La gestione corrente dell infezione cronica da HCV: la progressione verso la cirrosi. Simona Landonio I Div Mal inf H Sacco Milano

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1 La gestione corrente dell infezione cronica da HCV: la progressione verso la cirrosi Simona Landonio I Div Mal inf H Sacco Milano

2 HCV Natural History

3 Viganò M et al Gastroenterology 27;133:

4 Overall survival: cirrhosis at baseline is the only factor associated with reduced survival Viganò M et al Gastroenterology 27;133:

5 Ten-year Progression Rate of Chronic Hepatitis C to Cirrhosis 1 4 Progression rate x yr = 2.4% età Fibrosi basale Patients still at risk Months Viganò M et al Gastroenterology 27;133:

6 Factors Associated With Increased Risk Of Cirrhosis In Patients With HCV Patient characteristic McCombs, JAMA Intern Med 214;174: Cirrhosis (n=123,988) Hepatocellular Carcinoma (n=128,481) Events, No. (%) 17,926 (14.5%) 4,517 (3.5%) Male sex 1.35 ( ) 3.41 ( ) Age 1.2 ( ) 1.7 ( ) Race White Black Other HCV genotype Other 1 (reference).54 (.52.56).73 (.7.76) 1 (reference).64 (.61.68) 1.24 ( ).87 (.75 1.) 1 (reference).73 (.68.78).8 (.74.87) 1 (reference).52 (.46.58) 1.63 ( ).77 ( ) Diabetes at baseline 1.38 ( ) 1.31 ( ) Achieved undetectable viral load.62 (.54.73).62 (.42.81)

7 Cumulative probability of events The Long-Term Outcome of HCV Compensated Cirrhosis A Cohort Study of 214 Patients in Milan Annual Incidence rate HCC 3.9% Ascites 2.9% Jaundice 2.% GI haemor..7% PSE.1% Annual mortality rate 4% HCC Ascites Jaundice Gi haemorrhage Years PSE Sangiovanni A et al, Hepatology 26;43:133-1

8 Causes of Mortality Significantly Associated with HCV The REVEAL HCV Cohort Study Causes of death Multivariate-adjusted HR (95% CI) All causes 1.89 ( ) All liver-related ( ) HCC ( ) All extrahepatic diseases 1.35 ( ) 24 pz 195 HCV Follow up 16.2 anni All cancer, except HCC 1.32 ( ) Cardiovascular diseases 1.5 ( ) Nephritis/nephrosis 2.77 ( ) Lee et al, J Infect Dis 212;26:469-77

9 Development and Validation of a Comorbidity Scoring System for Patients with Cirrhosis Survival probabilities in the Danish Patient Registry cohort, by CirCom group CirCom score (validated in 4,656 HCV-RNA+) - COPD - AMI - PAD - Epilepsy - Substance Abuse - Heart Failure - Non Meta Cancer - Meta cancer - CKD Jepsen et al, Gastroenterology 214;146:147-56

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11 Follow up 2.5 anni

12 Results 58 pts enrolled Mean time between the two biopsies:42.6 months (95%CI ) 27/58 patients (46.5%) showed LFP; 9/58 (15.5%) progressed at least 2 stages. 5 patients developed cirrhosis.

13 MULTIVARIATE ANALYSIS FOR RISK FACTORS FOR LFP OR LI 95%C LS 95% C P Riduzione CD ALT>15UI/l

14 Time to progression related to decrease of CD4 cells Median survival Percent free of progression 1 5 CD4 decrease 38 no CD4 decrease 92 P value < time (months)

15 Expected time to chirrosis according antiretroviral therapy 6, 5, FIBROSIS 4, 3, 2, HAART SINGLE OR DUAL NO THERAPY 1,, TIME (YEARS) Non parametric ANOVA P=.87

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17 RISK OF LIVER DECOMPENSATION AMONG HIV/HCV COINFECTED PATIENTS WITH MILD FIBROSIS IN THE SHORT-TERM 1492 pazienti Follow up 6 anni Macias J et al Hepatology 215; 61 (5):

18 Mortalità 1,8% anno Rischio scompenso 1,5% anno Macias J et al Hepatology 215; 61 (5):

19 Variables Associated with HCV Worsening Not modifiable Older age Male gender HCV gt Modifiable Hepatic Inflammation Steatosis/BMI Alcohol Tobacco HBV HIV

20 Cirrhosis Regression In HCV Patients Responding To Interferon-based Therapy Study Patients with cirrhosis (n) Months from SVR Staging system Regression rates Reichard, et al Scheuer 3 (1%) Arif, et al Ishak 5 (83%) George, et al Ishak 6 (75%) Poynard, et al < 24 Metavir 25 (68%) D Ambrosio, et al Metavir 23 (61%) Everson, et al Metavir 2 (5%) Shiratori, et al Metavir 11 (46%) Mallet, et al Metavir 17 (44%) Pol, et al NA Metavir 4 (24%)

21 Pts (%) SVR and Mortality: IFN Era Long-term follow-up study of pts with chronic HCV infection and advanced fibrosis or cirrhosis (N = 53 treated ; median follow-up: 8.4 yrs) [1] Yr Cumulative Incidence SVR No SVR Baseline factors significantly associated with all-cause mortality: Older age Genotype 3 (2-fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use 1. van der Meer AJ, et al. JAMA. 212;38: Backus LI, et al. Clin Gastroenterol Hepatol. 211;9: SVR also reduces all-cause mortality even in absence of cirrhosis [2]

22 Extrahepatic Clinical Benefits of a SVR in Patients with Chronic Hepatitis C Clinical Event Number/Total Patients Reference SVR (+) SVR (-) Diabetes 26/1167 (2.2%) 117/1175 (9.9%) Arase et al 29 Malignant lymphoma /2161 (%) 25/148 (12.6%) Kawamura et al 27 Improved Neurocognitive Functions* 8/8 1% /6 % Byrnes et al 212 * Improved Brain Metabolism: basal ganglia Cho/Cr and ml/cr ratios

23 An SVR Improves Post-treatment Liver Fibrosis Stage 126 HCV SVR patients with a post-tx liver biopsy mean follow-up 3.3 years (.5 18 yrs) Post treatment Pre-TX F F1 F2 F3 F4 F 1 2 F F F F Maylin S, et al. Gastroenterology 28;135:

24 An SVR Improves Post-treatment Liver Fibrosis Stage 126 HCV SVR patients with a post-tx liver biopsy mean follow-up 3.3 years (.5 18 yrs) Post treatment Pre-TX F F1 F2 F3 F4 F 1 2 F F F F Fibrosis stage: -Improve 56% -Unchange 32% -Worse 12% Maylin S, et al. Gastroenterology 28;135:

25 Liver-related events(%) Liver-related events(%) The Impact Of Cirrhosis Regression On Clinical Events Liver biopsy 17 months after SVR: cirrhosis regression in 17/35 (49%) 1 p=.2 1 p=.1 8 Non-responder Responder 8 Non-reverser Reverser 6 6 No events among reversers Number at risk Non-resp. 61 Resp Month Number at risk Non-reversers 78 Reversers Month Mallet V, et al. Ann Intern Med 28;149:399 43

26 Survival Outcomes In Patients With Advanced Hepatic Fibrosis Due To HCV All-cause mortality (%) Liver-related mortality or Liver transplantation (%) 3 25 All-cause mortality p< Liver-related mortality or liver transplantation p< No SVR 15 No SVR SVR Time (years) No. at risk No SVR SVR SVR Time (years) No. at risk No SVR SVR Van der Meer JAMA 212;38:

27 Cumulative incidence (%) Cumulative incidence (%) The Impact Of An SVR On Development Of Esophageal Varices In HCV Cirrhotics 1 Log-Rank p<.1 1 Log-Rank p=.3 8 Non SVR SVR Years Patients at risk No SVR SVR Non SVR SVR Years Patients at risk No SVR SVR % 6% Bruno S, et al. Hepatology 21:51; D Ambrosio R, et al. Antivir Ther. 211;16:677 84

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30 Effects of Sustained Viral Response in Patients With HIV and Chronic Hepatitis C and Nonadvanced Liver Fibrosis 695 patients F, 77; F1, 29; F2, /695 with SVR. Median follow-up : 4.9 years SVR riduce la mortalità e il rischio di scompenso anche in pz con fibrosi moderata Berenguer J et al. J Acquir Immune Defic Syndr 214;66:28 287)

31 Survival Probability DAA Therapy and Risk of Mortality ANRS HEPATHER: multicenter observational cohort study assessing short-term effects of DAAs on mortality in pts with HCV (N = 9295) Median follow-up: 24 mos DAA treatment associated with decreased risk of death vs no DAA treatment in the short term *8482 person-yrs. 14 person-yrs. All-Cause Mortality DAA+ (n = 646)* DAA- (n = 2835) HR:.65 (95% CI: ; P =.258) Mos Carrat F, et al. AASLD 217. Abstract LB-28.

32 Veterans Affairs HCV Clinical Case Registry Impact of SVR with DAAs on Mortality and HCC All-cause mortality rates and incident HCC rates in Veterans ± advanced chronic liver disease (ACLD) in the HCV registry treated with DAAs through Sept 216 p<.1 p<.1 195/ / 13,992 14/ / 13,153 39/ / / / 39,918 SVR was associated with 8% reduction in mortality and 84% reduced incidence in HCC SVR was associated with 59% reduction in mortality Achieving SVR after DAA treatment significantly reduced lower all-cause mortality in both ACLD and non-acld patients and significantly reduced incident HCC rates in ACLD patients Backus, AASLD 217, Oral 78

33 How Accurate Is Transient Elastography to Monitor for Regression of Cirrhosis After SVR? 33 pts with HCV and biopsy-proven cirrhosis who achieved SVR after IFN based therapy FibroScan and biopsy ~ 6 mos post SVR Biopsy 2 pts regressed ( F3) 19 (95%) pts regressed (TE < 12 kpa) FibroScan 13 pts had persistent cirrhosis (F4) 5 (38%) pts regressed (TE < 12 kpa) Diagnostic accuracy of TE for diagnosing post-svr cirrhosis: 61% sensitivity, 95% specificity Regression of Fibroscan scores to sub-cirrhotic levels does not ensure true cirrhosis regression D Ambrosio R, et al. J Hepatol. 213;59:

34 Post HCV SVR Liver Stiffness Measurement (LSM) Not Predictive of HCC 828 patients without previous HCC from 2 French treatment centers May 28 - Nov 216; SVR: 94% (799/849) LSM assessed by FibroScan before HCV therapy and 1 time during wks of follow-up Post-SVR HCC screening every 6 mos by ultrasound Median LSM decrease from baseline to follow-up: -3.6 kpa (-6.2 to -1.1; P <.1) At median f/u of 6 mos, 2 patients died and 22 (2.8%) developed HCC Factors assoc. with HCC in multivariate analysis: age, sex, diabetes, and baseline LSM, but NOT change in LSM Factor HR (95% CI) P Value Age (per yr) 1.6 ( ).5 Diabetes 2.7 ( ).26 Baseline LSM Per kpa 1.5 ( ) <.1 Qualitative baseline LSM vs < ( ) 12.5 vs < ( ) Shili S, et al. EASL 218. Abstract PS Change in LSM, per kpa.99 ( ).75

35 HVPG Change (%) HVPG Change (%) SOF+RBV in Compensated and Decompensated Cirrhotics with Portal Hypertension HVPG Change Over Time Observation Period in Patients with BL HVPG 12 mmhg* (24 weeks) n=2 *No patient had HVPG 12 mm Hg at end of observation period Changes After Treatment in Patients with BL HVPG 12 mmhg (n=33) <1 1 There were clinically meaningful improvements in portal hypertension in addition to improvements in liver biochemistry, CTP and MELD scores The effect of SVR12 and viral suppression on HVPG is being monitored at 1 year post-treatment Patients with >2% decrease (8/33) a n=2 Baseline MELD Score -8 a Patients with HVPG 12 mm Hg at end of treatment HVPG = hepatic venous pressure gradient A reduction in HVPG 2% or below the 12-mm Hg threshold markedly reduces the risk of variceal bleeding, and varices may decrease in size a a a Afdhal, EASL, 215, LP13

36 RESIST-HCV: Long-term Outcomes Following SVR to HCV DAA Therapy Prospective cohort analysis of 4668 patients who started DAAs Mar Dec 216 (previous HCC or OLT excluded) 69% with CTP A cirrhosis; 8.8% with CTP B cirrhosis SVR: 9.7%; no SVR: 5% Primary endpoint: survival since initiating HCV DAAs Median follow-up: 72 wks Modified ITT analysis: N = 4468 Calvaruso V, et al. EASL 218. Abstract PS-149.

37 RESIST-HCV: Predictors of Mortality in Patients Treated With HCV DAAs SVR associated with reduced risk of liver-related mortality across disease stages, but benefit lower in CTP B cirrhosis Univariate HR for no SVR vs SVR in CTP B: 3.49; P =.36 Multivariate Cox Regression HR (95% CI) P Value Independent predictors of liver-related mortality in CTP A cirrhosis No SVR 18.5 ( ) <.1 Albumin < 3.5 g/dl 6.1 ( ) <.1 Independent predictors of cardiovascular mortality in DAA-treated patients No SVR 1.56 ( ) <.1 Diabetes 4.11 ( ).11 Calvaruso V, et al. EASL 218. Abstract PS-149.

38 Cumulative No. of Deaths HCV DAA Therapy and Survival in Pts With Decompensated Cirrhosis Comparison of incidence of death in pts with hepatic decompensation in the SOLAR studies of SOF/LDV + RBV (n = 212) and pre-daa era pts in OPTN meeting SOLAR criteria (model creation set, n = 271; validation set, n = 899) Survival prediction model created using OPTN data to determine expected mortality for 1 yr in pts not receiving DAA therapy; model included age, albumin, HE grades 1/2 and 3/4, MELD, sodium Kim WR, et al. AASLD 217. Abstract LB deaths in 1 yr in SOLAR study DAA therapy lowered risk of death by 6% Observed Expected SMR =.39 (95% CI: ) Mos

39 Benefits of Achieving SVR SVR Decreased transmission Improved clinical outcomes Extrahepatic Hepatic Cirrhosis Decompensation HCC Transplantation All-cause mortality QoL Malignancy Diabetes CVD Renal Neurocognitive Smith-Palmer J, et al. BMC Infect Dis. 215;15:19. Negro F, et al. Gastroenterology. 215;149: George SL, et al. Hepatology. 29;49:

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