Hepatitis C: Evaluation, Staging and Managing Those Prior to or Not Appropriate for Treatment

Transcription

1 Activity Code FA376

2 Hepatitis C: Evaluation, Staging and Managing Those Prior to or Not Appropriate for Treatment Gregory T Everson, MD Professor of Medicine Director of Hepatology University of Colorado Denver

3 Learning Objectives Upon completion of this presentation, learners should be better able to: Identify candidates for antiviral therapy of HCV Review current and emerging new drugs for HCV

4 Disclosures Advisory Boards: Consulting: DSMB: Stock/Ownership: Management: Research Grants: Roche/Genentech, Vertex, GlobeImmune, BMS, Abbvie, Eisai, HGS/Novartis, Pfizer, Gilead, Janssen/Tibotec, Abbvie/Abbott Roche-Genentech, HGS/Novartis, BMS, Three Rivers/Kadmon, Vertex, Abbvie, BioTest, Boehringer-Ingelheim Merck, Centocor, Galectin Source, HepQuant LLC HepQuant LLC Roche/Genentech, Schering/Merck, Vertex, GlobeImmune, Gilead, HGS/Novartis, BMS, Pfizer, Source, Eisai, GSK, Pharmassett, Ortho Biotech, Janssen/Tibotec, Abbvie

5 Hepatitis C Viral Infection Liver Disease Extrahepatic Manifestations

6 Eyeball Test

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9 What is your next step? A. Initiate Interferonbased therapy B. Initiate Interferonfree therapy C. Declare the patient a non-candidate D. Assess severity of liver disease 20% 20% 20% 20% 20% E. Other A. B. C. D. E. 8

10 Hepatitis C replicates primarily in the: A. Brain B. Heart C. Lung D. Intestine E. Lymphocytes F. Liver G. Other 14% 14% 14% 14% 14% 14% 14% A. B. C. D. E. F. G. 8

11 Hepatitis C damages primarily the: A. Brain B. Heart C. Lung D. Intestine E. Lymphocytes F. Liver G. Other 14% 14% 14% 14% 14% 14% 14% A. B. C. D. E. F. G. 8

12 Direct-acting antiviral drugs are processed or metabolized primarily in the: A. Brain B. Heart C. Lung D. Intestine E. Lymphocytes F. Liver G. Other 14% 14% 14% 14% 14% 14% 14% A. B. C. D. E. F. G. 8

13 Answers Liver

14 Key Liver Issues Standard laboratory tests: MELD score Clinical Score: Child-Turcotte-Pugh (CTP score) Fibrosis tests Biopsy Elastography Serum fibrosis tests Portal circulation HVPG: Portal hypertension Spleen stiffness Other Drug Metabolism

15 Standard Lab Tests

16 What the tests assess ALT, AST: Hepatocyte injury INR: Liver Synthetic function (Late) Albumin: Liver Synthetic function (Late) Bilirubin: Liver Excretory function (Late) Platelet Ct: Portal hypertension Models: HALT-C (online) predict cirrhosis MELD (90 day survival)

17 HALT-C Formula for Predicting Cirrhosis (N >1,100 patients with HCV) log odds (predicting cirrhosis) = x platelet (x103/mm3) x AST/ALT ratio x INR. The formula to calculate predicted probability is exp(logodds)/(1+exp(logodds)). Cutoff < 0.2 to exclude cirrhosis, would misclassify only 7.8% (24/309) of patients with cirrhosis (negative predictive value of 85%) Cutoff >0.5 to identify cirrhosis, would misclassify 14.8% (70/474) of noncirrhotics (positive predictive value of 75%). But, approximately half, 48.5%, of the patients fell between the two cutoff values. HALT C Model (online): Platelet count, INR, AST, ALT Yields Probability of Biopsy Demonstrating Cirrhosis Lok AS, Ghany MG, Goodman ZD, Wright EC, Everson GT, Sterling RK, Everhart JE, Lindsay KL, Bonkovsky HL, Di Bisceglie AM, Lee WM, Morgan TR, Dienstag JL, Morishima C. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT-C cohort. Hepatology Aug;42(2):

18 MELD: Model for End-Stage Liver Disease Score Bilirubin (mg/dl) Prothrombin time (INR) Creatinine (mg/dl) MELD score = 3.8ln(bili) ln(INR) + 9.6ln(creat) + 6 Range of MELD score: 6 to 40 MELD 10 15: Evaluate for Liver Transplantation MELD > 15: List for Liver Transplantation MELD > 25: MELD at which Transplant is performed There are several ONLINE calculators for MELD score. Original reference. Kamath, et al. Hepatology 2001; 33:

19 Clinical Scoring System

20 Child-Turcotte-Pugh (CTP)* 1 Point 2 Points 3 Points Bili (mg/dl) <2 2 to 3 >3 PBC/PSC <4 4 to 10 >10 INR < to 2.3 >2.3 Albumin (g/dl) > to 3.5 <2.8 Ascites None Controlled with Medical Rx Mod Severe Uncontrolled by Medical Rx Encephalopathy None Mild Mod-Severe CTP class A: 5 or 6; CTP class B: 7-9; CTP class C: * Developed to predict risk of dying from Portal-Systemic shunt surgery.

21 Another Patient

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24 Looks Good. Does he have significant fibrosis, or even Cirrhosis?

25 Measuring Fibrosis Liver Biopsy Gold Standard Sampling Error Inconvenient and Risky Elastography US- or MR-based FDA-approved 2013 Convenient and Safe Accuracy in high BMI? Serum Markers Good at high and low ends

26 Liver Biopsy

27 Metavir Fibrosis Stages Stg 0 Stg 3 Stg 1 Stg 4 Stg 2 Gregory T. Everson, MD, University of Colorado Denver

28 Fibroscan

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30 Serum Fibrosis Tests FIBROTEST/FIBROSURE Models from Standard Labs APRI HALT C

31 Diagnosis of Cirrhosis Liver Biopsy METAVIR Stage 4 ISHAK Stages 5 and 6 Elastography Varies somewhat with device >12.5 kpa APRI > 2 FIBROTEST > 0.73

32 And why does it matter?

33 Implications of Diagnosis of Cirrhosis At-risk for Varices At-risk for future complications Variceal Hemorrhage Ascites/SBP Encephalopathy At-risk for HCC Compensated stage risk is about 2%/yr Decompensated stage - >5%/yr May not respond as well to DAA Rx

34 Management of Cirrhosis EGD to diagnose and treat Varices Ongoing clinical evaluation for complications Variceal Hemorrhage Ascites/SBP Encephalopathy Radiologic Imaging for HCC Compensated stage 6 to 12 months Decompensated stage more frequently? Alter the DAA prescription multi-daas and/or longer duration

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39 Cirrhosis Impairs the Response to Antiviral Therapy Lowers Rate of SVR

40 Definitions 1. SVR: Sustained Virologic Response; undetectable HCV RNA at 12 weeks or more after end of treatment 2. ptvr: post-transplant Virologic Response; undetectable HCV RNA at week 12 posttransplantation. This applies to the situation where the patients is on treatment up to, but not beyond, the day of transplantation.

41 Treatment Goals 1. SVR: Avoid LTx 2. SVR: In Case of LTx, Protect the Graft 3. Suppress HCV to Prevent Recurrence ptvr: post-transplant Virologic Response ptvr: undetectable HCV RNA week 12 post-ltx

42 Current Choices GT1-6: GT 1: PEG/RBV SOF/PEG/RBV SOF/RBV** PEG/RBV + either SIM, TPV, or BOC SIM/SOF ** Only FDA-recommended Pre-transplant treatment option. Otherwise, treatment of clinically decompensated cirrhosis is considered off-label.

43 PEG/RBV

44 PEG (or IFN) ± RBV to Achieve SVR RNA Negative Author N Rx EOT SVR Iacobellis 66 PEG/RBV 49% 20% Forns 51 PEG/RBV 29% 20% Tekin 20 PEG/RBV 45% 30% Annicchiarico 15 PEG/RBV 47% 20% Everson 124 IFN/RBV 46% 24% Forns 30 IFN/RBV 30% 20% Thomas 20 IFN 60% 20% Amarapurkar 18 IFN±RBV 61% 38% Crippin 15 IFN±RBV 33% 0% Totals % 24% Martinez-Camacho A, Fortune BE, Everson GT. Treating HCV Prior to Liver Transplantation. In Chronic Hepatitis C: Advances in Treatment, Promise for the Future. ML Shiffman (ed) Springer Science-Business. NY.

45 PEG (or IFN) + RBV to Achieve ptvr RNA Negative Patients Author N LTx ptvr Carrion 51 29% 20% Everson 47 32% 26% Forns 30 30% 20% Thomas 20 60% 20% Everson (LADR-A2ALL) 44 59% 25%* Totals % 24% Martinez-Camacho A, Fortune BE, Everson GT. Treating HCV Prior to Liver Transplantation.In Chronic Hepatitis C: Advances in Treatment, Promise for the Future. ML Shiffman (ed). Springer Science-Business. NY, NY. *Everson GT, et al. A Randomized Controlled Trial of Pretransplant Antiviral Therapy to Prevent Recurrence of Hepatitis C After Liver Transplantation. Hepatology 2013;57: ptvr GT1,4,6 22%. ptvr GT2,3 29%.

46 LADR A2ALL: ptvr related to Rx Duration Everson GT, et al. A Randomized Controlled Trial of Pretransplant Antiviral Therapy to Prevent Recurrence of Hepatitis C After Liver Transplantation. Hepatology 2013;57:

47 PEG/RBV + BOC or TPV (no data with SIM or SOF)

48 PEG/RBV + either TPV or BOC: SVR % HCV RNA negative Boceprevir Telaprevir Rel/BT Part Resp Null Resp Overall Hezode C, et al. Effectiveness of Telaprevir or Boceprevir in Treatment-experienced Patients with HCV Genotype 1 Infection and Cirrhosis. Gastroenterology doi: /j.gastro Childs class A (95%). SAE 51-54%, Premature DC for SAE 14-21%, Infection 4-9%, Decomp 5-5%, Death %. ANEMIA EPO use in 63-57%, Blood Transfusion 14-18%

49 Impact of Disease Severity CUPIC French open-access Study Albumin 3.5 g/dl < 3.5 g/dl Platelet Count µl -1 > 100, ,000 N % SVR 55% 37% % SAE/Death 6% 12% N % SVR 29% 27% % SAE/Death 16% 51% Hezode C, et al. Effectiveness of Telaprevir or Boceprevir in Treatment-experienced Patients with HCV Genotype 1 Infection and Cirrhosis. Gastroenterology doi: /j.gastro

50 CUPIC Caveat Albumin: < 3.5 g/dl Platelet Count: < 100,000 µl These laboratory features indicate high-risk for treatment-related SAEs with PEG/RBV plus BOC or TPV.

51 % HCV RNA negative PEG/RBV/TPV: ptvr Week 4 of TT Week 8 of TT Week 12 of TT ptvr Verna EC, et al. Columbia and Georgetown. Hepatology 2012;56:218A. Submitted. High Rates of SAEs, ANEMIA EPO + Transfusions of prbcs. One pt underwent LTx at Week 3 of Rx, RNA negative post-ltx.

52 Verdict on PEG-based Rx? GT1-6: GT 1: PEG/RBV SOF/PEG/RBV SOF/RBV PEG/RBV + either SIM, TPV, or BOC SIM/SOF Interferon-free treatment is the current and future paradigm! Pre-transplant current options are either SOF/RBV for up to 48 weeks, or SIM/SOF.

53 SOF/RBV

54 SOF/RBV in Cirrhosis GT1 (?4-6?): SVR Mean 72% (50 to 84%) SVR in Cirrhosis -? SVR in Rx-Experienced Cirrhosis? GT2: Rx-Naïve, 12 Wks, SVR 94% Rx-Experienced: 12, 16, 24 Wks Rx SVR 60%, 78%, 88%. GT3: Rx-Naïve, 12 vs 24 Wks, SVR 34% vs 92% Rx-Experienced: 12, 16, 24 Wks Rx SVR 19%, 61%, 60%.

55 Impact of Cirrhosis on SVR with SOF % SVR 12 NO Cirrh CIRRH GT1,4,5,6 12Wk +P GT 2,3 12Wk GT2 12Wk GT3 12Wk GT2 12Wk GT2 16Wk GT3 12Wk GT3 16Wk Rx-Naïve Neutrino Rx-Naïve Fission Rx-Intol, Inelig, Unwill Positron Rx-Experienced Fusion N Engl J Med 2013; DOI: /NEJMoa ; N Engl J Med 2013; DOI: /NEJMoa

56 ptvr % Achieving ptvr SAE 46% Death 15% SAE 31% Death 3% Curry MP, et al. Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation. Hepatology 2013;58:3134A. SAE 18%* Death 0% PEG/RBV TT-TPV SOF/RBV Center Multi Single Multi N 11/44 8/12 24/37 %HCC 62% 39% 100% MELD * No SAE was attributed to SOF. Rate of SAEs was similar to rate of SAEs in Controls in LADR-A2ALL.

57 SOF/RBV: ptvr is related to Duration of undetectable HCV RNA % Achieving ptvr <30 Days >30 Days Curry MP, et al. Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation. Hepatology 2013;58:3134A.

58 SOF/RBV Will SOF/RBV achieve ptvr in Sicker Patients? Afdahl N, Everson GT, et al. Sofosbuvir and Ribavirin for the Treatment of Chronic HCV with Cirrhosis and Portal Hypertension with and without Decompensation: Early Virologic Response and Safety. EASL 2014.

59 SOF/RBV in Cirrhosis with Portal Hypertension (N=50, 1:1 Rx:No Rx Cntrl for 24 Wks, 48 Wks Rx, HVPG 16 (7-29), CTP<10) % with undetectable HCV RNA CTP A CTP B Week 2 Week 4 Week 8 Week 12 Week 24 No increase in SAEs or complications compared to untreated controls.

60 SIM/SOF

61 SIM/SOF 1. SIM: FDA-approved 2. SOF: FDA-approved 3. SIM/SOF: Not currently FDA-approved AASLD/IDSA Guidelines: Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weightbased RBV (1000 mg [<75kg] to 1200 mg [ 75 kg) for 12 weeks is recommended for IFN-ineligible patients with HCV genotype 1infection, regardless of subtype...is recommended for retreatment of HCV genotype 1 infection,regardless of subtype or IFN eligibility. The basis for these recommendations were an average SVR of 72% in 211 Rx-Naïve GT1 patients treated with 24 Wks SOF/RBV. SIM/SOF, 12 Wks, might be a more effective regimen in these patients.

62 % SVR12 SIM/SOF COSMOS Cohort 2: F3/F4, 54% Null Responders RBV No RBV /27 13/14 27/30 16/16 12 Weeks 24 Weeks AASLD Guidelines January 30, 2014; Presented at EASL 2013, 2014 and AASLD 2013.

63 SIM/SOF 1. Published dataset is very small 2. Post-approval experience is extensive 3. No data on SVR in Decompensated Cirrhosis 4. CAUTION: Concerns about SIM PK in CTP B and CTP C patients

64 Summary of Current Pre-Transplant Options GT1-6: GT 1: SOF/RBV, up to 48 weeks Goal is 30 d of undetectable HCV RNA prior to LT SIM/SOF, 12 weeks* * Longer duration of 24 weeks and addition of RBV may be required for more advanced cirrhosis.

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66 Disease Progression Reduces CYP P450 Activity but with Varied Time Course for the Different CYPs Frye RF, et al. Clin Pharmacol Ther 2006;80:

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68 Disease Progression (Fibrosis) Increases Shunt and Reduces Clearance from the Portal Circulation Helmke S, et al. Hepatology 2012;56:678A. AASLD Abstract #1005.

69 Potential Future Choices ** GT1-6: GT 1: SOF/LDV ± RBV SOF/DAC ± RBV SOF/GS-5816 ABT450/r/Ombitasvir/Dasabuvir ± RBV BMS /Daclatasvir/Asunaprevir MK-5172/MK-8742 ± RBV SIM combinations ** None of these regimens are currently FDA-approved.

70 Gane EJ, Agarwal K. Am J Transplant 2014;14:

71 Reported SVRs of IFN-free, Multi-DAA Rx % SVR

72 Resources for DDIs Outstanding University of Liverpool (David Back, Editorial Board, EASL reps); sponsored by Janssen, MSD, Roche, Vertex: FDA: Other Online Resources Epocrates Micromedex, Lexicomp and Others

73 Paradigm Shift 1. From IFN-based Treatment Low efficacy (both pre- and post-lt) High Toxicity (especially in cirrhosis) Limited Applicability 2. To IFN-free Treatments Improved efficacy (both pre- and post-lt) Limited Toxicity (both pre- and post-lt) Treat either pre- or post-lt

74 Activity Code FA376