Massimo Puoti SC Malattie Infettive ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA MILANO. Beyond HCV cure: reversibility of liver damage

Transcription

1 Massimo Puoti SC Malattie Infettive ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA MILANO Beyond HCV cure: reversibility of liver damage

2 Beyond HCV cure: reversibility of liver damage Progression of Liver Damage Physiopathology of cirrhosis regression Factors affecting reversibility of Cirrhosis Regression of viral cirrhosis Impact of cirrhosis regression on prognosis of HCV infected patients Beyond cirrhosis regression: impact of SVR in patients with not reversible and decompensated cirrhosis

3 Beyond HCV cure: reversibility of liver damage Progression of Liver Damage Physiopathology of cirrhosis regression Factors affecting reversibility of Cirrhosis Regression of viral cirrhosis Impact of cirrhosis regression on prognosis of HCV infected patients Beyond cirrhosis regression: impact of SVR in patients with not reversible and decompensated cirrhosis

4 VIRUS REPLCATION REVERSIBLE LIVER DAMAGE INTERACTION WITH CELLULAR REGULATORY MECHANISMS PRO- ONCOGENESIS

5 Post-Necrotic Fibrosis Pattern of Development: porto-central Prevalent Mechanisms: chronic wound healing Fibrogenic cells: portal MF >> stellate cells Key Events: early involvement of centrilobular vein, angiogenesis and portocentral shunting

6 Fibrosis progression in chronic hepatitis C Cirrhosis Moderate Severe Mild Fibrosis Long term asymptomatic process Progression speed change over time and is heterogeneous across the liver tissue

7 Stage No Fibrosis Portal tract expansion Bridging few or many but only Porto portal Many bridges palso porto central Cirrhosis Metavir Scheuer F0 F1 F2 F3 F4 Ishak S0 S1 S2 S3 S4-S5

8 Biopsy: the best standard but risk of sampling error

9 Non-Invasive Techniques for Detecting Cirrhosis Cut off for cirrhosis F0 F1 F2 F3 F4: Cirrhosis APRI 0.5 >1.5 >1.0 has a 76% sensitivity/ 72% specificity for cirrhosis FIB4 FibroTest Positive predictive value of 65% for advanced fibrosis > % specificity diagnostic value 0.96 prognostic value FibroScan kpa Greater reliability in F3/F4 than F1/F2 14 kpa has ~90% probability of cirrhosis Wai et al Hepatology : Vallet-Pichard et al Hepatology :769

10 Fibrosis Stage Elasticity (kpa) Liver Fibrosis: a Dynamic Path Reduction of apoptosis leads to a maximal hyperplasia of ECMproducing cells Phase of slow progression High relevance of genetic factors: some patients do not progress beyond this stage Progressive Increase In Tissue Stiiffness Viral Hepatitis Castera L. et al. Gastroenterology 2005 Reduced anti-oxidant Alcohol and immune responses with aging NASH Biochemical changes in ECM composition Phase F1 of rapid F2 F3 F4 progression Fibrosis and structure stage (Metavir) Time (and patient s age)

11 Beyond HCV cure: reversibility of liver damage Progression of Liver Damage Physiopathology of cirrhosis regression Factors affecting reversibility of Cirrhosis Regression of viral cirrhosis Impact of cirrhosis regression on prognosis of HCV infected patients Beyond cirrhosis regression: impact of SVR in patients with not reversible and decompensated cirrhosis

12 Liver biopsies Baseline biopsy : F4 6 Years Post-Tx biopsy: F1

13 3 years after sustained virological response (SVR) Liver cell regeneration Remodelling of portal tract Thinning of fibrous septa

14 Thinning of fibrous septa Fibrous tissue equilibrium Synthesis Digestion HSC activation Matrix-degrading enzymes (Metalloproteases) Metalloproteases (MMP) : a familly of proteases digesting ECM molecules In situ production of MMPs «Old» fibrous septa more resistant to degradation (extensive crosslinking, elastin fibers)

15 Liver cell regeneration Inflammation Regeneration Chronic inflammation block hepatocyte regeneration : halting inflammatory process The mitotic clock : regeneration is extended in hepatocyte but not unlimited. Progressive telomere erosion lead to exhaustion capacity of regeneration Decreasing regenerative capacity in advanced cirrhosis

16 Resurgence of portal tract Disappearance of fibrous septa is associated with vanishing of shunting neovessels Reversal to a normal blood inflow through residual portal veins and arterial vessels Reconstruction of near-normal portal tracts

17 Viral cirrhosis may regress. But not every cirrhosis 1. Enzymatic degradation of fibrous septa : early or «young» cirrhosis. 2. Reshaping of portal tract : Persisting portal vessels and central veins within annular fibrous tissue - Absence of extensive vascular thrombosis 3. Hepatocyte regeneration : Stopping necroinflammation Virus eradication or supression

18 Beyond HCV cure: reversibility of liver damage Progression of Liver Damage Physiopathology of cirrhosis regression Factors affecting reversibility of Cirrhosis Regression of viral cirrhosis Impact of cirrhosis regression on prognosis of HCV infected patients Beyond cirrhosis regression: impact of SVR in patients with not reversible and decompensated cirrhosis

19 Factors Affecting the Reversibility of Fibrosis and Cirrhosis 1.- CHANGES IN THE ANGIOARCHITECTURE OF THE LIVER 2.- INCREASING DEGREE OF FIBRILLAR COLLAGEN CROSS-LINKING AND PRESENCE OF ELASTIN 3.- RESISTANCE TO APOPTOSIS OF HUMAN HEPATIC STELLATE CELLS 4.- INCREASED TISSUE STIFFNESS

20 CAST: ONLY SCAR TISSUE CAST: ONLY VESSELS Hepatic Microvasculature in Normal and Cirrhotic Human Liver

21 REVERSIBILITY OF LIVER FIBROSIS ACCORDING TO THE PATTERN FIBROSIS PATTERN EARLY PORTAL TO CENTRAL SEPTA NEO ANGIOGENESIS REVERSIBILITY POST-NECROTIC BILIARY CENTROLOBULAR PERICELLULAR - PERISINUSOIDAL Fernandez M. et al. J Hepatol 2009 in press

22 Factors Affecting the Reversibility of Fibrosis and Cirrhosis 1.- CHANGES IN THE ANGIOARCHITECTURE OF THE LIVER 2.- INCREASING DEGREE OF FIBRILLAR COLLAGEN CROSS-LINKING AND PRESENCE OF ELASTIN 3.- RESISTANCE TO APOPTOSIS OF HUMAN HEPATIC STELLATE CELLS 4.- INCREASED TISSUE STIFFNESS

23 Biochemical and Biological Evolution of Fibrillar Extracellular Matrix Inter-fiber filaments (type VI) EARLY FIBROSIS MMP-1 Fibrillar Collagen (type I,III, V) MMP-1 COLLAGEN CROSS-LINKING PRESENCE OF ELASTIN ACELLULAR FIBROSIS DOWNREGULATION OF MMP-1 AND UPREGULATION OF TIMP-1 ESTABLISHED FIBROSIS INCREASE IN TISSUE RIGIDITY AND TENSION

24 Factors Affecting the Reversibility of Fibrosis and Cirrhosis 1.- CHANGES IN THE ANGIOARCHITECTURE OF THE LIVER 2.- INCREASING DEGREE OF FIBRILLAR COLLAGEN CROSS-LINKING AND PRESENCE OF ELASTIN 3.- RESISTANCE TO APOPTOSIS OF HUMAN HEPATIC STELLATE CELLS 4.- INCREASED TISSUE STIFFNESS

25 Activated Human HSC Develop Resistance to Apoptosis In vitro: freshly isolated HSC 32 activated passage 7 freshly isolated HSC 32 activated passage 7 Bcl-2 29 kda 23 kda Bax p-akt 56 kda 32 kda actin Akt actin In vivo: HCV-cirrhosis 56 kda 32 kda 44 kda 42 kda 44 kda 42 kda p-erk ERK Novo E. et al., Gut 2006; 55:

26 Factors Affecting the Reversibility of Fibrosis and Cirrhosis 1.- CHANGES IN THE ANGIOARCHITECTURE OF THE LIVER 2.- INCREASING DEGREE OF FIBRILLAR COLLAGEN CROSS-LINKING AND PRESENCE OF ELASTIN 3.- RESISTANCE TO APOPTOSIS OF HUMAN HEPATIC STELLATE CELLS 4.- INCREASED TISSUE STIFFNESS

27 HSC Require a Stiff Environment for Myofibroblastic Differentiation Olsen AL et al. Am J Physiol Gastrointest Liver Physiol 2011

28 Beyond HCV cure: reversibility of liver damage Progression of Liver Damage Physiopathology of cirrhosis regression Factors affecting reversibility of Cirrhosis Regression of viral cirrhosis Impact of cirrhosis regression on prognosis of HCV infected patients Beyond cirrhosis regression: impact of SVR in patients with not reversible and decompensated cirrhosis

29 Histological outcome during long-term Lamivudine treatment Biopsies from 63 patients before and after 3 years of lamivudine treatment HAI score improved or was stabilized in 56/63 patients (89%) Bridging fibrosis improved by 1 stage in 12/19 (63%) and cirrhosis improved in 8/11 (73%) Fibrosis (including cirrhosis) regresses in most patients after three years of lamivudine therapy Dienstag JL, et al. Gastroenterology 2003; 124:

30 Histological outcome during long-term Adefovir treatment Treatment with Adefovir Dipivoxil in patients with (HBeAg)-neg. chronic hepatitis B for 48, 192 or 240 wk 24 patients with pretx and 240 wk biopsy Ishak fibrosis scores improved in 35%, 55%, and 71% of patients after 48, 192, and 240 weeks of adefovir Seven of 12 (58%) patients with bridging fibrosis or cirrhosis improved their Ishak F scores by at least 2 points Regression of fibrosis (including cirrhosis) increase with time and duration of treatment Hadziyannis G, et al. Gastroenterology 2006;131:

31 Number of patients Number of patients Histological outcome during long-term Entecavir treatment A patients with CHB, at least 3 years of Entecavir therapy and paired liver biopsy (median interval bw biopsies: 6yr) Histological improvement (2-point in the HAI and no worsening of the fibrosis score) was observed in 96% of patients, Baseline Week 48 Long-term Knodell HAI Missing 88% of patients improved Ishak score of fibrosis, including all patients with advanced fibrosis or cirrhosis at baseline (100%) The majority of patients with chronic hep B who were treated with entecavir achieved regression of fibrosis or cirrhosis B Baseline Week 48 Long-term Ishak Fibrosis Score Missing Adapted from Chang TT, et al. Hepatology 2010; 52: Chang TT, et al. Hepatology 2010; 52:886-93

32 Histological outcome during long-term tenofovir treatment 348 patients with paired biopsies before and after 5 years treatment with tenofovir DF (centralized reading) 87% (304/348) of patients had global histological improvement (> 2 Knodell index and no Ishak fibrosis score) 51% (176/348) of patients had fibrosis regression ( 1 unit in Ishak score) and 96% had prevention of fibrosis progression Cirrhosis (Ishak 5) regression occurred in 71/96 of patients (74%) with cirrhosis at baseline Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis Marcellin P, et al. Lancet 2013

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34 Number of patients Distribution of Metavir fibrosis stages in pre-treatment and post-treatment liver biopsies 38 patients, Hepatitis C cirrhosis, Child-Pugh A 24/48 weeks standard bitherapy and SVR Paired biopsy, mean interval : 6 years 25 Area of fibrosis (%) (18%) 38 2 (5%) Pre-treatment 15 (39%) 14 (37%) Post-treatment 61% patients with F4 at baseline had cirrhosis regression to lower METAVIR stages D Ambrosio et al Hepatology F4 F3 F2 F Morphometry 1 Morphometry 2 Baseline Bx After SVR

35 Courtesy by Prof M Colombo

36 Beyond HCV cure: reversibility of liver damage Progression of Liver Damage Physiopathology of cirrhosis regression Factors affecting reversibility of Cirrhosis Regression of viral cirrhosis Impact of cirrhosis regression on prognosis of HCV infected patients Beyond cirrhosis regression: impact of SVR in patients with not reversible and decompensated cirrhosis

37 Courtesy by Prof M Colombo

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39 Transient Elastography fails to identify cirrhosis regression D Ambrosio R et al. J Hep 2013

40 Collagen proportionate area (CPA) predicts portal hypertension and clinical decompensation in patients with HCV cirrhosis No clinical decompensation Clinical decompensation p = by Log rank test Calvaruso V, et al. Alimentary and Pharmacological Therapy 2014 Tsochatzis E, et al. Journal of Hepatology 2014

41 CPA correlates with HVPG and predict decompensation in patients with post-olt recurrence of HCV and cirrhosis CPA correlates with HVPG CPA predicts decompensation p < p = by Log rank test Calvaruso V, et al. Journal of Gastroenterology and Hepatology 2012

42 Courtesy by Prof M Colombo

43 Courtesy by A Aghemo and M Colombo

44 Natural history and prognostic indicators for survival in Cirrhotic Patients Markedly longer survival in patients with compensated cirrhosis vs those with decompensated cirrhosis Median survival Compensated cirrhosis: > 12 years Decompensated cirrhosis: ~ 2 years 1 year risk D Amico G, et al. J Hepatology. 2006;44:

45 Courtesy by Prof M Colom

46 Deaths due to HCC or liver decompensation after P/R treatment in 440 patients with HCV cirrhosis Di Marco et al, Gastroenterology, submitted

47 Not all cirrhosis are the same * Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Garcia-Tsao G, Friedman S, Iredale J, Pinzani Hepatology Apr;51(4):1445-9

48 Beyond HCV cure: reversibility of liver damage Progression of Liver Damage Physiopathology of cirrhosis regression Factors affecting reversibility of Cirrhosis Regression of viral cirrhosis Impact of cirrhosis regression on prognosis of HCV infected patients Beyond cirrhosis regression: impact of SVR in patients with not reversible and decompensated cirrhosis

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50 Prognosis in Cirrhosis: HVPG PROGNOSTIC VALUE OF HVPG IN LIVER CIRRHOSIS Measurement Significance 1-5 mmhg Normal 6-10 mmhg Preclinical sinusoidal portal hypertension > 10 mmhg Clinically significant portal hypertension > 12 mmhg Increased risk for rupture of varices > 16 mmhg Increased risk of Mortality > 20 mmhg Treatment failure and mortality in acute variceal bleeding

51 SOF+RBV in Compensated and Decompensated Cirrhotics with Portal Hypertension Effect of SOF+RBV on Hepatic Venous Pressure Gradient Week HVPG Assessment Arm 1 n=25 SOF + RBV SVR12 Arm 2 n=25 RBV mg Observation SOF + RBV SVR12 Arm 1 n=25 Arm 2 n=25 All With Paired HVPG n=37 Male, n (%) 18 (72) 20 (80) 28 (76) Mean age, y (range) 55 (43 69) 56 (44 69) 55 (44 69) HCV GT 1, n (%) 19 (76) 15 (60) 25 (68) HCV GT 2, 3, 4, n (%) 2 (8), 2 (8), 2 (8) 1 (4), 8 (32), 1 (4) 2 (5), 8 (22), 2 (5) Prior HCV treatment 17 (68) 23 (92) 28 (76) HVPG = hepatic venous pressure gradient Afdhal, EASL, 2015, LP13

52 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) 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 Afdhal, EASL, 2015, LP13 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) Patients with >20% decrease (8/33) a Baseline MELD Score <10 10 n=2 a Patients with HVPG 12 mm Hg at end of treatment HVPG = hepatic venous pressure gradient A reduction in HVPG 20% or below the 12-mm Hg threshold markedly reduces the risk of variceal bleeding, and varices may decrease in size a a a

53 Child-Pugh classification and scoring of liver diseases Clinical/Biochemical Indicator Serum bilirubin (mg/dl) Serum albumin (g/dl) Prothrombine time (s > control) Encephalopathy (grade) 1 point 2 points 3 points < > 3 > < 2.8 < > 6 none 1 or 2 3 or 4 Ascites absent slight moderate Points are summed, and the total score is classified according to severity as follows: GROUP A (mild) = 5 6 points GROUP B (moderate) = 7 9 points GROUP C (severe) = points Verbeeck RK. Eur J Clin Pharmacol 2008; 64:

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55 MELD SCORE MELDScore = 10 * ((0.957 * ln(creatinine)) + (0.378 * ln(bilirubin)) + (1.12 * ln(inr)))

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57 Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. Changes in CPT and MELD Scores from Baseline.

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59 Treatment of CTP B cirrhosis Pros and Cons Candidates for LT: To treat before or after Tx? Not candidates for LT: To treat or not to treat? Pros Better MELD at Ltx improved survival Ideal in HCC candidates for LDLT Low rate of Post Tx complications Issues with Post Ltx Improvement in MELD and CTP demonstrated in > 30% Improvement of HVPG in 4/50 Reduced risk of HCC Cons Potential for DILI MELD purgatory HCV+ donors will be discarded longer waitlist No Evidence based data on benefits Potential for DILI Cost for futile treatment in countries with limited budget for HCV drugs

60 <<.la malattia nel principio del suo male, e facile a curare e difficile a conoscere, ma, nel progresso del tempo, non l avendo in principio conosciuta ne medicata, diventa facile a conoscere e difficile a curare.» in the early phase of a disease the diagnosis is difficult but the cure is easy but as time goes by if it has been neither recognized nor cured the diagnosis becomes easy and the cure difficult Nicolò Machiavelli. Il Principe. DE PRINCIPATIBUS MIXTIS, 1513