New York State HCV Provider Webinar Series. Overview of Fibrosis-Staging, Child s Pugh, MELD Scores

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2 New York State HCV Provider Webinar Series Overview of Fibrosis-Staging, Child s Pugh, MELD Scores

3 Objectives Discuss the rationale to assess fibrosis in HCV infected patients Review prevalence of advanced fibrosis in US HCV infected patients Discuss techniques to assess fibrosis Lab testing Non-invasive imaging Liver Biopsy Review Childs-Pugh Score and MELD related to predicting patient outcomes Analyze treatment response rates in HCV infected patients with cirrhosis

4 What is the Prevalence of Cirrhosis in US Patients Infected with HCV?

5 Prevalence of Cirrhosis in the US Approximately 0.27% of the US population, corresponding to 633,323 persons Sixty-nine percent reported that they were unaware of having liver disease. Estimated 28.5% of HCV patients have cirrhosis Gordon et al. AJG 2-15

6 Epidemiologic Patterns of HCV Infection in the US Total HCV Infections (millions) Ever infected Chronic HCV Acute HCV Cirrhosis Year Peak Cirrhosis Davis GL, et al. Gastroenterology. 2010;138:

7 Importance of Assessing Fibrosis Determines urgency of therapy Selects patients in need of additional screening Varices Hepatocellular carcinoma Allows for selection of proper treatment plan and duration of therapy Used by many payors as a way to restrict access to therapy

8 Rationale to Assess Fibrosis in Patients with HCV Does not require liver biopsy! Non invasive tests APRI/Fib-4/elastography/MRI/Fibroscan/Fibrosure All patients with HCVshould undergo an assessment of fibrosis

9 Compensated vs. Decompensated Cirrhosis Patients with Decompensated Cirrhosis have portal hypertension and/or one or more of the following complications Ascites (Hepato-renal Syndrome, hepatic hydrothorax) Hepatic Encephalopathy Varices (esophageal,gastric) Portal Hypertensive Gastropathy Hepatocellular Carcinoma

10 Poor Survival Rates in Patients with Decompensated Cirrhosis 100 Compensated HCV cirrhosis Survival Probability (%) HCV cirrhosis with a complication 0 e.g. Decompensated Cirrhosis Months A B Patients at risk Patients with HCC at time zero were excluded Fattovich, et al. Gastro. 1997:112:

11 Tools to Assess: Fibrosis/Cirrhosis/Portal Hypertension Physical Exam Nodular liver, splenomegaly Presence of spider angiomata, palmar erythema, gynecomastia, caput medusa Caveat: findings are specific for cirrhosis and/or portal HTN, but are not sensitive Radiology Helpful if studies reveal: Nodular liver Enlarged caudate lobe Enlarged Spleen Reversal of flow in portal vein or the presence of portal vein collaterals

12 Assessing Fibrosis Ø Liver biopsy Widely available In real life, it is not as good as advertised Ø Vibration-controlled transient elastography VCTE FDA approved, not yet widely available in in the U.S. Ø MRI elastography Expensive, not readily available Ø Serum tests and formulas: Fibrosure, APRI, AST/ALT ratio, Forns index, FIB-4, etc. Work well in cases of no fibrosis or established cirrhosis No single test is accurate enough!

13 Lab Tests to Assess Fibrosis Liver Enzymes ( AST/ALT) may be normal or elevated in patients with advanced fibrosis or cirrhosis Normal ALT does not mean inactive HCV Liver Tests including bilirubin, albumin, INR may be normal until patients have advanced cirrhosis Liver tests that suggest advanced fibrosis/ cirrhosis include: Platelet count < 150 K AST:ALT ration > 1

14 Noninvasive Methods to Assess Hepatic Fibrosis Serum Tests AST to platelet ratio (APRI) FIB4: Age, AST, ALT, platelets Fibrosure (Fibrotest in Europe) Other lab techniques: ELF Forns Hepascore Measurement of liver stiffness Transient elastography Acoustic radiation force impulse imaging Magnetic resonance elastography Castera L. Gastroenterology. 2012;142:

15 APRI and FIB-4 Calculation > 1.0 specificity 72% for F4 fibrosis < 1.45 = F0-F1 fibrosis > 3.25 = F3-F4 fibrosis Zhu X. Dig Dis Sci. 2011:56:

16 Fibrosure Fibrosure ( available in US) Fibrotest ( available in Europe) Components of these tests: Age Gender serum y-glutamyl transferase (GGT) total bilirubin (TB) a-2 macroglobulin Haptoglobin apolipoprotein A1 alanine aminotransferase (ALT) if also assessing inflammation Result METAVIR F F3-F F F F1-F F F0-F F0 Results

17 How Accurate are Non-Invasive Tests of Fibrosis? Systematic Review of 172 Studies Test Sensitivity Specificity AUROC Platelet < APRI > 0.5 APRI > AST/ALT > ELF > FIB-4 > 1.45 FIB-4 > Fibrotest > 0.1 Fibrotest > Forns > 4.2 Forns > Hepascore > Chou and Wasson. Ann Int Med. 2013;158:

18 Liver Biopsy Pros Gold standard for intermediate fibrosis stages Assess activity (inflammation) Other diagnoses Cons Fatty liver Autoimmune Invasive Complications* Sampling error Expensive Requires experts Biopsy Pathology *Complications include: Pain, bleeding, hollow viscus perforation mortality in 0.005%

19 Liver Biopsy Appearance and Categories of Fibrosis 1. Brunt EM. Hepatology. 2000;31: ; 2.Standish R, et al. Gut. 2006;55: ; 3. Knodell RG, et al. Hepatology. 1981;1: ; 4. Bedossa P, Poynard T. Hepatology. 1996;24:

20 Indications for Liver Biopsy Documented HCV infection (HCV RNA positive) plus: Inconclusive, unreliable, or unavailable noninvasive tests Diagnostic uncertainty Concern about concomitant condition Fatty liver Alcohol Autoimmune hepatitis Drug-induced liver injury Other i.e, unexplained lab results (AMA, ANA, Ceruloplasmin, Alpha 1 AT, Ferritin)

21 How Good is Liver Biopsy? Widely regarded as the Gold Standard Compared to what? Published data may not represent real-life results What is an optimal liver biopsy?

22 Liver Biopsy in HCV Specimen size matters >11 portal tracts should be represented Colloredo G, et al. J Hepatol 2003;39:

23 How Can You Get an Accurate Liver Biopsy Interpretation? Size matters! Ideal specimen: >2cm, 16 or 14 gauge needle (1.4mm width) 93.7% of biopsies 2cm long had >11 portal tracts Pathologist matters! 391 HCV patients underwent liver biopsies 2 hepatopathologists read the biopsies, reading compared to community pathologist Agreement among readings: 50% Community pathologists under-staged fibrosis in 73% of cases Colloredo G, et al. J Hepatol 2003;39: Robert M, et al. Clin Gastroenterol Hepatol 2009;7:

24 Interobserver Agreement Between Hepatopathologists and Community Pathologists Kappa values: >0.75 = excellent; 0.4 to 0.74 = good; <0.4 = poor Robert M, et al. Clin Gastroenterol Hepatol 2009;7:

25 Liver Biopsy May Not be As Good As Advertised How many of your biopsies: Are >2cm in length and a single intact specimen? Obtained with a 14 or 16 gauge needle? Pathology report states the number of portal tract present? Read by a hepatopathologist? Liver biopsy is one of several components of fibrosis assessment

26 Vibration-Controlled Transient Elastography (VCTE) Non-invasive method to assess fibrosis Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36

27 Liver Stiffness by Transient Elastography Ultrasound-based technique Determines liver stiffness Correlates well with fibrosis No ceiling, ie, increases with worsening cirrhosis predicts complications (eg, varices) Simple to use minimal training Other methods in development Shear wave elastography Caveats: Fails in up to 20% (especially in obese patients) improved with XL probe. Influenced by inflammation it falsely elevates measurements

28 VCTE Analyzes a Larger Volume of Liver Tissue VCTE Liver Biopsy ~ 1 cm x 4 cm ~ 0.14 cm x 2-3 cm

29 VCTE vs. Liver Biopsy ADVANTAGES Non-invasive Safer, less expensive Can be used for serial assessment of fibrosis DISADVANTAGES Test failure or unreliable results BMI >30 kg/m2 Inexperienced operator (<100 exams; best: >500) Best to differentiate F0/F1 from F4 Gives no information on inflammation HCV: >7.3 kpa suggests significant fibrosis; >12.5 kpa suggests cirrhosis Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36

30 Correlation Between Liver Stiffness (kpa) & Fibrosis Stage *Gastroentérol Clin Biol. 2008;32,58-67; **J Hepatol. 2009;49: Aliment Pharmacol Ther. 2008;28: ; ***Hepatology. 2010;51: GastroentérolClin Biol. 2008;32:58-67.

31 Fibroscan and Fibrosure Results Predict Overall 5 Year Patient Survival in HCV Infection B Overall Survival (%) kpa >9.5 kpa >30 kpa >20 kpa >40 kpa >50 kpa C Overall Survival (%) >.75 >.80 >.85 >.90 > P<.0001 P< Follow-up (Months) Follow-up (Months) Verginol, et al. Gastroenterology. 2011;140:1970.

32 Combining Fibroscan and Fibrotest/Fibrosure May Increase Accuracy of Fibrosis Assessment and Decrease Requirement for Liver Biopsy FS 7.1 kpa and FT 0.48 (n=49) Disagree FS < 7.1 kpa and FT > 0.48 (n=29) HCV patients (n=302) FIBROSCAN + FIBROTEST (n=302) FS failure (n=8) FS < 7.1 kpa and FT 0.48 (n=87) Agree FS 7.1 kpa and FT > 0.48 (n=129) Liver Biopsy was required to assess fibrosis infrequently and only when Fibroscan and Fibrotest results did not concur LIVER BIOPSY NEEDED (n=86) Significant fibrosis absent or present No need for liver biopsy (n=216) Castera L. J Hepatology. 2010;52:

33 Non-Invasive Assessment of Fibrosis VCTE + serum markers fibrosis Discordant results Concordant results Recheck Still discordant Liver Biopsy Cirrhosis Cancer and Varices Screen No Cirrhosis Diseasespecific follow-up Tapper EB, et al. Clin Gastroenterol Hepatol 2015;13:27-36

34 Measures stiffness of liver by introducing shear waves via MRI. Older MRI units can be upgraded to perform MRE Software Upgrade allows assessment of Liver Stiffness Not widely available Expensive Yin M, et al. Radiology :

35 Take Home Message: Use All Your Tools! Serum fibrosis tests AST/ALT ratio >1 suggests advanced fibrosis if no alcohol APRI AST/ULN divided by platelet count x 100; >2 suggests cirrhosis Platelet count <150,000 suggests portal hypertension Ultrasound Splenomegaly or PV diameter >13mm suggests portal hypertension VTCE >7.3 kpa suggests advanced fibrosis

36 Methods to Predict Outcomes in Patients with Liver Disease

37 Child-Turcotte-Pugh (CTP) Calculator This calculator is used for the classification of the severity of cirrhosis. CTP score is obtained by adding the score for each parameter. Encephalopathy Ascites Points* None None Grade 1-2 (or precipitant-induced) Mild/Moderate (diuretic-responsive) Grade 3-4 (or chronic) Severe (diuretic-refractory) Bilirubin (mg/dl) <2 2-3 >3 Albumin (g/dl) > <2.8 PT (sec prolonged) or INR <4 < >6 >2.3 Childs Class A= 5-6 points B= 7-9 points C= points CTP has better prognostic utility in predicting outcomes after Surgical Procedures

38 MELD=Model for End Stage Liver Disease MELD and MELD Sodium are useful to predict survival in patients with cirrhosis

39 MELD and Prognosis Cumulative Waiting List Survival (%) >35 < P< As MELD rises, survival decreases Time (Months) Kamath P, et al. Hepatology. 2001;33(2):

40 MELD PREDICTS PRE- & POST- TRANSPLANT OUTCOMES 7 Hazard Ratio Mortality risk transplanted vs waitlist Merion, et al. AJT. 2005;2: xt Any MELD > 15 predicted better outcomes IF PATIENT WAS TRANSPLANTED vs Remaining on waiting list 1 0 MELD Hazard Ratio p-values <0.001 < <0.01 <0.001 <0.001 <0.001 <0.001 <0.001

41 MELD- Na Model Mortality (%) Normal serum sodium Hyponatremia 17% 0% 0% 1.5% 3.5% 0% 0% < 10 (n=15) 36% 25% 66% (n=70) (n=63) (n=25) (n=14) MELD Score Categories 50% 100% 30 (n=7) At any MELD score > 10, patients with serum Na+ < 136 had higher death rates when compared to patients with normal serum Na+ Kim R, et al. NEJM. 2008;359: , Biggins S, et al. Gastro. 2006;130:

42 As of January 2016, MELD-Na is used by UNOS for organ allocation

43 What is the One Year Survival in Patients With and Without Various Manifestations of Portal HTN?

44 Baveno IV International Consensus Workshop Staging System for Cirrhosis: 1-Year Outcome Probabilities Patients without portal HTN have low death rates and low rates of developing manifestations of portal HTN. However, as pts develop varices and/or ascites, death rates increase Compensated Decompensated Stage 1 Stage 2 Stage 3 Stage 4 NO VARICES NO ASCITES 7% VARICES NO ASCITES ASCITES ± VARICES BLEEDING ± ASCITES 4.4% 6.6% 4% 7.6% 1% 3.4% 20% 57% DEATH D Amico G, et al. J Hepatol. 2006;44:

45 Sample SVR rates in Compensated Cirrhosis

46 LDV/SOF ± RBV for 12 vs 24 Weeks: SVR12 in GT 1 Treatment-naïve Patients Non-Cirrhotic Cirrhotic SVR12 (%) SVR12 (%) / 180 LDV/S OF 178/ 184 LDV/SOF + RBV 181/ 184 LDV/S OF 179/ 181 LDV/SOF + RBV / 34 LDV/S OF 34/ 34 LDV/SOF + RBV 31/ 33 LDV/SO F 36/ 36 LDV/SOF + RBV 12 Weeks 24 Weeks 12 Weeks 24 Weeks Afdhal, et al. N Eng J Med. 2014;370:

47 Effect of Tx Duration and RBV in Cirrhotic, PI-Experienced, GT1 Pts (LDV/SOF) 12 wks of LDV/SOF + RBV 24 wks of LDV/SOF SVR12 (%) Pts with previous IFN, riba, boceprevir, telaprevir, simeprevir, or faldaprevir failure 20 N = Bourlière M, et al. Lancet Infect Dis. 2015;15:

48 Ombitasvir/Paritaprevir/r + Dasabuvir in HCV Genotype 1b With Cirrhosis Phase 3, open-label study (n=60) Treatment-naïve (n=27) or pegifnexperienced (n=33), genotype 1b HCV RNA >1000 IU/mL Compensated cirrhosis (Child-Pugh A), no history of decompensation Creatinine clearance >30 ml/min 12 weeks of treatment Safety No discontinuations due to adverse events SVR12 (%) SVR12 100% NO Riba!! 0 Compensated Cirrhosis (n=60) Feld JJ, et al. J Hepatol. 2016;64:

49 SVR12 in GT 1b Cirrhotic Patients Treated with PTV/RTV/OMV + DSV + RBV for 12 vs 24 Weeks Pooled analysis of Phase 3 trials All treated with RBV SVR12 (%) 67 /68 51 /51 Overall 22 /22 18 /18 Treatment naive 12 Weeks 24 Weeks 14 /14 10 /10 Relapse 86 6 /7 3 /3 Partial response 25 /25 20 /20 Null response Colombo M, et al. AASLD 2014, Boston. #1931. Treatmentexperienced

50 Subjects Achieving SVR, % Elbasvir and grazoprevir: Efficacy in Treatment-Naive HCV GT1-Infected SVR Rates for GT1 Subjects Receiving 12 Weeks of Therapy Overall SVR n N 95% SVR by GT1 Subtype GT1a GT1b b SVR by Cirrhosis Status 98% 92% 94% 97% <1% (1/288) of subjects experienced on-treatment virologic failure 3% (10/288) of subjects relapsed after treatment Kwo, et al. Gastroenterology. 2017;152: Without With Cirrhosis Compensated Cirrhosis

51 Sofosbuvir/Velpatasvir for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients SVR12 (%) / / / /423 Total Non- Cirrhotic Cirrhotic 200/201 Treatment- Treatment- Naïve Experienced N Engl J Med. 2015;373(27):

52 Benefits of SVR in HCV: The expected and the unexpected

53 Regression of Advanced Fibrosis or Cirrhosis by FibroScan Post SVR Retrospective chart review of SVR12 and prospective FibroScan, biopsy, and/or clinical assessment after SVR12 (n=100) Cirrhosis/F3-F4 (65%/35%) Regimens Sofosbuvir-based (45%), telaprevir + PR (29%), PR (16%), clinical trial/other (10%) Overall median time to improvement: 2.5 years after SVR Cirrhosis versus F3-F4: 3.0 versus 2.5 years Predictor of regression in F3-F4 at baseline: APRI (P<0.05) Surrogate marker of improvement of baseline cirrhosis: decrease in ALT (P=0.03) Patients (%) Change in Fibrosis by FibroScan 60% Improved No change Worsen 34% Overall (n=100) 6% 69% 14% 17% F3-F4 (n=35) Baseline 55% 45% Cirrhosis (n=65) 0% CrissienAM, et al. Hepatology. 2015;62(supplS1):264A-265A. Abstract 108.

54 SVR Decreases Mortality in Patients with Advanced Fibrosis Baseline factors significantly associated with all-cause mortality: Older age GT 3 (2-fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use Van der Meer A, et al. JAMA. 2012; 308: year Cumulative Occurrence Rate (%) 530 patients followed for a median of 8.4 years SVR patients All-cause mortality Liver-related mortality or liver transplant Non-SVR patients HCC Liver failure

55 SVR to HCV Therapy Reduced HCC and Liver- Related Complications in Patients With Bridging Fibrosis or Cirrhosis HCC (n=307) Liver-Related Complications* (n=307) Cumulative Incidence (%) SVR 100 Therapy: Interferon and Ribavirin: SVR 33% Non-SVR P<.001 Cumulative Incidence (%) Non-SVR P<.001 SVR Follow-Up (years) Follow-Up (years) *Ascites, varicealbleeding. Cardoso A-C, et al. J Hepatol. 2010;52:

56 The Expected: HCV Cure Decreases Risk of Liver and Non-liver complications SVR associated with decreased incidence of HCC reduced risk of hepatic decompensation reduced risk of cardiovascular events reduced risk of bacterial infections Nahon et al. Gastro 2017; 152:

57 The Unexpected: Viral Reactivation after SVR Hepatitis B reactivation 1 24 reported cases, including 2 deaths Includes isolated HBc IgM All patients initiating HCV DAA therapy should be assessed for HBV coinfection with HBsAg, anti-hbs and anti-hbc. For HBsAg+ patients who are not already on HBV suppressive therapy, Monitoring of HBV DNA levels during and immediately after DAA therapy for HCV is recommended Antiviral treatment for HBV should be given if treatment criteria for HBV are met. The FDA now requires a boxed warning for all DAAs. Herpesvirus 2 10 reactivations 7 cutaneous 2 ocular 1 labialis 1. AASLD guidance document. Accessed Perello et al. Clin Gastro and Hep 2016;14:

58 Post-SVR Treatment Monitoring: Recommendations Clinicians should evaluate patients with persistent abnormal transaminase levels after SVR for other causes of liver disease and consult with a liver disease specialist. Clinicians should screen for hepatocellular carcinoma (HCC) every 6 months. Clinicians should recommend EGD for screening for esophageal varices every 2-3 years

59 Summary It is critical to identify those HCV patients with bridging fibrosis and cirrhosis Prevalence of cirrhosis in HCV is increasing Assessment of fibrosis is critical in all patients with HCV May affect therapy choice Requires surveillance for varices and liver cancer Non-invasive assessment of fibrosis is possible Plat count < 150 APRI, Fib-4, Fibrosure Fibroscan, MRE SVR rates are high in patients with bridging fibrosis and cirrhosis