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Il danno d ’ organo provocato dal Virus C

This study examines the long-term outcome of HCV-compensated cirrhosis, including the progression of fibrosis, development of complications, and survival rates. Factors associated with advanced fibrosis and risk factors for rapid fibrosis progression are also analyzed. The impact of SVR on the histological outcome of HCV-induced cirrhosis is evaluated.

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Il danno d ’ organo provocato dal Virus C

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  1. Il danno d’organo provocato dal Virus C Gloria Taliani 8 Maggio 2014 Malattie Infettive e Tropicali Sapienza Università di Roma Policlinico Umberto I, Roma Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione

  2. Natural History of HCV Infection Acute HCV Resolved15% Chronic HCV85% Stable80% (68%) Cirrhosis20% (17%) Slowlyprogressive75% (13%) HCCLiver failure25% (4%)

  3. Hepatitis C Disease Pathogenesis CD4+ CD8+ Cytokines(IL-2, IFN-TNF-a, TGF-PDGF) Cell killing TGF- Activation Death Kupffer cell Hepatic stellate cells Hepatocytes Fibrosis

  4. Influence of HIV-1 replication and its treatment on the liver in HCV coinfection Kim RY and Chung RT GASTROENTEROLOGY 2009;137:795– 814

  5. Advanced Liver Disease • Histologic • Bridging fibrosis • Ishak 3/6-4/6 • Metavir 3/4 • Cirrhosis • Ishak 5/6-6/6 • Metavir 4/4 Ishak KG, et al. J Hepatol. 1995;22:696-699. Bedossa P, et al. Hepatology. 1996;24:289-293.

  6. Complications of Advanced Liver Disease • Clinical • Portal hypertension • Thrombocytopenia, varices, nodular liver • Impaired hepatic function • Albumin, bilirubin, INR • Decompensation • Ascites • Encephalopathy • Variceal hemorrhage • Jaundice Sangiovanni A, et al. Hepatology. 2006;43:1303-1310.

  7. 214 196 186 168 142 129 116 110 96 89 74 66 57 48 36 153 214 197 182 163 142 133 114 105 92 86 74 68 60 55 39 151 214 196 184 164 144 134 122 114 100 89 75 69 60 54 40 152 214 198 188 171 151 142 129 122 105 94 81 73 64 58 42 160 214 198 190 173 152 146 129 122 108 98 84 77 66 59 43 162 The long-term outcome of HCV compensated cirrhosis: a 17-yr follow-up of 214 Pts 100 Annual Incidence rate HCC 3.9% Ascites 2.9% Jaundice 2.0% GI bleeding 0.7% EPS 0.1% 50 HCC Cumulative probability of events Ascites 25 Jaundice GI bleeding EPS 0 Years Pts still at risk Sangiovanni A et al Hepatology 2006

  8. Effect of Inflammation on Fibrosis Progression in HCV Patients Ghany MG, et al. Gastroenterol. 2003;124:97-104.

  9. Patients Developing Cirrhosis According to Initial Level of Fibrosis Yano M, et al. Hepatology. 1996;23:1334-1340.

  10. Factors Associated With Advanced Fibrosis • Retrospective study of 460 pts with chronic hepatitis C (41% F3-4) • Multivariate analysis of factors associated with F3-4 Risk Factor Adjusted Odds Ratio (95% CI) P Value 3.444 Age at entry (≥ 60 years) Duration of infection (≥ 25 years) BMI (≥ 30) History of diabetes AST (≥ 80 U/L) AFP (≥ 15 µg/L) Grades 2 and 3 steatosis .0334 1.750 .0378 1.917 .0173 2.251 .0304 4.032 .0087 3.875 .0383 .0378 2.790 0.01 1.0 15.0 Hu S, et al. J Clin Gastro. 2009

  11. Insulin Resistance Associated With More Rapid Fibrosis Progression in HCV Pts • In 260 HCV-infected subjects, insulin resistance independently associated with stage of fibrosis • OR: 1.3; P < .001 for trend 5 4 3 HOMA-IR 2 1 0 F0 F1 F2 F3 F4 Fibrosis Score Hui JM, et al. Gastroenterol. 2003;125:1695-1704.

  12. Cannabis Use Significantly Associated With Faster Rate of Fibrosis Progression • 270 untreated HCV-infected patients undergoing liver biopsy evaluated for risk factors of rapid fibrosis progression • 52.2% noncannabis users; 14.8% occasional cannabis users; 33.0% daily cannabis users Odds Ratio of Accelerated Fibrosis Progression Rate* (95% CI) P Value Cannabis Use 1.3 Occasional .57 3.4 Daily .005 0.01 1.0 10.0 *Compared with median progression rate of cohort: 0.074 Metavir U/yr. Hezode C, et al. Hepatology. 2005;42:63-71.

  13. Alcohol Consumption Increases Risk of Cirrhosis in HCV Patients 100 P < .01 85 P < .01 80 P < .01 64 58 60 HCV Cirrhosis (%) 40 HCV + alcohol* 40 31 18 20 12 6 0 10 20 30 40 Years Following Exposure† *Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men.†Duration of exposure defined as either first blood transfusion before 1990 or from the year of initial intravenous drug use. Wiley TE, et al. Hepatology. 1998:28:805-809.

  14. 100 % Survival at 1 year 80 % 45 %

  15. 1-year mortality rate accordingtoclinicalstages Classification from a systematicreview of 118 studies 1% No varices No ascites Stage 1 Compensated 4.4% 7% 3.4% Varices No ascites Stage 2 DEATH 4% 6.6% Ascites +/- varices Stage 3 20% Decompensated 7.6% Bleeding +/- ascites 57% Stage 4 D’Amico G et al J Hepatol 2006

  16. Survival Probability in HCV Patients With Cirrhosis Compensated Survival Probability 100 After first major complication 80 60 Patients (%) 40 20 0 0 12 24 36 48 60 72 84 96 108 120 Mos Patients at Risk384 376 342 288 236 165 126 79 52 39 25 65 39 21 11 7 4 4 3 3 2 1 Fattovich G, et al, Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology, 1997: 112, , 463-472.

  17. Cirrhosis

  18. The impact of SVR on histological outcome of HCV-induced cirrhosis Post-treatment specimens were collected a median of 6 months after treatment cessation Comparison of liver fibrosis stage between pre-treatment and post-treatment paired liver biopsy in 126 patients Maylin S et al Gastroenterology 2008

  19. Rate (%) of patients with hystological regression of cirrhosis after the achievement of SVR in HCV-induced disease 96 patients with biopsy-provencirrhosis (METAVIR score F4); treated with IFN; posttreatmentliverbiopsy. The median follow-up was 118 months (interquartile range, 86 to 138 months). Eighteenpatientshadregression of cirrhosis. Mallet V et al Ann Int Med 2008

  20. Cumulative incidence of esophageal varices in 149 IFN ± RBV-treated patients with compensated HCV-induced cirrhosis according to response to therapy * Years since initiation of antiviral treatment Bruno S, et al Hepatology 2010

  21. Impact of SVR on long-term outcome in 848 patients with HCV-related histologically-proven cirrhosis (stage 1) treated with IFN MT (14 yers FU) (p: 0.001 by log-rank test) (p: 0.001 by log-rank test) liver-related complications Liver mortality Bruno S et al Hepatology 2007

  22. Survival Outcomes in Pts With CHC and Advanced Fibrosis Liver-Related Mortality or Liver Transplantation All-Cause Mortality 30 30 P < .001 P < .001 20 20 Liver-Related Mortality or Liver Transplantation (%) All-Cause Mortality (%) 10 10 With SVR With SVR 0 0 0 10 1 2 4 0 3 5 6 10 7 8 1 2 4 3 5 6 9 7 8 9 Yrs Yrs Pts at Risk, n Without SVRWith SVR Pts at Risk, nWithout SVRWith SVR 405192 392181 380168 358162 334155 305144 277125 22988 18756 14640 11928 405192 393181 382168 363162 344155 317144 295125 25088 20756 16440 13528 Hepatocellular Carcinoma Liver Failure 30 30 P < .001 P < .001 20 20 Hepatocellular Carcinoma (%) Liver Failure (%) 10 10 With SVR With SVR 0 0 0 10 1 2 4 0 3 5 6 1 2 4 10 7 8 3 5 6 9 7 8 9 Yrs Yrs Pts at Risk, n Without SVRWith SVR Pts at Risk, n Without SVRWith SVR 405192 390181 375167 349161 326152 294142 269124 22986 19154 15139 12227 405192 384180 361166 337160 314152 288141 259123 21688 18456 14340 11328 Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

  23. Achieving Sustained Virologic Response: Impact on Long-Term Outcomes in HIV/HCV-Coinfection GESIDA 3603 Cohort: 711 pts treated for HCV Achieved SVR Did not achieve SVR 4.33 (3.16,5.8) 3.12 (2.16,4.37) Long-Term Outcome Rate (per 100 person/years) 1.65 (0.98,2.16) 1.02 (0.50,1.82) 0.93 (0.44,1.70) 0.83 (0.38,1.58) 0.46* (0.06,1.65) 0.23† (0.01,1.27) 0.23‡ (0.01,1.27) 0.23 (0.01,1.27) 0 (0,0.84) 0§ (0,0.84) Liver Decompensation Hepato- carcinoma New AIDS Conditions Overall Mortality Liver-Related Mortality Liver Transplantation *P=0.003, †P=0.028, ‡P<0.001, and §P=0.034 versus not attaining a sustained virologic response. n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin. Berenguer J. et al. Hepatology 2009.

  24. Event-free survival according to response to therapy in 102 patients with HCV-induced cirrhosis and portal hypertension (stage 2) 100 SVR (16 pts) 80 60 % of Patients Without Events Liver-related 40 NR (86 pts) 20 p= 0.006 by log rank test 0 0 6 12 18 24 30 36 42 48 54 60 Months Di Marco V et al J Hepatol 2007

  25. Cumulative probability of survival of SVRs versus Non SVRs and controls in patients with decompensated HCV-induced cirrhosis p= 0.07 Iacobellis A et al J Hepatol 2007

  26. Factors Associated With Greater Benefit or Greater Risk of Treatment in Cirrhotics

  27. Deaths and AEs in the first 6 month of follow-up according to treatment or not OR=2.4 (1.02 – 5.77) OR=0.7 OR=0.6 OR=2.9 OR=1.2 OR=0.6 OR=1.9 OR=0.9 Iacobellis A et al J Hepatol 2007

  28. HCC occurrence in patients with HCV-related cirrhosis according to SVR Singal AK Clin Gastroenterol Hepatol 2010

  29. Meta-analysis: Risk of HCC in HCV Pts With Advanced Fibrosis Following SVR • 1000 patients with bridging fibrosis or cirrhosis who achieved SVR following IFN-based HCV therapy followed for median of 5.7 yrs • Cirrhotics at greatest risk of HCC following SVR 12 8-Yr HCC Rate, % (95% CI) 10 8.5 (5.8-11.2) Cirrhosis 8 Cumulative HCC Occurrence (%) 6 P = .064 4 Bridging Fibrosis 1.8 (0-4.3) 2 0 0 1 2 3 4 5 6 7 8 Yrs Van der Meer AJ, et al. AASLD 2013. Abstract 143.

  30. Age as a Risk Factor for HCC Following SVR in HCV Pts With Advanced Fibrosis • HCC risk increased with age; highest for those > 60 yrs 8-Yr HCC Rate, % (95% CI) 12.2%(5.3-19.1) 12 > 60 yrs of age45-60 yrs of age< 45 yrs of age 10 9.7%(5.8-13.6) 8 Cumulative HCC Occurrence (%) 6 P = .006 4 2.6%(0-5.5) 2 0 0 1 2 3 4 5 6 7 8 Yrs Van der Meer AJ, et al. AASLD 2013. Abstract 143. Reproduced with permission.

  31. Cirrhosis: A Continuous Spectrum of Disease ESLD Child-Pugh B Portal hypertension – high risk Cirrhosis – treatment candidate Liver disease is not optimally represented by Child-Pugh stage (A, B, or C) or MELD score

  32. Severity of Disease Increases Need for HCV Therapy but Also Impairs Response • May not need immediate treatment • BUT • Easier to treat • High likelihood of response • Greater need for treatment • BUT • Response to current • IFN-based therapy may be impaired Mild disease Advanced disease/ cirrhosis

  33. DAA Classes and Subclasses: antiviral potency and resistance barrier according to HCV genotype High  Moderate  Low Very low

  34. Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione

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