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HCV INFECTION AND MANAGEMENT IN ADVANCED LIVER DISEASE Kimberly Brown, M.D. Chief, Division of Gastroenterology and Hepatology Henry Ford Hospital.

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Presentation on theme: "HCV INFECTION AND MANAGEMENT IN ADVANCED LIVER DISEASE Kimberly Brown, M.D. Chief, Division of Gastroenterology and Hepatology Henry Ford Hospital."— Presentation transcript:

1 HCV INFECTION AND MANAGEMENT IN ADVANCED LIVER DISEASE Kimberly Brown, M.D. Chief, Division of Gastroenterology and Hepatology Henry Ford Hospital

2 Disclosures - Grants/Research Support: Merck, Vertex, Ikaria, Hyperion, Exelenz, Gilead, BMS, ABBVIE, Janssen - Consultant: Merck, BMS, Gilead, Janssen, ABBVIE - Speakers’ Bureau: Gilead, ABBVIE, Simply Speaking, HCV Viewpoints - Stock Shareholder: none - Boards: CLDF, CLD Journal - Other Financial or Material Support: none

3 Learning Objectives - Review epidemiologic trends of liver-related morbidity and mortality in chronic HCV infection - Discuss HCV-related management approaches for patients with advanced fibrosis and cirrhosis - Discuss HCV-related management approaches for patients who are candidates for liver transplantation

4 Advanced Liver Disease: Basic Principles ●Hepatic fibrosis - Not reliably diagnosed by ultrasound or other imaging modalities ●Liver fibrosis rates - Not predictable or linear ●Progression from compensated cirrhosis to decompensated liver disease - Occurs in 5% of patients per year ●Hepatocellular carcinoma - Develops in 1% to 2% of patients with hepatitis-related cirrhosis each year Sherman KE. Top HIV Med. 2011;19:

5 Chronic HCV Infection: Natural History Liver Decompensation (5%/year) HCC (2%-8%/year) Resolved Exposure (Acute phase) Cirrhosis Chronic 5%-30% Over Years 15%-45% 55%-85% Poynard T, et al. Lancet. 1997;349: Co-morbidities

6 Progression of Fibrosis in Viral Hepatitis on Biopsy (Metavir) No Fibrosis Stage 1 Fibrous expansion of some portal areas Stage 2 Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 3 Stage 4 Cirrhotic Liver Fibrous expansion of portal areas with marked bridging (portal-to-portal and portal-to-central) Cirrhosis Faria SC, et al. Radiographics. 2009;29: Adapted from Everson GT.

7 FibroScan The probe induces an elastic wave through the liver The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface Diagnostic accuracy: Significant fibrosis: 0.79 Advanced fibrosis: 0.91 Cirrhosis: FibroScan (kPa) Liver Fibrosis (METAVIR) F0-F1 F2 F3 F4 Ziol M, et al. Hepatology. 2005;41:48-54.

8 Projected Burden of Advanced Fibrosis Over the Next Decade Davis GL, Gastroenterology. 2010;138:  77.6% F0/1; cirrhosis =5% 2010  41.8% F0/1; cirrhosis =25% 2020  cirrhosis = 37.2%

9 Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans Progressive Increase in Incidence of HCV-Related Cirrhosis and HCC in US El-Serag HB. Gastroenterology 2012;142:1264–1273.

10 Years after diagnosis After 1st complication Adapted from Fattovich G et al. Gastroenterology. 1997;112: Survival probability (%) Compensated Natural History of HCV Cirrhosis Deaths Liver-related (70%) Other cause (30%)

11 By 2007, Deaths From HCV Surpassed Those From HIV Change in Mortality Rates From 1999 to 2007 Rate per 100,000 People Year HIV Hepatitis C Hepatitis B 15,106 12,734 1,815 Ly KN, et al. Ann Intern Med. 2012;156(4):

12 Risk Factors for Progressive Fibrosis and Cirrhosis ●Persistently elevated ALT levels ●Longer duration of infection ●Alcohol excess (>50 g/day) ●Age >40 years at time of infection ●HIV or HBV coinfection ●High BMI ●Male gender ●Presence of steatosis on biopsy Poynard T, et al. Lancet. 1997;349: Kim WR, et al. Gastroenterology. 2004;127:

13 HCV Incremental All-Cause Health Care Costs by Liver Disease Severity (USD 2009) Difference between HCV and non-HCV matched controls. Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index. McAdam-Marx C, et al. J Manag Care Pharm. 2012;17: Incremental All-Cause Costs (per-patient-per-year) 5879 (157) 5330 (491) 27,845 (965) 810 (49) 974 (194) 15,464 (710) 1721 (123) 1081 (275) 5818 (292) 641 (37) 93 (130) 4526 (213) 2659 (41) 3102 (157) 1893 (123) No liver disease (n=26,977) Compensated cirrhosis (n=1521) Decompensated cirrhosis (n=4249) Inpatient Total Health Care Costs Outpatient Physician Services Pharmacy Costs Place of Service

14 Ghany MG, et al. Hepatology. 2009;49(4): HCV Can Now Be Cured in Most Patients ●Unlike HIV and HBV infection, HCV infection is a curable disease ●What does cure mean? - Sustained Viral Response - Undetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infection - Long term morbidity and mortality benefits

15 Treatment Goals HCV Infection Viral Eradication Prevent HCC? Delay Disease Progression Delay Time to Decompensation

16 Time (years) Percent All-Cause Mortality International, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada. Patients with chronic HCV infection started an interferon-based treatment regimen between 1990 and 2003 (n=530). van der Meer AJ, et al. JAMA. 2012;308: SVR Was Associated With Reduced Long-Term Risk of All-Cause Mortality in an International, Multicenter Study

17 Years Cumulative Mortality (%) Genotype 1 (n=12,166) Genotype 2 (n=2904) Genotype 3 (n=1794) SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility ( ). SVR=sustained virological response. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9: SVR rate: 35%SVR rate: 72%SVR rate: 62%

18 Percent Cumulative Incidence of Any Liver-Related Outcome Among Patients With Bridging Fibrosis or Cirrhosis Analysis of liver outcomes (decompensation, HCC, or death) in the HALT-C trial database. All comparisons P< *Detectable HCV RNA at treatment week 20 (combination therapy was discontinued at week 24). HALT-C=Hepatitis C Antiviral Long-Term Treatment against Cirrhosis. Morgan TR, et al. Hepatology. 2010;52: SVR Was Associated With Improved Long-Term Liver-Related Outcomes in the HALT-C Trial Database

19 Yoshida H et al. Ann Intern Med. 1999;131:178. Cumulative incidence Years Untreated Interferon Hepatocellular Carcinoma in HCV

20 AASLD/IDSA Recommendations: HCV-Related Cirrhosis ●Treatment-naive patients with compensated cirrhosis, including those with HCC - Should receive the same treatment as recommended for patients without cirrhosis AASLD and IDSA. Available at: Version January 29, 2014.

21 HCV-Infected Persons in the US: Estimated Rates of Detection, Referral to Care and Cure Infected Diagnosed Referred HCV RNA Treated ‘Cure’ to care test X1000 persons 50% 32-38% 20-23% 7-11% 5-6% CDC & USPSTF recommend 1-time testing of baby boomers (born ) Holmberg S, N Engl J Med 2013; 368: 1859

22 Barriers to Cure for Hepatitis C: Data From a Large Integrated Health System ●Evaluate linkages between HCV screening and treatment ●Calculate the “missed opportunity” at each transition of care ●Analyze patient characteristics which may influence the “missed opportunity” at each transition of care Brown et al, AASLD 2013

23 HCV Ab+ N=566 Death < 365 Days Testing N=39 Left System < 6 mo Testing N=69 RNA Screen? N=458 No RNA Screen N=87 (19%) RNA Screen N=371 (81%) Negative RNA N=63 (17%) Positive RNA N=308 (83%) Brown KA. et al., AASLD 2013 Brown et al, AASLD 2013

24 HCV Ab+ (586 patients) Death < 365 days testing (39 patients) Left system < 6 mo testing (69 patients) RNA Screen Excluded No RNA 87 (19%) RNA Screen 371 (81%) 458 Referral? N=308 No Referral N=125 (41%) Self Referral N=3 (1%) Referred N=180 (58%) Gastro Visit? N=183 No Visit N=66 (36%) Visit N=117 (64%) Treat- ment No Treatment 96 (82%) Treatment 21 (18%) NoSV R 13 (62%) SVR 8 (38%) RNA negative (3) Substance Abuse (14) No follow up (11) Transplant evaluation (15) Co-morbidities (23) External follow up VA (3) Waiting for new treatment (6) Patient declined (12) Previous treatment (9) Only 38% (117/308) of patients with positive HCV-RNA were seen by Gastroenterology Brown KA. et al., AASLD 2013 Brown et al, AASLD 2013

25 HCV Ab+ (586 patients) Death < 365 days testing (39 patients) Left system < 6 mo testing (69 patients) RNA Screen Excluded No RNA 87 (19%) RNA Screen 371 (81%) 458 Negative RNA 63 (17%) Positive RNA 308 (83%) Referral No Referral 125 (41%) Self Referral 3 (1%) Referred 180 (58%) Treatment Decision N=117 No Treatment* N=96 (82%) Treatment N=21 (18%) No SVR N=13 (62%) SVR N=8 (38%) *Reasons for No Treatment: RNA negative (3); substance abuse (14); no follow up (11); transplant evaluation (15); co- morbidities (23); external follow up VA (3); waiting for new treatment (6); patient declined (12); previous treatment (9) Only 6.8% (21/308) of patients with positive HCV-RNA were treated Only 2.6% (8/308) SVR Brown KA. et al., AASLD 2013 Brown et al, AASLD 2013

26 HCV TREATMENT CONSIDERATIONS IN ADVANCED FIBROSIS AND CIRRHOSIS

27 French National Early Access Program: Interim Analysis of the CUPIC Cohort (Genotype 1) ●Prospective cohort, HCV genotype 1, compensated cirrhosis - Relapse or prior partial responders to PR ●SVR12 - Telaprevir: 40% (range: 29%-53%) - Boceprevir: 41% (range: 11%-51%) ●Discontinuations: 47% ●Serious adverse events: 40% - Early treatment discontinuation: 21.3% - Death: 2.0% - Anemia (<9.0 g/dL): 29.4% - Hepatic decompensation: 2.4% Fontaine H, et al. J Hepatol. 2013;58(suppl 1):S27. Abstract 60. Hezode C, et al. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51. Hezode C, et al. J Hepatology. 2013;59: Adjusted Odds Ratio Platelet <100,000/mm (P=0.0105) Serum albumin <35 g/dL6.33 (P=0.0001) Factors Associated With Death and Severe Complications (n=62) Platelets (/mm 3 ) >100,000<100,000 Albumin (g/dL) >35 (n=298/69) <35 (n=28/34) Risk of Death or Severe Complications (%)

28 Sofosbuvir + RBV + PegIFN: SVR12 by Fibrosis Stage (Genotypes 1-6) ●Retrospective analysis of 4 phase 3 clinical trials ●Baseline fibrosis stage by FibroTest/FibroSure - F0-F2 (55%), F3 (17%), F4 (28%) ●General decline in SVR with advancing fibrosis ●SVR12 rates among patients with thrombocytopenia (platelets <125/mm 3 ) were similar to rates in cirrhotic patients across all HCV genotypes Patel K, et al. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.

29 Sofosbuvir + RBV + PegIFN (Multiple Genotypes): SVR12 by Baseline Fibrosis Stage (FibroTest) Patel K, et al. Hepatology. 2013;58(suppl 1):738A-739A. Abstract Patients (%) 100% Sofosbuvir + RBV (FUSION) (16 weeks, treatment-experienced) 80% F1-F2 (n=14/21) F4 (n=9/27) F3 (n=5/10) F0 (n=4/5) Genotype 2 Genotype 3 67% 100% Patients (%) 96% 97% F1-F2 (n=105) F4 (n=86) F3 (n=54) F0 (n=78) 85% 79% Sofosbuvir + PR (NEUTRINO) (12 weeks, treatment-naïve) Genotypes 1, % 40% 63% 89% PR: pegIFN + RBV.

30 COSMOS Subgroup Analysis: HCV Genotype 1, METAVIR F3-F4 Simeprevir + Sofosbuvir qd (n=14) Simeprevir + Sofosbuvir qd + RBV (n=27) Phase 2a Open-label Genotype 1 Prior PR null responder or treatment-naïve METAVIR F3-F4 No BMI limit <70 years of age Week Simeprevir + Sofosbuvir qd (n=16) Simeprevir + Sofosbuvir qd + RBV (n=30) Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor). Weight-based ribavirin dosing ( mg). Baseline demographics and disease characteristics: Male: 67%; age: 58 years; black: 9%. Genotype 1a: 78%. Genotype 1a with Q80K: 40%. IL28B non-CC: 79%. Cirrhosis: 47%. HCV RNA (log 10 IU/mL): 6.6. Prior PR null responders: 54%. Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.

31 COSMOS Subgroup Analysis: SVR12 in HCV Genotype 1, METAVIR F3-F4 SVR12 (%) SVR12 93% 24 Weeks (n=16/30) 12 Weeks (n=14/27) Simeprevir + sofosbuvir No RBV With RBV 93% 100% 93% SVR12 (%) SVR12 by HCV Subtype 100% Genotype (n=18/40/26) 1b 95% 96% Simeprevir + sofosbuvir + RBV 94% 98% 95% 1a1a + Q80K IL28B Genotype (n=17/48/19) CC CTTT Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O % Discontinuation

32 LDV/SOF Phase 2 and 3 Program ●513 patients with HCV GT 1, compensated cirrhosis ●Pooled data from Phase 2 and 3 LDV/SOF ± RBV studies – LONESTAR, ELECTRON, ELECTRON-2, (Japan), ION-1, ION- 2, SIRIUS ●Primary efficacy endpoint: SVR12 Wk 0Wk 12Wk 36Wk 24 SVR12 LDV/SOF SVR12 LDV/SOF + RBV SVR12 LDV/SOF + RBV SVR12 LDV/SOF n=118 n=204 n=133 n=58 Bourliere et al, AASLD 2014 An Integrated Safety and Efficacy Analysis of >500 Patients with compensated Cirrhosis Treated with Ledipasvir/Sofosbuvir with or without Ribavirin

33 SVR12 Overall and by Treatment Duration LDV/SOF Phase 2 and 3 Program: Cirrhotic Subjects 493/513 SVR12 (%) Error bars represent 95% confidence intervals. 305/ /191 Overall 12 Weeks 24 Weeks ●Out of 513 patients, 20 failed to achieve SVR Relapsed - 1 LTFU, 1 Death (presumed infection) Bourliere et al, AASLD 2014

34 Total Treatment Naïve Treatment Experienced Overall SVR12 Duration 12 wk 24 wk Regimen LDV/SOF LDV/SOF + RBV Duration/± RBV LDV/SOF 12 wk LDV/SOF + RBV 12 wk LDV/SOF 24 wk LDV/SOF + RBV 24 wk SVR12 by Regimen and Duration LDV/SOF Phase 2 and 3 Program: Cirrhotic Subjects SVR12, % 96%98%95% 97%94% 98%99%98% 95%96%95% 97%99%96% 92%96%90% 96%98%96% 98%97%98% 100% Bourliere et al, AASLD 2014

35 Relapse Among Cirrhotic Subjects LDV/SOF Phase 2 and 3 Program: Cirrhotic Subjects (3.9%) 493 (96.1%) 182 SVR12 failed LTFU;Deathrelapse Plts < 75Plts ≥ FDC 12 = LDV/SOF for 12 weeks Other = LDV/SOF + RBV for 12 weeks or LDV/SOF for 24 weeks LTFU = Lost to Follow Up (n=1) % (1.1%-9.7%) 2% (1.1%-4.5%) 27% (7.8%-55.1%) 5% (0.1%-22.8%) FDC 12 Other Bourliere et al, AASLD 2014 ‡

36 SIRIUS Study ●Double-blinded ●Treatment-experienced patients with compensated cirrhosis who did not achieve SVR following sequential PEG + RBV and PI + PEG + RBV regimens Bourliere et al, AASLD wk36 wk24 wk0 wk LDV/SOF + Placebo RBV SVR12 LDV/SOF + RBV Placebo SVR12

37 Demographics SIRIUS (GS-US ) Bourliere et al, AASLD 2014

38 Disposition SIRIUS (GS-US ) *1 patient was randomized to receive placebo 12 weeks then LDV/SOF+RBV for 12 weeks but received LDV/SOF for 24 weeks. Efficacy is assessed as ITT; for demographics and safety, they are analyzed according to treatment received. Randomized N=155 LDV/SOF + RBV 12 Wk n=77 Completed study treatment n=77 Completed follow-up wk 12 n=77 D/C treatment due to AE (n=1) LDV/SOF 24 Wk n=77* Completed study treatment n=77 Completed follow-up wk 12 n=77 Placebo 12 wk n=78 Bourliere et al, AASLD 2014

39 SVR12 SIRIUS (GS-US ) Error bars represent 95% confidence intervals. 75/77 74/77 LDV/SOF 24 Weeks LDV/SOF+RBV 12 Weeks Bourliere et al, AASLD 2014

40 Adverse Events ≥15% SIRIUS (GS-US ) ●Most AEs mild or moderate in severity Bourliere et al, AASLD 2014

41 HCV INFECTION BEFORE LIVER TRANSPLANTATION: TREATMENT OF DECOMPENSATED PATIENTS STRATEGIES TO PREVENT RECURRENCE OF HCV POST LIVER TRANSPLANT

42 AASLD and IDSA Recommendations: HCV-Related Cirrhosis ●Patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C) - Should be referred to a medical practitioner with expertise in that condition (ideally in a liver transplant center) AASLD and IDSA. Available at: Version January 29, Preferred Regimen Sofosbuvir + RBV for up to 48 weeks (consider creatinine clearance and hemoglobin) Any Genotype Any IFN-based therapy Monotherapy with pegIFN, RBV, or a DAA Telaprevir-, boceprevir-, or simeprevir-based regimens Any Genotype Regimens Not Recommended

43 Antiviral Therapy Before Liver Transplantation ●Challenges - Poor tolerance - Increased adverse events Risk of hepatic decompensation - Suboptimal SVR rates ●HCV treatment in this patient population requires significant oversight and input in an experienced practice ●Expectations??? Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354. Fried MW, et al. N Engl J Med. 2002;347: Manns MP, et al. Lancet. 2001;358: Hadziyannis SJ, et al. Ann Intern Med. 2004;140: Bruno S, et al. Hepatology. 2010;51:

44 Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68. Sofosbuvir qd + RBV (n=25) Observation (n=25) Open-Label Genotypes 1-4 Treatment-naïve and experienced Compensated cirrhosis (Child-Pugh 5-6, A) Decompensated cirrhosis (Child-Pugh 7-9, B) Esophageal or gastric varices Hepatic venous gradient (HVPG): >6 mm Hg) Week Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV ( mg). HVPG at day 0 and 48 in the sofosbuvir-treated patients. Baseline demographics and disease characteristics: Male: 72%-80%; age: years; white: 84%-96%, treatment-naive: 68%-92%. Genotype 1a, 1b, 2, 3, 4: 36%-40%, 24%-36%, 4%-8%, 8%-32%, 4%-8%. IL28B non-CC: 72%-88%. HVPG >12 mm Hg: 76%-80%. CTP score 5-6, 7-9: 36%-44%, 56%-60%. MELD <10, 10-15: 32%, 56%-60%. Albumin: g/dL; platelets: x10 3. ALT, AST: , U/mL. Ascites: 24%-36%. Encephalopathy 8%-20%. Sofosbuvir qd + RBV Current Analysis

45 Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation ●High rates of virologic suppression irrespective of severity of liver disease ●Decreased necroinflammation with ALT normalization ●Improvements - Platelet count and albumin - Ascites and hepatic encephalopathy ●Low rates of treatment discontinuation due to adverse events (4%) Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68. Sofosbuvir + RBV (n=25) Observation (n=25) HCV RNA

46 SOLAR-1 (Decompensated Cirrhosis) GT 1 and 4, CPT Class B and C ●108 patients randomized 1:1 to 12 or 24 Weeks of Treatment ●Broad inclusion criteria - Total bilirubin ≤10 mg/dL, Hemoglobin ≥ 10 g/dL - CL cr ≥ 40 mL/min, platelets > 30,000 x 10 3 /µL, - CPT ≤ 12 ●Stratified by CPT score B or C LDV/SOF + RBV Wk 0 Wk 12Wk 24 SVR12 Wk 36 Flamm, et al, AASLD 2014

47 Baseline Disease Characteristics GT 1 and 4, CPT Class B and C Flamm, et al, AASLD 2014

48 SVR12 GT 1 and 4, CPT Class B and C 6 subjects (2 CPT B/24 Wk, 1 CPT C/12 Wk and 3 CPT C/24 Wk) excluded (transplant on study); 3 subjects CPT C/24 Wk have not reached SVR12.. CPT BCPT C SVR12 (%) 26/3019/2218/20 Overall 24/2745/5242/47 LDV/SOF + RBV 12 WeeksLDV/SOF + RBV 24 Weeks Flamm, et al, AASLD relapses 1 death 1 relapse 2 deaths 1 relapse 2 death 1 LTFU 1 relapse 1 death

49 Change in MELD Score Baseline Through Follow-up Week 4 GT 1 and 4, CPT Class B and C 49 n=5 n=2 n=3 (-8) (+10) CPT B CPT C 12 wk (n=30)*24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)* *Missing FU-4: n=2 CPT B 12 wks; n=4 CPT B 24 wks; n=2 CPT C 12 wk; n=7 CPT C 24 wk. Flamm, et al, AASLD 2014

50 Safety Summary GT 1 and 4, CPT Class B and C  Related SAEs: Anemia (2), Hepatic Encephalopathy, Peritoneal Hemorrhage Flamm, et al, AASLD 2014

51 Risk of HCC Remains After SVR in HCV Patients With Advanced Hepatic Fibrosis ●Meta-analysis (n=1000) - 10 cohorts, individual patient data - SVR with IFN-based therapy - Bridging fibrosis or cirrhosis ●51 events of HCC over 5.1 years of follow-up ●Patients with HCV-induced cirrhosis who achieve SVR remain at risk for HCC ●Risk increased with age, severity of liver disease, and presence of diabetes mellitus van der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143. Rate (%) Cumulative HCC by Age Group Years After SVR P= % 2.6% 9.7% Age Group <45 years 45 to 60 years >60 years

52 Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL) ●First, randomized, controlled trial of pre-transplant PR (LADR) to prevent recurrent HCV post-transplant ●Randomized to either pegIFN + RBV (LADR) or control (untreated) ●Primary endpoint - Post-transplant HCV RNA undetectable at week 12 Everson GT, et al. Hepatology. 2013;57: PR: pegIFN + RBV; LADR: low accelerating dose regimen. Treatment (n=63) Control (n=16) Male (%)7381 Age (years)56 Genotype (%) 1/4 or 6 2/3 47/4 24/25 88/12 0/0 HCV RNA (log 10 IU/mL)5.7 HCC upgrade (%)5494 MELD12.0 CPT score Hemoglobin (g/dL) ANC (/µL) Platelets (x10 3 /µL)9293 Previous IFN treatment (%)9293 Baseline Characteristics

53 A2ALL Study: Virologic Response With PR Treated Patients (%) Overall (n=44) 59% 25% 22% 2, 3 (n=21) Virologic Response by Genotype 52% HCV RNA Undetectable At liver transplantation Week 12 post-transplant Everson GT, et al. Hepatology. 2013;57: % 67% 1, 4, 6 (n=23) HCV Genotype Per protocol analysis. PR: pegIFN + RBV. Treated Patients (%) <8 (n=8) 25% 0% 18% >16 (n=14) Virologic Response by Treatment Duration 68% HCV RNA Undetectable At liver transplantation Week 12 post-transplant 50% 64% 8 to 16 (n=22) PegIFN + RBV Duration (Weeks)

54 HCV Treatment Before Liver Transplantation in Patients With Decompensated Cirrhosis G1 (%) Child-Pugh (%)Treatment EOTR G1/non-G1 (%) SVR G1/non-G1 (%) HCV RNA Negative Post Transplant (%) Crippin 2002 (pilot study; n=15) IFN + RBV33 (overall) NA0 Thomas 2003 (single cohort; n=20) IFN60 (overall) NA20 Everson 2005 (single cohort; n=124) 707.4IFN + RBV (LADR) 30/8213/5026 Forns 2003 (single cohort; n=30) 70A (50%); B (43%); C (7%) IFN + RBV30 (overall) NA20 Carrion 2009 (case controlled; n=51) 80A (45%); B (43%); C (4%) PR20/100NA20 Everson 2013 (randomized, controlled; n=79) 567.0PR (LADR) 41/53NA25 Crippin JS, et al. Liver Transpl. 2002;8: ; Thomas RM, et al. Liver Transpl. 2003;9: ; Everson GT, et al. Hepatology. 2005;42: ; Forns X, et al. J Hepatol. 2003;39: ; Carrion JA, et al. J Hepatol. 2009;50: ; Everson GT, et al. Hepatology. 2013;57: G: genotype; EOTR: end-of-treatment response (HCV RVA undetectable); PR: peg IFN + RBV; LADR: low accelerating dose regimen.

55 Pre-Liver Transplant Sofosbuvir + RBV: Prevention of Recurrent HCV ●Open-label, phase 2 study conducted at 16 sites (n=61) - Deceased donor liver transplantation candidates with HCV - HCC meeting MILAN criteria - MELD exception for HCC - CPT <7 - Exclusion: decompensated cirrhosis, prior solid organ transplantation, HBV or HIV coinfection, renal impairment ●Up to 48 weeks of sofosbuvir 400 mg + RBV ( mg) pre-transplant Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213. Baseline Characteristics Treatment (n=61) Male (%)80 Age (years)59 BMI <30 kg/m 2 (%)43 Genotype (%) 1a/1b 2/3 4 39/34 13/12 4 HCV RNA >6 log 10 IU/mL (%)41 IL28 B non-CC (%)78 MELD8 CPT score 5-7 (%)95% Prior HCV treatment (%)75

56 Pre-Liver Transplant Sofosbuvir + RBV: Virologic Response in HCV Genotypes 1-4 ●HCV recurrence prevented in 64% of patients HCV RNA 12 Weeks Treatment (n=33) At Transplant

57 Pre-Liver Transplant Sofosbuvir + RBV: Target Not Detected and Safety in Genotypes 1-4 ●Median days TND - No HCV recurrence (n=28): 95 - HCV recurrence (n=10): 5.5 (P<0.001) ●Sofosbuvir + RBV was generally well tolerated - Discontinuations due to adverse events: 3% (none related to sofosbuvir) Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213. TND: target not detected. Individual Patient Data Days Continuously TND Before Liver Transplant and Preventing HCV Recurrence HCV RNA Continuously TND (Days) >30 days TND HCV recurrence (n=10) No HCV recurrence (n=28)

58 HCV Treatment Considerations for Transplant Recipients ●Achieving sustained virologic response - Possible in some well-selected patients with HCV and decompensated cirrhosis ●Post-transplantation recurrence of HCV may be prevented if SVR is achieved pretransplant ●Potential benefits of HCV therapy need to be balanced against the risk of sepsis, hepatic failure, and death ●Child’s C cirrhotics - Risks usually outweigh benefits ●Transplantation evaluation - Complete before initiating HCV treatment begins (in case patient should decompensate) Ghany MG, et al. Hepatology. 2009;49:

59 HCV THERAPY AFTER LIVER TRANSPLANTATION

60 Early Antiviral Therapy to Prevent HCV Recurrence After Liver Transplantation G1 (%) Treatment Initiation Post-Transplant (weeks)Treatment SVR (%) Treatment Discontinuation (%) Rejection (%) Mazzafero 2001 (single cohort; n=36) 833IFN + RBV33 (G1/4: 20 G2/3: 100) 00 Sugawara 2004 (single cohort; n=21) 834IFN + RBV39 (G1/4: 33 G2/3: 100) 2526 Chalasani 2005 (phase 3b study; n=54) 743PR Untreated 8 (G1/4: 5 G2/3: 14) Shergill 2005 (randomized, controlled; n=54) NR2 to 6pegIFN PR NR 22.7 NR Bzowej 2011 (randomized, controlled; n=115) 7910 to 26PR Untreated NR 5.6 NR Mazzafero V, et al. Transplant Proc. 2001;33: ; Sugawara Y, et al. Transplantation. 2004;78: ; Chalasani N, et al. Hepatology. 2005;41: ; Shergill AK, et al. Am J Transplant. 2005;5: ; Bzowej N, et al. Liver Transplant. 2011;17: PR: pegIFN + RBV; G: genotype; NR: not reported.

61 Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation ●Advantages of delaying treatment until established HCV recurrence - Reduced risk of acute cellular rejection - Better graft function - Lower doses of immunosuppression ●Numerous studies with PR - SVR rates: 8% to 45% - Challenges High discontinuation rates Poor tolerability (fatigue, asthenia, pyrexia, cytopenias), especially in severe hepatitis post-transplant Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354. Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26: Roche B, et al. Liver Int. 2011;32(suppl 1): PR: pegIFN + RBV.

62 Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation G1 (%) Advanced Fibrosis (%) Treatment Initiation Post-Transplant (months)Treatment SVR (%) Treatment Discontinuation (%) Dumortier 2004 (single cohort; n=20) 80NR28PR4520 Oton 2006 (2-center cohort; n=55) PR44 (G1: 40) 24 Angelico 2007 (randomized, controlled; n=42) 83NR44PR pegIFN Carrion 2007 (randomized, controlled; n=81) PR Untreated Picciotto 2007 (single center; n=61) PR Hanouneh 2008 (retrospective, medical records; n=53) PR Dumortier J, et al. J Hepatol. 2004;40: ; Oton E, et al. Am J Transplant. 2006;6: ; Angelico M, et al. J Hepatol. 2007;46: ; Carrion JA, et al. Gastroenterology. 2007;132: ; Picciotto FP, et al. J Hepatol. 2007;46: ; Hanouneh IA, et al. Liver Transplant. 2008;14: PR: pegIFN + RBV; G: genotype; NR: not reported.

63 Direct-Acting Antiviral Agents to Treat HCV Recurrence After Liver Transplantation ●Telaprevir or boceprevir + PR - Promising preliminary SVR rates in genotype 1 - Significant dose reductions required for cyclosporine and tacrolimus - Increased adverse event profile Anemia occurs in most patients RBV dose reduction and hematologic growth support factors/blood transfusions - No data on viral resistance and impact on post-transplant period ●IFN-free regimens - Simplified dosing - Promising preliminary SVR rates in multiple genotypes - No drug interactions with common immunosuppressant agents (?SMV) - Lower incidence of adverse events, including anemia Lucey MR, et al. Liver Transplant. 2013;19:3-26; Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354; Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26: ; Roche B, et al. Liver Int. 2011;32(suppl 1): PR: pegIFN + RBV.

64 REFRESH Study: Telaprevir + PR in HCV Genotype 1 Liver Transplant Recipients ●Interim results with telaprevir + PR show promising efficacy ●Anemia - Mild or moderate: 41% - Severe: 6.5% - RBV dose reduction: 43% - Erythropoietin/blood transfusions: 30%/6.5% ●No reports of - Rejections, autoimmune hepatitis, or deaths - Severe or potentially life- threatening cases of rash or pruritus Brown K, et al. Hepatology. 2013;58(suppl 1):209A. Abstract 3. Patients (n=46) HCV RNA <25 IU/mL (%) Week 4 Week Serious adverse events (%)15 Adverse events (%) Fatigue Anemia Headache Nausea Anorectal Diarrhea Rash Pruritus Grade 3/4 creatinine increase (%)4 Renal failure11 Interim Results PR: pegIFN + RBV.

65 CRUSH-C: Virologic Response in HCV Genotype 1 ●eRVR is highly predictive of SVR12 ●Treatment duration <36 weeks negatively affects SVR12 rates ●Adverse events led to treatment - Discontinuations: 20% - Interruption: 7% SVR12 Patients (%) Yes (n=56) Overall (n=90) No (n=32) <36 (n=5/10) >36 (n=46/11) Achieved eRVR Treatment Duration (weeks) 16% 59% 50% 93% † *P<0.001 versus not achieving an eRVR. † P=0.04 versus <36 weeks (eRVR). ‡ P=0.003 versus <36 weeks (no eRVR). Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract % eRVR No eRVR 5% 33% ‡

66 CRUSH-C (All Patients): Safety in HCV Genotype 1 High rates of hospitalizations (27%) and >0.5 mg/dL increase in creatinine (41%) Anemia is a significant problem – PegIFN + RBV dose reduction: 38%/86% – Erythropoietin/blood transfusions: 84%/56% Death (7%) – Mainly due to liver-related causes, usually in patients with advanced disease Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461.

67 Sofosbuvir Compassionate Use Program: Recurrent HCV Following Liver Transplantation ●Patients with severe recurrent HCV infection following liver transplantation - Likely to have <1 year life expectancy ●Sofosbuvir 400 mg qd + RBV + pegIFN for up to 48 weeks Patients (n=104) Male (%)73 Age (years)55 Genotype (%) 1a/1b 2/3/4 28/49 1/7/8/ ALT (IU/L)71 Bilirubin (mg/dL)3.1 Albumin (g/dL)3.1 INR1.3 MELD score15 Time from liver transplantation (months) 17 Baseline Characteristics PR: pegIFN + RBV. Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.

68 Sofosbuvir Compassionate Use Program: Initial Treatment Evaluations ●Overall, liver function tests significantly improved over time ●Most patients improved clinically or remained stable ●All serious adverse events (48%) - Leading to treatment discontinuation (13%) ●Deaths (13%) were mostly a result of disease progression in this very sick population - On treatment (n=8) - Post treatment follow-up (n=5) Patients (%) Treatment Outcomes 62% 21% SVR12 (n=85) Improved*Stable *Improved: improvement in decompensation events (ie, significant decrease in hepatitic encephalopathy episodes, improvement or disappearance of ascites, and improvement in liver-related laboratory values. Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62. Worse Clinical Outcomes (n=104) 21%

69 Sofosbuvir + RBV: Treatment of Recurrent HCV After Liver Transplantation ●Open-label study - Genotype 1(83%), 3 (15%), 4 (3%) - CTP <7 and MELD <17 - Time liver transplantation: 4.3 years - METAVIR F3/F4: 23%/40% ●Sofosbuvir 400 mg qd + RBV (starting at 400 mg) for up to 24 weeks ●Safety - No deaths, graft losses, or rejection - Discontinuations due adverse events: 5% Patients (n=40) HCV RNA <25 IU/mL (%) Week 4 SVR4 SVR12 SVR Concomitant immunosuppression (%) Tacrolimus Mycophenolate mofetil Prednisone Cyclosporin Azathioprine Adverse events (%) Fatigue Headache Arthralgia Grade 3/4 laboratory abnormalities (%)25/28 Key Results Samuel D, et al. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.

70 SOLAR: GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C ●223 patients randomized 1:1 to 12 or 24 weeks of treatment ●GT 1 or 4 treatment-naïve or -experienced post-transplant patients ●≥ 3 months from liver transplant ●RBV dosing - F0–F3/CPT A cirrhosis: weight-based - CPT B and C cirrhosis: dose escalation, 600–1200 mg/d LDV/SOF + RBV Wk 0Wk 12Wk 24 SVR12 Wk 36 Reddy et al, AASLD 2014

71 Baseline Disease Characteristics – 12 and 24 Weeks GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C Reddy et al, AASLD 2014

72 F0–F3 SVR12 (%) 53/5522/2615/18 CPT B 55/56 25/2624/25 2/3 CPT A SVR12 GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks 3/5 CPT C Reddy et al, AASLD 2014 *Subject completed 8 days of treatment and withdrew consent 8 CPT B 24 Week and 1 CPT C 24 Week subjects have not reached the Week 12 post treatment visit..

73 Deaths GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C Observation Period: Day 1 through Post-treatment Week 12 † per family request Reddy et al, AASLD 2014

74 CORAL-I Study: ABT-450/r/Ombitasvir + Dasabuvir + RBV for HCV Genotype 1 After Liver Transplantation ●Ongoing phase 2 study of 24 weeks of ABT-450/r/ombitasvir + dasabuvir + RBV - HCV genotype 1 (n=34) - Liver transplantation due to HCV infection - Median time from txp 39.5 mo - METAVIR

75 Summary ●HCV eradication in advanced liver disease - Reduces decompensation - Does not prevent HCC - Prevents HCV recurrence post transplant ●IFN-based therapy is suboptimal in decompensated cirrhosis - Lower SVR rate - Higher toxicity ●Data with new DAAs evolving - Promise for IFN-free therapy pre- and post-transplant in the future


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