 11 12 IFN-Riba Treatment (Weeks) 84 lundi 25 janvier 2010 84
    • 25 janv. 2010 Effect of Adherence on SVR PEG-IFN α-2b 1.5 μg/kg QW α-2b + ribavirin 800-1,400 mg/day Adherent ≥80% of both drugs (n=35/146) Not Adherent <80% of one or both drugs (n=7/21) 0,97 0,84 0,71 0,76 HCV 2 HCV 3 Zeuzem et al, J Hepatol, 2004 85 lundi 25 janvier 2010 85
    • 25 janv. 2010 Dose Modifications / Discontinuations Rebetol > 10.6 mg/kg Peg2b 1.5 ug/Kg IntronA 3MU Discontinuations Due to AE’s 14% 12% Dose Modification 49% 33% Anemia 12% 14% Neutropenia 21% 8% lundi 25 janvier 2010 86
    • 25 janv. 2010 Neutrophils Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6 Mean Neutrophil Counts x 10 9/l 5 4 3 2 1 0 0 2 4 6 8 12 18 24 30 36 42 48 4 12 24 Treatment Week Follow-up Week lundi 25 janvier 2010 87
    • 25 janv. 2010 Hemoglobin Mean Hemoglobin Concentration g/dl Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6 17,0 16,3 15,6 14,9 14,2 13,5 12,8 12,1 11,4 10,7 10,0 0 2 4 6 8 12 18 24 30 36 42 48 4 12 24 Treatment Week Follow-up Week lundi 25 janvier 2010 88
    • 25 janv. 2010 Platelets Peg1.5/R<10.6 Peg1.5/R>10.6 I/R<10.6 I/R>10.6 Mean Platelet Counts x 10 6/l 250 200 150 100 50 0 0 2 4 6 8 12 18 24 30 36 42 48 4 12 24 Treatment Week Follow-up Week lundi 25 janvier 2010 89
    • 25 janv. 2010 Difficult to treat patients • Adverse events • Cirrhotic • Coinfected HIV • Aged patients • Anemic • IV drug user • Uremic • Neutropenic • Hemophiliac • Thrombopenic • Thalassemic 90 lundi 25 janvier 2010 90
    • Large Scale Studies (Boston 2004) 32,527 patients: Fibrotest-Actitest-HCV-FibroSURE and ALT ALT 50 IU/L: 65 years+ n=3,084 for F2F3F4 Se=60% NPV 42% (prevalence 73%) for Cirrhosis Se=69% NPV 75% (prevalence 40%) 91 lundi 25 janvier 2010 91
    • 25 janv. 2010 HCV treatment in aged patients n=166 65-80 yrs >80 yrs Number of treated patients 162 4 Number of treatments 275 4 Type of treatment -IFN alone 143 0 -IFN-Ribavirin 42 1 -PEGinterferon alone 11 0 -PEG Ribavirin 16 2 -Ribavirin alone 30 0 -Other 33 1 Interruption of treatment 55 (20 %) 0 Thabut et al AJG 2006 92 lundi 25 janvier 2010 92
    • 25 janv. 2010 Sustained Virological Response in aged patients n=166 Genotype 1 Genotype 2 Genotype 3 Other Total Classic IFN 4/79 0/10 1/2 5/52 10/143 (7 %) Ribavirin 1/16 0/1 0/0 1/13 2/30 (7 %) PEG alone 0/6 0/0 0/0 0/4 0 /10 IFN-Ribavirin 3/28 3/5 0/0 1/9 7 /42 (16 %) PEGIFN- 5/12 1/1 1/2 2/5 9/19 (45%) Ribavirin Thabut et al AJG 2006 93 lundi 25 janvier 2010 93
    • 25 janv. 2010 Difficult to treat patients • Adverse events • Cirrhotic • Coinfected HIV • Aged patients • Anemic • IV drug user • Uremic • Neutropenic • Hemophiliac • Thrombopenic • Thalassemic 94 lundi 25 janvier 2010 94
    • 25 janv. 2010 Renal Diseases • Renal insufficiency • Hemodialysis • Renal transplantation 95 lundi 25 janvier 2010 95
    • 25 janv. 2010 Renal insufficiency • IFN, PEG-IFN: • Same dose or slightly reduced • Ribavirin: • Adjusted plasma concentration ?, • 10-15 micromol/L ? • Start 200mg per week • Range 170-300 mg/day • EPO: 20,000-30,000 UI/week 96 lundi 25 janvier 2010 96
    • 25 janv. 2010 Kinetics of PEG-IFN 2a in renal failure Group 1: Cl >100 (n=5) 6.0 Group 2: 100 < Cl >80 (n=4) PEGASYS® Conc. [ng/mL] 5.0 Group 3: 80 < Cl >60 (n=5) Group 4: 60 < Cl >40 (n=6) 4.0 Group 5: 40 < Cl >20 (n=3) 3.0 2.0 1.0 0.0 0 48 96 144 192 240 288 336 384 432 480528 Time [h] Martin et al. AASLD 2000. 97 lundi 25 janvier 2010 97
    • 25 janv. 2010 Renal Diseases • Renal insufficiency • Hemodialysis • Renal transplantation 98 lundi 25 janvier 2010 98
    • 25 janv. 2010 Interferon alfa for HCV infection in hemodialyzed • INF alfa is feasible in dialysis patients • Poorly tolerated • discontinuation: 20-40%; • reduction: 60% • Efficient: at least as efficient than in the general population (pharmacokinetic of INF) • Frequent histological improvement 99 lundi 25 janvier 2010 99
    • 25 janv. 2010 Ribavirin in Hemodialyzed • Warning Hemolysis +++ • Increased risk despite the absence of variation of the level of serum ribavirin • Long duration of the risk; accumulation of metabolites in erythrocytes • Particularly with aziathioprine • Low doses of ribavirin • 200 mg after each dialysis • 200 daily • Increased doses of EPO Thervet et al. Transplantation 1994 Thevenot et al. JVH 1997 100 lundi 25 janvier 2010 100
    • 25 janv. 2010 Renal Diseases • Renal insufficiency • Hemodialysis • Renal transplantation 101 lundi 25 janvier 2010 101
    • 25 janv. 2010 Summary Treatment options in HCV patients with Renal disorders • No Transplantation scheduled: As in non uremic: • F0F1: Follow-up FibroTest /12mo or biopsy /3y • F1-F2: FibroTest /6mo or biopsy /y • F2F3F4: Treatment A la Carte • Transplantation scheduled: • Treatment A la Carte as soon as possible • Double transplantation in F4 non-responders • Transplanted: • F0F1: Follow-up FibroTest /12mo or biopsy /3y • F1-F2: FibroTest /6mo or biopsy /y • F2F3F4: – Ribavirin – Liver Transplantation in F4 non-responders 102 lundi 25 janvier 2010 102
    • 25 janv. 2010 Difficult to treat patients • Adverse events • Cirrhotic • Coinfected HIV • Aged patients • Anemic • IV drug user • Uremic • Neutropenic • Hemophiliac • Thrombopenic • Thalassemic 103 lundi 25 janvier 2010 103
    • 25 janv. 2010 Hemophiliac Patients • Massively contaminated, • Coinfection HIV, • Same natural history, • Biopsy worse cost-benefit rate • Same treatments, including transplantation • Same results than in non-hemophiliacs 104 lundi 25 janvier 2010 104
    • 25 janv. 2010 Thalassemic Patients • Massively contaminated, • Progression of fibrosis • Iron overload • Insulin-resistance • Same treatments, including bone marrow transplantation • Blood transfusion sometimes needed 105 lundi 25 janvier 2010 105
    • 25 janv. 2010 Anemic Patients • Ribavirin dose dependent reversible hemolytic anemia • Erythropoietin (epoetin alfa) • 40,000 U/week vs standard • Hemoglobin drop: 0.3 g vs 2.9 g/dL • 900 vs 700 mg/day ribavirin • When to start ? – Anemic at baseline <11g Hb? – During treatment if <11g Hb ? 106 lundi 25 janvier 2010 106
    • AFSSAPS lundi 25 janvier 2010 107
    • 25 janv. 2010 Neutropenic Patients • Granulocyte colony-stimulating factor (G-CSF) • Potentiates effect of EPO • 300 microG SC 1-3 / week • Maintain Neutrophils >750/mm3 • Adverse events – Skin rash – Vasculatis – Bone pain, myalgia – Thrombocytopenia, splenomegaly – Leukemoid reaction – Exacerbation of psoriasis 108 lundi 25 janvier 2010 108
    • 25 janv. 2010 Thrombopenic Patients • Problematic in cirrhotic patients • Severe thrombopenia exceptional in non cirrhotic • Thrombopoietin 109 lundi 25 janvier 2010 109
    • 25 janv. 2010 Elthrombopag: 4 weeks impact + 12 weeks PEG-Riba 74 HCV Cirrhosis 20,000-70,000 platelets >100,000 /mm3 week 4 100% 95% 75% 79% 75% 50% 25% 0% 0% 0% Placebo 30mg 50mg 75mg McHutchison NEJM 2007 lundi 25 janvier 2010 110
    • 25 janv. 2010 Elthrombopag: 4 weeks impact + 12 weeks PEG-Riba 74 HCV Cirrhosis 20,000-70,000 platelets Completed HCV treatment week 12 100% 75% 65% 53% 50% 36% 25% 6% 0% Placebo 30mg 50mg 75mg McHutchison NEJM 2007 lundi 25 janvier 2010 111
    • 25 janv. 2010 Elthrombopag: Adverse events • Headache • Thrombosis 112 lundi 25 janvier 2010 112
    • 25 janv. 2010 Traitement hépatite C 2010 • Intensifier dépistage • Simplifier bilan initial et suivi • Traiter « à la carte »: • Fibrose, Poids, Stéatose, Age • Tolérance • Efficacité non virologique: • Freiner la progression de la Fibrose 113 lundi 25 janvier 2010 113