Follow-up of patients with SVR Lawrence Serfaty Service d Hépatologie, UMR_S 938 Hôpital Saint-Antoine Université Pierre&Marie Curie Paris, France

9th Paris Hepatitis Conference, January 11-12, 2016 Follow-up of patients with SVR Lawrence Serfaty Service d Hépatologie, UMR_S 938 Hôpital Saint-Antoine Université Pierre&Marie Curie Paris, France

Disclosures Consulting, advisory committees or review panel Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche Speaking and teaching Abbvie, Aptalis, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, Roche

New all-oral regimens are transforming the HCV treatment landscape BOC, boceprevir; IFN, interferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir 1. Adapted from Manns MP, et al. Gut 2006;55:1350 9. 2. Tran TT. Am J Manag Care 2012;18(14 Suppl.):S340 9. 3. Goralczyk AD, et al. BMC Gastroenterology 2013;13:148. 4. Feld JJ, et al. N Engl J Med. 2014;370:1594-603. 5. Sulkowski M, et al. N Engl J Med. 2014;370(3):211-21. 6. Afdhal N, et al. N Engl J Med. 2014;370:1889 98. 7. Afdhal N, et al. N Engl J Med. 2014;370:1483-93. SVR (%) 94 100% 95 98%** 67 79%* 54 63% 38 43% 45 47% 31 35% 6% 13 19% IFN 24 wk IFN 48 wk IFN/RBV IFNα/RBV IFNα/RBV pifnα/rbv pifnα/rbv 3 DAAs 2 DAAs (daily) 3 times/wk 24 wk 48 wk 48 wk 48 wk + BOC or + ±RBV TVR RBV 12/24 wk5 7 48 wk 12 wk4 19921 2001 >20131-3 2016 and beyond patients with HCV genotype 1 only; ** In treatment-naïve patients; Includes treatment-naïve and -experienced patients

SVR is associated with improvement of survival (meta-analysis n=34 563 ) Effect of SVR on death (all cause) HCV 10 studies HCV cirrhosis 3 studies HIV/HCV 2 studies Risk reducton of death % 0-10 -20-30 -40-50 -60-70 -80-90 -62-84 -73 Simmons B, et al. Clin Infec Dis 2015

Plan The durability of SVR with DAAs regimens Liver-related morbidity/mortality in SVR patients Long term fibrosis outcome in SVR patients Predictors of liver disease outcome in SVR patients: the role of comorbidities Monitoring of SVR patients: the value of non invasive markers

The durabilty of SVR with DAAs regimens 779 patients treated with sofosbuvir-containing regimen Yoshida EM, et al. Hepatology 2015

The durabilty of SVR with DAAs regimens Long term follow-up studies in DAAs-related SVR patients are ongoing. Persitence of occult HCV infection? Radkowski M, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 2005; 41: 106 14. Castillo I, et al. Hepatitis C virus replicates in the liver of sustained responder patients to Long term antiviral SVR treatment. and Clin Infect shorter Dis 2006; 43: duration 1277 83. regimen?

Risk of reinfection following SVR (meta-analysis n=34 563 ) 5 yrs risk of reinfecton post SVR 25 Low risk n = 6 046 Mean FU 4.1 yrs IVDU/inmate n = 1 203 Mean FU 5 yrs HIV/HCV n = 1 106 Mean FU 3.1 yrs 23.6 EASL guidelines Following SVR, monitoring for HCV reinfection through annual HCV RNA assessment should be undertaken in people who inject drugs or men who have sex with men with on-going risk behaviour (B2) HCV reinfecton at 5 yrs (%) 20 15 10 5 0 0.9 Low risk 8.2 IVDU/ inmate Coinfected Hill AM, et al. AASLD 2014

The risk of liver transplantation or HCC according to SVR (meta-analysis n=34 563 ) % of patents afer 5 yrs 20 18 16 14 12 10 8 6 4 2 0 Liver transplantaton risk at 5 yrs HCV n = 108 Mean FU 4.2 yrs 0 2.2 HCV cirrhosis n = 1 046 Mean FU 7.7 yrs 0.2 SVR 7.3 HIV/HCV n = 2 039 Mean FU 4.9 yrs Non SVR 0.6 2.7 HCV infected Cirrhosis HIV/HCV % of patents afer 5 yrs 20 18 16 14 12 10 8 6 4 2 0 HCV n = 12 496 Mean FU 6.1 yrs 2.9 9.3 HCC risk at 5 yrs HCV cirrhosis n = 4987 Mean FU 6.6 yrs 5.3 13.9 0.9 HIV/HCV n = 2 085 Mean FU 4.7 yrs 10 HCV infected Cirrhosis HIV/HCV Simmons B, et al. Clin Infec Dis 2015

Excess liver-related morbidity following discharge of SVR patents 1215 HCV patients treated between 1996-2007, follow-up 5.3 yrs Adjusted standardized morbidity ratio (liver-related hospitalizations) Innes HA, et al. Hepatology 2011

Risk of HCC in non cirrhotic patients following HCV eradication 642 SVR patients followed 53 mo: 86 cirrhotics, 556 non-cirrhotics 22.6 % at 5 yrs 3.2 % at 5 yrs Huang CF, et al. J Hepatol 2014

Plan The durability of SVR with DAAs regimen Liver-related morbidity/mortality in SVR patients Long term fibrosis outcome in SVR patients Predictors of liver disease outcome in SVR patients: the role of comorbidities Monitoring of SVR patients: the value of non invasive markers

Regression of fibrosis in SVR patients is slow 183 HCV patients with SVR 2nd liver biopsy at 3.7 yrs Fibrosis stage on second LB 4 3 2 1 0 Fibrosis stage on first LB Mean rate of fibrosis regression: 0.28±0.03 unit/yr Shiratori Y, et al. Ann Intern Med 2000

Tachi Y, et al. Hepatol Res 2015; 45: 238 46. Regression of fibrosis in SVR patients is slow 97 SVR patients with paired LB, 5.8 yrs 60 50 40 30 20 45 49 10 0 Improvement Stable Progression 6

Long term fibrosis outcomes in SVR patients according to non invasive markers 933 HCV patients with paired Fibrotest, median FU 5.3 yrs 415 patients with advanced fibrosis at 10 yrs atients at risk n= 415 263 80 Poynard T, et al. J Hepatol 2013

Wiese M, et al. Hepatology 2014 ;59:49 57. Overweight is a risk factor of cirrhosis occurrence in SVR patients 16 12 German HCV (1b)-contaminated anti-d cohort: Clinical outcome after 35 yrs follow-up 14.2 15.3 Overall survival was significantly enhanced after SVR, compared to treatment-naïve patients or non-svr (p=0.027) (%) 8 4 0 1.9 9.3 4.2 Overall cohort 1.1 4.8 2.5 6.6 Spontaneous Treatment recovery naïve 0.7 6.0 SVR 0.7 3.3 3.8 Non SVR Independent factors associated with cirrhosis No response to treatment No spontaneous recovery BMI >25 kg/m2 (RR: 1.125) Fibrosis F3 Cirrhosis Death

Risk factors of HCC following SVR SVR patients Follow-up (yrs) Risk factors Chang 2012 871 3.4 -Age -Fibrosis -Post SVR AFP Arase 2013 1751 8.1 -Age -Male -Alcohol -Diabetes Oze 2014 1425 3.3 -Age -Post SVR AFP Yamashita 2014 562 4.8 -Age -Fibrosis -Alcohol -Post SVR AFP Huang 2014 642 4.4 -Age -Fibrosis -Diabetes Chang 2015 801 5.0 -Age -Fibrosis Courtesy by P Nahon -Post SVR AFP 20

etabolic syndrome and risk of HCC n SVR cirrhotic patients Risk of HCC according to SVR and Met S CirVir CO12 ANRS CO12 CirVir EASL 2015

Risk factors of HCC following SVR in non cirrhotic patients 556 non-cirrhotic patients with SVR Predictive factors of HCC : age, GGT, type 2 diabetes and APRI Huang CF, et al. J Hepatol 2014

Predictive score of HCC occurrence in cirrhotic patients Independent predictors: Age>50yrs, Alcohol, GGT>N, platelets, SVR Score 5 : low risk; 6-10 : moderate risk; 11-14: high risk; > 14: very high risk CirVir CO12 P < 0.0001 CirVir ANRS CO12, AFEF/ILCA 2015

Progression of fibrosis is associated with HCC occurrence in SVR patients Tachi Y, et al.. Hepatol Res 2015; 45: 238 46. 97 SVR patients with paired LB, 5.8 yrs

Mallet L, et al. Ann Intern Med 2008;149:399 403 Reversion of cirrhosis and clinical outcome n=57 n=39 SVR n=78 n=18 Reversion CHC: 14 (23.3%) CHC: 17 (22.1%) CHC: 3 (7.7%) * CHC: 0

Difference between biopsy and FibroTest estimates of fibrosis progression in treated patients 134 patients treated with IFN and 352 treated with IFN+RBV Poynard et al 2002, SVR Poynard et al 2003, SVR Poynard et al 2003, NR Poynard et al 2003, NR Total -100-50 0 50 100 Mean difference Poynard T, et al. Antivir Ther 2010

Accuracy of APRI, FIB-4 and Forns index at post-svr for predicting fibrosis in the second liver biopsy 115 SVR patients with control liver biopsy at 5 yrs APRI FIB-4 Forns ROC>0.8 Accuracy>70% APRI FIB-4 Forns Tachi Y, et al. PloS One 2015

Accuracy of fibroscan following SVR 33 biopsy-proven cirrhotic CHC patients with SVR Liver biopsy + LSM 61 (48-104) months after SVR F0-3 F4 TE <12 kpa TE 12 kpa 19 5 1 8 D Ambrosino R, et al. J Hepatol 2013

Liver stiffness and antiviral treatment: lower cut-off for cirrhosis diagnosis? Fibrosis Steatosis Inflammation Liver stiffness (kpa) F4 F4 Cirrhosis diagnosis Courtesy by J Boursier

Take-Home Message After the cure of HCV infection, regression of fibrosis varies and the risk of liver-related complications remains, even in the absence of cirrhosis. Comorbidities such as diabetes, obesity or alcohol consumption can play a major role in the outcome of liver disease in SVR patients and should be managed. Although not currently recommended in guidelines, noninvasive tests could be useful for assessing the outcome of fibrosis in SVR patients without cirrhosis. Screening for HCC after HCV cure is recommended in patients with extensive fibrosis.

Baseline F0/F1 F2/F3 Cirrhosis Antiviral tt SVR12 SVR12 SVR12 W48FU PCR NIT=F0/F1 PCR NIT=F2/F3 PCR Persistent risk factors IVDU, MMS Age>60, GGT Alcohol, obesity, diabetes - + 1 PCR/yr NIT/yr Lifestyle change Control of diabetes LB if abnormal LFT US/6mo NIT: non invasive test