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 Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione

Natural History of HCV Infection Stable 80% (68%) HCC Liver failure 25% (4%) Slowly progressive 75% (13%) Resolved 15% Acute HCV Cirrhosis 20% (17%) Chronic HCV 85%

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

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

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: Bedossa P, et al. Hepatology. 1996;24:

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:

The long-term outcome of HCV compensated cirrhosis: a 17-yr follow-up of 214 Pts Cumulative probability of events Years HCC GI bleeding Ascites Jaundice EPS Sangiovanni A et al Hepatology 2006 Annual Incidence rate HCC 3.9% Ascites 2.9% Jaundice 2.0% GI bleeding 0.7% EPS 0.1% Pts still at risk

Effect of Inflammation on Fibrosis Progression in HCV Patients Change in Fibrosis Score According to Necrosis Score at Baseline Piecemeal Necrosis Score at Baseline > 4 Patients, n Mean change in fibrosis score per yr Ghany MG, et al. Gastroenterol. 2003;124:

Patients Developing Cirrhosis According to Initial Level of Fibrosis Yano M, et al. Hepatology. 1996;23: Fibrosis ScoreDescription of FibrosisPatients Progressing to Cirrhosis by Year 10, % ≤ 1.9 (n = 27)None; too mild to alter portal tract size (n = 28)Portal/periportal ± portal- portal bridging (n = 15)Septal + regions of partial nodular regeneration 100

Factors Associated With Advanced Fibrosis Adjusted Odds Ratio (95% CI) Risk Factor 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 Retrospective study of 460 pts with chronic hepatitis C (41% F3-4) Multivariate analysis of factors associated with F3-4 Hu S, et al. J Clin Gastro P Value

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 Hui JM, et al. Gastroenterol. 2003;125: HOMA-IR Fibrosis Score F0F1F2F3F4

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 Hezode C, et al. Hepatology. 2005;42: Odds Ratio of Accelerated Fibrosis Progression Rate* (95% CI) Cannabis Use Occasional 3.4 P Value Daily *Compared with median progression rate of cohort: Metavir U/yr.

Alcohol Consumption Increases Risk of Cirrhosis in HCV Patients *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: Years Following Exposure † Cirrhosis (%) HCV HCV + alcohol* P <.01

100 % Survival at 1 year 80 % 45 %

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

Survival Probability in HCV Patients With Cirrhosis Fattovich G, et al, Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology, 1997: 112,, Compensated After first major complication Survival Probability 100 Patients (%) Mos Patients at Risk

Cirrhosis

The impact of SVR on histological outcome of HCV-induced cirrhosis Maylin S et al Gastroenterology 2008 Post-treatment Pre-treatmentF0F1F2F3F4 F F F F F Comparison of liver fibrosis stage between pre-treatment and post-treatment paired liver biopsy in 126 patients Post-treatment specimens were collected a median of 6 months after treatment cessation

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

Cumulative incidence of esophageal varices in 149 IFN ± RBV- treated patients with compensated HCV-induced cirrhosis according to response to therapy Bruno S, et al Hepatology 2010 Patients still at risk No SVR SVR * Years since initiation of antiviral treatment

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) liver-related complications Liver mortality Bruno S et al Hepatology 2007 (p: by log-rank test)

Survival Outcomes in Pts With CHC and Advanced Fibrosis P <.001

Achieving Sustained Virologic Response: Impact on Long-Term Outcomes in HIV/HCV-Coinfection Overall Mortality Long-Term Outcome Rate (per 100 person/years) Liver-Related Mortality Liver Decompensation 0.46*(0.06,1.65) Hepato- carcinoma 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. 3.12(2.16,4.37) 1.65(0.98,2.16) 4.33(3.16,5.8) 0.83(0.38,1.58) 1.02(0.50,1.82) 0.93(0.44,1.70) 0.23 † (0.01,1.27) 0.23 ‡ (0.01,1.27) 0(0,0.84) 0 § (0,0.84) 0.23(0.01,1.27) New AIDS Conditions GESIDA 3603 Cohort: 711 pts treated for HCV Berenguer J. et al. Hepatology Achieved SVR Did not achieve SVR

Event-free survival according to response to therapy in 102 patients with HCV-induced cirrhosis and portal hypertension (stage 2) Di Marco V et al J Hepatol 2007

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

Factors Associated With Greater Benefit or Greater Risk of Treatment in Cirrhotics Factors Associated With Greater Benefit of Therapy Factors Associated With Greater Risks of Therapy  ↓ Child-Pugh score  ↓ MELD score  ↑ Platelet count  ↑ Albumin level  ↓ Age  ↑ Child-Pugh score  ↑ MELD score  ↓ Platelet count  ↓ Albumin level  ↑ Age

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

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

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 Van der Meer AJ, et al. AASLD Abstract 143. Cumulative HCC Occurrence (%) Cirrhosis Bridging Fibrosis P = Yr HCC Rate, % (95% CI) 8.5 ( ) 1.8 (0-4.3) Yrs

Age as a Risk Factor for HCC Following SVR in HCV Pts With Advanced Fibrosis Van der Meer AJ, et al. AASLD Abstract 143. Reproduced with permission. HCC risk increased with age; highest for those > 60 yrs Cumulative HCC Occurrence (%) Yrs > 60 yrs of age yrs of age < 45 yrs of age P = % ( ) 9.7% ( ) 2.6% (0-5.5) 8-Yr HCC Rate, % (95% CI)

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 Cirrhosis: A Continuous Spectrum of Disease

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 Advanced disease/ cirrhosis Mild disease  Greater need for treatment  BUT Response to current IFN-based therapy may be impaired

DAA Classes and Subclasses: antiviral potency and resistance barrier according to HCV genotype Drug ClassSubclass 1 b1a234 Protease inhinbitors 1 st Generation first wave i.e. Telaprevir/Boceprevir  1 st Generation 2 nd wave i.e. Faldaprevir/Simeprevir/  2nd Generation MK5172 §  NS5a Inhibitor 1 st Generation Daclatasvir Ledipasvir ABT 267  2 nd Generation MK 8742 GS 5816  NN Polymerase Inhibitors ABT 333 GS 9669 Deleobuvir  Nucleos/tides Polymerase inhibitors 2 nd Generation : Sofosbuvir  33  High  Moderate  Low  Very low

Seminario Nadir Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione