Epatite Cronica C Definizione dei Prototipi Clinici per la Personalizzazione Terapeutica Genotipo 4. Gloria Taliani Sapienza Università di Roma

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1 Epatite Cronica C Definizione dei Prototipi Clinici per la Personalizzazione Terapeutica Genotipo 4 Gloria Taliani Sapienza Università di Roma

2 Genotype 4 HCV Virus Predictors of SVR IL28B, Insulin Resistance, Steatosis, Viral Load, Fibrosis, Schistosomiasis Antiviral Treatment IFN, Peg-IFN, New Drugs Cirrhosis, HCC, OLT

3 Genomic Heterogeneity of Hepatitis Viruses (A-E): Role in Clinical Implications and Treatment Zahid Hussain DOI: /55231

4 Estimated HCV genotype distribution among HCV-infected individuals in Europe Esteban JI Hepatol 2008; 48:

5 Phylogenetic analysis and epidemiological profiles of Geno newly identified geno-4 patients in the Amstedam area Phylogenetic analysis revealed three monophyletic clusters Each cluster is associated to a specific epidemiological profile C1: Immigrants from Egypt (4a) C2: Individuals reporting IDU (4d) C3: HIV positive MSM (4d) (Bruijne Jd et al, J Clin Microbiol 2009)

6 The virus Different HCV genotype-4 clusters with different subtype specificity, epidemiological origin, risk factors, metabolic and biologic characteristics, potential comorbidities and sensitivity to IFN

7 Genotype 4 HCV Virus Predictors of SVR IL28B, Insulin Resistance, Steatosis, Viral Load, Fibrosis, Schistosomiasis Antiviral Treatment IFN, Peg-IFN, New Drugs Cirrhosis, HCC, OLT

8 Predictors of Response to Treatment Viral load (< IU/nl), quasispecies, subtype (Kamal SM et Al, Gut 2005; 54: Hasan F, et al. Am J Gastroenterol 2004; 99: , Zekri AR et al. Virol J Feb 14;4:16.) Age < 45 years (Papastergiou V et al. J Med Virol 2012; 84: Wirth S et al, J Hepatol 2010; 52: 501 7) Fibrosis F3-F4 Metavir (Gad RR et al. Liver Int 2008; 28: ; De Nicola Hepatol 12; 55: ; Abdel-Rahman M et al. Clin Res Hepatol Gastroenterol Mar 26. S Obesity (leptin), Steatosis (De Careaga BO et al Ann Hepatol 2006; 5: S24 8. Esmat G et al. Indian J Gastroenterol 2009; 28: 45 8) Insulin Resistance (adiponectine) (El-Shazly Y et al. Journal of Diabetology 2012; 2: 3. Khattab M et al. Am J Gastroenterol 2010; 105: Khattab M et al, Liver Int 2010; 30: ) Coinfection with HIV, HBV, Schistosoma, H Pylori (Kamal Jhepatol 00; El-Zayadi A. Arab J Gastroenterol 2007; 8: Elsharkawy A et al. J Hepatol 2012; 56(Suppl): S61. Esmat G et al. J Viral Hepat 2012; 19: 473 9) El Ray A et al. Europ J Gastroenterol Hepatol 2013; 25: ; El-Awady et Al. Hepatol Monit 2012 IL28B (Asselah T et al. J Hepatol 2012; 56: De Nicola S et al. Hepatol 2012; 55: Khairy M, et al Hepat Mon. 2013;13.Antaki N et al, JViral Hepat 2013; 20: Derbala M et al. Virology 2013; 444: Ragheb M et al. Liver Int. in press)

9 Efficacy of therapy Unfavourable predictors of antiviral efficacy also predictors of progression SVR is the best predictor of non progression in Genotype 4 HCV infection (Alfaleh FZ et al. Liver Intern 13; 33: )

10 Genotype 4 HCV Virus Predictors of SVR IL28B, Insulin Resistance, Steatosis, Viral Load, Fibrosis, Schistosomiasis Antiviral Treatment IFN, Peg-IFN, New Drugs Cirrhosis, HCC, OLT

11 Response of HCV Genotype-4 to Peg-IFN and ribavirin treatment according to etnicity Country EVR ETR SVR Peg-IFN Ribavirin mg Kuwait, Egypt, Saudi Arabia, Qatar, Syria Greece, Austria, France, Belgium % % % % NA % Thakeb Hepatol 03; Diago Ann Intern Med 04; Hasan Am J Gastroenterol 04; Alfaleh Liver Intern 04; El Zayadi Am J Gastroenterol 05; Kamal Gut 05; Kamal Hepatol 07; Ferenci Gastroenterol 08; Derbala J Viral Hepat 08; Martin Carbonero J Viral Hepat 08; Moucari Gut 09; El Makhzanghy J Med Virol 09 ; Kamal Liver Int 09; Dahlan World J Gastroenterol 09; Elefsiniotis Intervirology 09; Varghese Hepatogaastroenterol 09; Rossignol Gastro 09; Khattab Am J Gastroenterol 10; Khattab Liver Int 10; De Galocsy Acta Gastroenterol Belg 10; Al Ali Ann Hepatol 10; Elsharkawy A et al. J Hepatol 2012; Esmat G et al. J Viral Hepat 2012; Asselah T. J Hepatol 2012; De Nicola S. Hepatol 2012; 55: Khairy M, et al Hepat Mon. 2013; Antaki N et al, JViral Hepat 2013; Derbala M et al. Virology 2013; Ragheb M et al. Liver Int. in press

12 cumulative disease regression or stationary course in HCV genotype 4 versus non-4 Genotype 4 with SVR (n 24) Non-genotype 4 with SVR group (n 8) Non-genotype 4 No SVR (n 14) Genotype 4 No SVR group (n 29) P = by the Log-Rank (Mantel-Cox) test Alfaleh FZ et al. Liver Int. 2013: 33:

13 PEG versus Standard IFN plus ribavirin in genotype 4 Five RCT, 386 patients Quality of evidence moderate due to Heterogeneity No effect of Ribavirin dose (Aljumah AA and Murad MH, Hepatol Res 2013)

14 Management of Genotype 4 Recommendations of an International Expert Panel Khattab MA et al. J Hepatol 2011; 54:

15 Outcome by Virological Response at week 4 and 12 in Genotype 4 patients Study N. Pts Week 4 Week 12 RVR N. (%) SVR N. (%) EVR N. (%) SVR N. (%) Kamal et al Hepatology 2007 Ferenci et al Gastroenterol (19.8) 66 (85.7)* 275 (71.0) (19) 26 (86.6)* 28 (42.4) 170 (61.8)** 13 (46.4)*** *Patients treated for 24 weeks ** Patients treated for weeks *** Patients treated for 48-72weeks (Kamal SM et al, Hepatol 07; 46: 1732; Ferenci P et al. Gastroenterol 08; 135: 451)

16 Peg-IFN a-2b Therapy in Acute Hepatitis C: Impact of Onset According to Genotype SVR Start at week 8 Start at week 12 Start at week 20 Kamal SM et al. Gastroenterology. 2006;130:

17 Delayed Therapy: Optimal Duration? Kamal SM et al. Hepatology. 2006;43: Predictors of SVR - neg HCV RNA at week 4

18 Virological response rates in Geno-4 patients treated with Nitazoxanide-Peg-IFN-Ribavirin % RVR % SVR Nitazoxanide Peg-IFN Riba Nitazoxanide Peg-IFN P= Peg-IFN Riba Rossignol JF et Al Gastroenterology Mar;136(3): RVR cevr SVR Peg-IFN Riba 30/49* (61.2%) 35/50 (70%) 24/50 (48%) Peg-IFN Riba Nitazoxanide 25/47* (53.2%) 36/50 (72%) 25/50 (50%) Pvalue * Missing results for one patient in group 1 and 3 patients in group 2 (Shehab HM et al, Liver International 2013)

19 Changes in the hepatitis C virus (HCV) RNA load over 14 days treatment with Telaprevir for each patient, by G4 HCV subtype and treatment group. Telaprevir Telaprevir Peg-IFN RIBA Peg-IFN RIBA SVR 5/8 SVR 4/8 SVR 5/8 (BenhamouY et al, J Infect Dis 2013)

20 Genotype 1, 4, 5, 6 Treatment-Naïve SOFOSBUVIR+PEG-IFN+RBV x 12 Weeks NEUTRINO SVR12 by HCV Genotype Patients with HCV RNA <LLOQ (%) 295/ /292 27/28 7/7 Overall GT 1 GT 4 GT 5,6 Error bars represent 95% confidence intervals Lawitz E, et al. EASL Amsterdam, The Netherlands. Oral #1411 Lawitz E, et al. N Engl J Med May 16;368(20):

21 Genotype 4 Antiviral Treatment Peg-IFN and ribavirin: mainstay. RGT Predictors-oriented Treatment?? Nitazoxanide, Telaprevir: efficacy?, not approved Sofosbuvir: great efficacy, cost (?), not yet approved

22 Genotype 4 HCV Virus Predictors of SVR IL28B, Insulin Resistance, Steatosis, Viral Load, Fibrosis, Schistosomiasis Antiviral Treatment IFN, Peg-IFN, New Drugs Cirrhosis, HCC, OLT

23 HCV Genotype 4, Cirrhosis and Response to IFN Author Journal N. Pts % SVR Histology duration Koshy A et al J Clin Gastroenterol IFN 14 Peg-IFN F4 48 Hasan F et al Am J Gastroenterol F3-F4 48 Derbala M et al J Viral Hepat F4 38 Derbala M et al World J Gastroenterol F3-F4 52 Males S et al Antiviral Ther F4 48 Kamal SM et al Hepatol F Roulot D et al J Viral Hepat F3-F4 48 Ferenci P et al Gastroenterol /4 (75%) F3-F4 48 Gad RR et al Liver Int F3-F4 48 El Makhzangy H et al J Med Virol F3-F4 48 Giannini EG et al J Intern Med F4 Portal Hypert Antaki N et al J Viral Hepat 13 82??? (63 tot) F3-F4 48 Asselah T et al J Hepatol 12 82??? (52 tot) F2-F3-F4 48 Abdo AA et al Hepatol intern 13 61??? (55.8 tot) F2-F3-F4 48 De Nicola S et al Hepatol 12 26??? (49 tot) S5-S

24 Survival and Fibrosis progression after OLT 46 HCV patients (29 Genotype 4) The effect of genotype following OLT is controversial (Wali MH et al. Liver Transpl. 2003; 9: Gane E et al. N Engl J Med. 1996; 20: Zekry A et al. Liver Transpl. 2003;9: Sugo H et al. Surg Today. 2003; 33: ). HCV RNA level at the time of biopsy : Predictor of advanced histological score Geno-4 Risk of fibrosis progression similar in genotype 4 and other genotypes p=0.99 Survival analysis in genotype-4 patients (green) versus those with other genotypes (blue), P=.297 by logrank test (Mudawi H et Al Ann Saudi Med 2009)

25 Cirrhosis: Lack of studies dedicated to this population HCC: no systematic data OLT: scanty information