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 HCV Survey Participants (%) NHANES: Prevalence of Cirrhosis and Advanced Fibrosis Among US Adults With HCV ( and ) An estimated 37,5 Americans with cirrhosis and 347,8 with advanced fibrosis (27-212) Nearly one in five US adults with HCV infection have cirrhosis During Prevalence of Cirrhosis or Advanced Fibrosis Among US Residents With HCV % 16% Cirrhosis was associated with Increasing age (OR: 1.4) 1 7% 8% 9% 1% Diabetes (OR: 2.33) Obesity (OR: 2.96) 5 Advanced fibrosis was associated with Increasing age (OR: 1.8) Diabetes (OR: 3.37) Udompap P, et al. J Hepatol. 216;64; Cirrhosis (APRI >2 [Ishak 5-6]) Advanced Fibrosis (FIB-4) Rates of Fibrosis are Increasing as the Patient Population Ages

6 Rationale to Assess Fibrosis in Patients with HCV Presence of cirrhosis: Triggers routine cirrhosis care Evaluation for esophageal and/or gastric varices Surveillance for hepatocellular carcinoma May effect rate of SVR May affect treatment duration May require use of ribavirin Does not require liver biopsy! Non invasive tests APRI/Fib-4/elastography/MRI/Fibroscan/Fibrosure All patients with liver disease should undergo an assessment of fibrosis

7 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

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

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

10 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 < 15 K AST:ALT ration > 1 Elevated globulins

11 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. 212;142:

12 APRI and FIB-4 Calculation > 1. specificity 72% for F4 fibrosis < 1.45 = F-F1 fibrosis > 3.25 = F3-F4 fibrosis Zhu X. Dig Dis Sci. 211:56:

13 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 F-F F Results

14 Hepascore Forn s Score APRI Fibrosure Fibrotest MP3 Fibrometer Benefits of Non-Invasive Fibrosis Testing Good for mild vs advanced fibrosis Cheap, noninvasive Best validated in hepatitis C 1. Significant overlap across stages May be influenced by other factors Caveat: may not be so sensitive for F2-F Leroy. J Hepatol. 27;

15 How Accurate are Non-Invasive Tests of Fibrosis? Systematic Review of 172 Studies Test Sensitivity Specificity AUROC Platelet < APRI >.5 APRI > AST/ALT > ELF > FIB-4 > 1.45 FIB-4 > Fibrotest >.1 Fibrotest > Forns > 4.2 Forns > Hepascore > Chou and Wasson. Ann Int Med. 213;158:87-82.

16 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 2% (especially in obese patients) improved with XL probe. Influenced by inflammation it falsely elevates measurements

17 Logarithm of Transient Elastometry Measurement (log kpa) Transient Elastometry Measurement (log kpa) Liver Stiffness by Transient Elastography Very good for minimal fibrosis (F-2) vs cirrhosis (F4) Lots of overlap in the middle Becoming more widely available P < Boursier J, et al. Am J Gastroenterol. 211;16: n = 15 n = 49 n = 26 n = 14 n = Fibrosis Stage

18 Correlation Between Liver Stiffness (kpa) & Fibrosis Stage *Gastroentérol Clin Biol. 28;32,58-67; **J Hepatol. 29;49: Aliment Pharmacol Ther. 28;28: ; ***Hepatology. 21;51: Gastroentérol Clin Biol. 28;32:58-67.

19 Shearwave Elastography allows Ultrasound and Assessment of Fibrosis to be performed Simultaneously F1: Patient with F1 liver fibrosis, exhibiting mean elasticity values of 6.8 kpa. Standard deviation of,7 kpa demonstrate tissue homogeneity

20 Combining Fibroscan and Fibrotest/Fibrosure May Increase Accuracy of Fibrosis Assessment and Decrease Requirement for Liver Biopsy FS 7.1 kpa and FT.48 (n=49) Disagree FS < 7.1 kpa and FT >.48 (n=29) HCV patients (n=32) FIBROSCAN + FIBROTEST (n=32) FS failure (n=8) FS < 7.1 kpa and FT.48 (n=87) Agree FS 7.1 kpa and FT >.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. 21;52:

21 Overall Survival (%) Overall Survival (%) Fibroscan and Fibrosure Results Predict Overall 5 Year Patient Survival in HCV Infection B kpa >9.5 kpa >3 kpa >2 kpa C >.75 >.8 >.85 >.9.4 >4 kpa.4.2 >5 kpa.2 >.95. P<.1 P< Follow-up (Months) Follow-up (Months) Verginol, et al. Gastroenterology. 211;14:197.

22 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 Yin M, et al. Radiology :16622.

23 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.5%

24 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)

25 Options for Liver Biopsy in Patients Unable to Undergo Transcutaneous Liver Biopsy In patients who are coagulapathic and/or have significant ascites, transcutaneous liver biopsy may not be possible Transjugular liver biopsy with hepatic and portal pressure measurements can provide liver tissue and assess if the patient has portal HTN Portal pressure free hepatic vein pressure > 1 mmhg = clinically significant portal HTN, when ascites, varices, encephalopathy may occur liver deflated balloon Free hepatic Vein pressure liver Inflated balloon Wedged Hepatic Vein pressure to assess Portal pressure

26 Liver Biopsy Appearance and Categories of Fibrosis 1. Brunt EM. Hepatology. 2;31: ; 2.Standish R, et al. Gut. 26;55: ; 3. Knodell RG, et al. Hepatology. 1981;1: ; 4. Bedossa P, Poynard T. Hepatology. 1996;24:

27 Methods to Predict Outcomes in Patients with Liver Disease

28 Child-Turcotte-Pugh (CTP) Calculator This calculator is used for the classification of the severity of cirrhosis 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 CTP has better prognostic utility in predicting outcomes after Surgical Procedures Albumin (g/dl) > <2.8 PT (sec prolonged) or INR <4 < >6 >2.3 *CTP score is obtained by adding the score for each parameter. CTP class: A= 5-6 points B= 7-9 points C= 1-15 points

29 Surgical Outcomes Total (n=64) Morbidity (n=28) Mortality at 3 mo (n=7) Mortality at 1 y (n=17) CTP class A 23 7 (3) () 2 (9) CTP class B (42) 3 (1) 8 (26) CTP class C 1 8 (8) 4 (4) 7 (7) Emergent 1 9 (9) 2 (2) 6 (6) Ascites (62) 6 (18) 14 (41) Number of patients (percentages) shown. Ascites=ascites present on physical examination and/or imaging studies; emergent=emergency surgery performed; morbidity=postoperative complications or death within 3 days. Causey, et al. American Journal of Surgery. 212;23:

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

31 Cumulative Waiting List Survival (%) MELD and Prognosis P<.1 As MELD rises, survival decreases Time (Months) 3 36 Kamath P, et al. Hepatology. 21;33(2):464-7.

32 Cumulative Waiting List Survival (%) MELD and Prognosis <1 P< As MELD rises, survival decreases Time (Months) 3 36 Kamath P, et al. Hepatology. 21;33(2):464-7.

33 Cumulative Waiting List Survival (%) MELD and Prognosis <1 P< As MELD rises, survival decreases Time (Months) 3 36 Kamath P, et al. Hepatology. 21;33(2):464-7.

34 Cumulative Waiting List Survival (%) MELD and Prognosis <1 P< As MELD rises, survival decreases Time (Months) 3 36 Kamath P, et al. Hepatology. 21;33(2):464-7.

35 Cumulative Waiting List Survival (%) MELD and Prognosis <1 P< As MELD rises, survival decreases Time (Months) 3 36 Kamath P, et al. Hepatology. 21;33(2):464-7.

36 Cumulative Waiting List Survival (%) MELD and Prognosis <1 P< As MELD rises, survival decreases > Time (Months) 3 36 Kamath P, et al. Hepatology. 21;33(2):464-7.

37 Hazard Ratio MELD PREDICTS PRE- & POST- TRANSPLANT OUTCOMES Any MELD > 15 predicted better outcomes IF PATIENT WAS TRANSPLANTED vs Remaining on waiting list 2 1 MELD Hazard Ratio p-values <.1 <.1.41 <.1 <.1 <.1 <.1 <.1 <.1

38 Hazard Ratio MELD PREDICTS PRE- & POST- TRANSPLANT OUTCOMES Mortality risk transplanted vs waitlist Merion, et al. AJT. 25;2:37-313xt 4 3 Any MELD > 15 predicted better outcomes IF PATIENT WAS TRANSPLANTED vs Remaining on waiting list 2 1 MELD Hazard Ratio p-values <.1 <.1.41 <.1 <.1 <.1 <.1 <.1 <.1

39 Mortality (%) MELD- Na Model Normal serum sodium Hyponatremia 17% % % 1.5% 3.5% % % < 1 (n=15) 36% 25% 66% 1-14 (n=7) (n=63) 2-24 (n=25) (n=14) MELD Score Categories 5% % 3 (n=7) At any MELD score > 1, patients with serum Na+ < 136 had higher death rates when compared to patients with normal serum Na+ Kim R, et al. NEJM. 28;359: , Biggins S, et al. Gastro. 26;13:

40 As of January 216, MELD-Na is used by UNOS for organ allocation

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

42 Baveno IV International Consensus Workshop Staging System for Cirrhosis: 1-Year Outcome Probabilities Decompensated Compensated 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 Stage 1 Stage 2 Stage 3 NO VARICES NO ASCITES 7% VARICES NO ASCITES ASCITES VARICES 4.4% 6.6% 4% 7.6% 1% 3.4% 2% DEATH Stage 4 BLEEDING ASCITES 57% D Amico G, et al. J Hepatol. 26;44:

43 Summary Non Invasive Evaluation of Liver Tissue Fibrosis (Staging) APRI Fib-4 Fibrosure Plat < 15K CT, MRI Consider hepatic vein catheterization with Hepatic Vein and Portal Vein Pressure Measurements with Transjugular liver biopsy to Assess for Portal Hypertension

44 Algorithm to Assess Severity of Liver Disease Complications of cirrhosis (variceal hemorrhage, ascites, encephalopathy) OR Plt <,/µl + AST > ALT Cirrhotic liver on imaging Patient has cirrhosis Screen for Liver Cancer Assess for Liver Transplantation HCV-RNA positive History + physical exam CBC Liver profile Ultrasound Fibrosis assessment with transient elastography and/or fibrosis serum panel Reliable/Agree Manage HCV according to fibrosis stage Disagree, unreliable, unavailable, or diagnostic uncertainty Liver Biopsy

45 1-year Cumulative Occurrence Rate (%) 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. 212; 38: 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

46 Patients (%) 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=) Cirrhosis/F3-F4 (65%/35%) Regimens Sofosbuvir-based (45%), telaprevir + PR (29%), PR (16%), clinical trial/other (1%) Overall median time to improvement: 2.5 years after SVR Cirrhosis versus F3-F4: 3. versus 2.5 years Predictor of regression in F3-F4 at baseline: APRI (P<.5) Surrogate marker of improvement of baseline cirrhosis: decrease in ALT (P=.3) Change in Fibrosis by FibroScan 6% Improved No change Worsen 34% Overall (n=) 6% 69% F3-F4 (n=35) 14% 17% Baseline 55% 45% Cirrhosis (n=65) % Crissien AM, et al. Hepatology. 215;62(suppl S1):264A-265A. Abstract 18.

47 Cumulative Incidence (%) SVR to HCV Therapy Reduced HCC and Liver- Related Complications in Patients With Bridging Fibrosis or Cirrhosis Cumulative Incidence (%) HCC (n=37) Liver-Related Complications* (n=37) Non-SVR 6 Non-SVR 4 P< SVR 2 P<.1 SVR Follow-Up (years) Follow-Up (years) *Ascites, variceal bleeding. Cardoso A-C, et al. J Hepatol. 21;52:

48 Cumulative Incidence (%) SVR to HCV Therapy Reduced HCC and Liver- Related Complications in Patients With Bridging Fibrosis or Cirrhosis Cumulative Incidence (%) HCC (n=37) Liver-Related Complications* (n=37) Therapy: Interferon and Ribavirin: SVR 33% Non-SVR 6 Non-SVR 4 P< SVR 2 P<.1 SVR Follow-Up (years) Follow-Up (years) *Ascites, variceal bleeding. Cardoso A-C, et al. J Hepatol. 21;52:

49 Cumulative Incidence (%) SVR to HCV Therapy Reduced HCC and Liver- Related Complications in Patients With Bridging Fibrosis or Cirrhosis Cumulative Incidence (%) HCC (n=37) Liver-Related Complications* (n=37) Therapy: Interferon and Ribavirin: SVR 33% Non-SVR 6 Non-SVR 4 P< SVR 2 P<.1 SVR Follow-Up (years) Follow-Up (years) *Ascites, variceal bleeding. Cardoso A-C, et al. J Hepatol. 21;52:

50 SVR12 (%) SVR12 (%) LDV/SOF ± RBV for 12 vs 24 Weeks: SVR12 in GT 1 Treatment-naïve Patients Non-Cirrhotic Cirrhotic / 18 LDV/S OF 178/ 184 LDV/SOF + RBV 181/ 184 LDV/S OF 179/ 181 LDV/SOF + RBV 2 32/ 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. 214;37:

51 SVR12 (%) LDV/SOF ± RBV for 12 vs 24 Weeks: SVR12 in GT 1 Treatment-experienced Patients 12 Weeks 24 Weeks No cirrhosis Cirrhosis / 87 19/ 22 LDV/SOF 89/ 89 18/ 22 86/ 87 22/ 22 LDV/SOF + RBV LDV/SOF 88/ 89 22/ 22 LDV/SOF + RBV Afdhal, EASL. Abst O19. N Engl J Med. 214 Apr 17;37(16):

52 SVR12 (%) 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 Pts with previous IFN, riba, boceprevir, telaprevir, simeprevir, or faldaprevir failure 4 2 N = Bourlière M, et al. Lancet Infect Dis. 215;15:

53 SVR12 (%) 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 /68 51 /51 Overall 22 /22 18 /18 Treatment naive 12 Weeks 24 Weeks 14 /14 1 /1 Relapse 86 6 /7 3 /3 Partial response 25 /25 2 /2 Null response Colombo M, et al. AASLD 214, Boston. #1931. Treatmentexperienced

54 SVR12 (%) Ombitasvir/Paritaprevir/r + Dasabuvir in HCV Genotype 1b With Cirrhosis Phase 3, open-label study (n=6) Treatment-naïve (n=27) or pegifnexperienced (n=33), genotype 1b HCV RNA > IU/mL Compensated cirrhosis (Child-Pugh A), no history of decompensation Creatinine clearance >3 ml/min Ombitasvir/paritaprevir/r + dasabuvir for 12 weeks All patients achieved SVR12 Safety No discontinuations due to adverse events No grade 3/4 hemoglobin declines SVR12 % Compensated Cirrhosis (n=6) Feld JJ, et al. J Hepatol. 216;64:31-37.

55 SVR12 (%) Ombitasvir/Paritaprevir/r + Dasabuvir in HCV Genotype 1b With Cirrhosis Phase 3, open-label study (n=6) Treatment-naïve (n=27) or pegifnexperienced (n=33), genotype 1b HCV RNA > IU/mL Compensated cirrhosis (Child-Pugh A), no history of decompensation Creatinine clearance >3 ml/min Ombitasvir/paritaprevir/r + dasabuvir for 12 weeks All patients achieved SVR12 Safety No discontinuations due to adverse events No grade 3/4 hemoglobin declines SVR12 % NO Riba!! Compensated Cirrhosis (n=6) Feld JJ, et al. J Hepatol. 216;64:31-37.

56 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 SVR by Cirrhosis Status 98% 92% 94% 97% GT1a b GT1b <1% (1/288) of subjects experienced on-treatment virologic failure 3% (1/288) of subjects relapsed after treatment Kwo, et al. Gastroenterology. 217;152: Without With Cirrhosis Compensated Cirrhosis

57 SVR12 (%) Sofosbuvir/Velpatasvir for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients / /51 12/ /423 Total Non- Cirrhotic Cirrhotic 2/21 Treatment- Treatment- Naïve Experienced N Engl J Med. 215;373(27):

58 Summary Prevalence of cirrhosis in patients with 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 < 15 APRI, Fib-4, Fibrosure Fibroscan, MRE Despite the presence of cirrhosis, SVR rates are high in patients who undergo therapy