Managing cirrhotic HCV patients. Whom to treat, how to treat.2014
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Managing cirrhotic HCV patients. Whom to treat, how to treat.2014
- 1. Marc Bourlière, MD Graham R. Foster, FRCP, PhD Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat This program is supported by an educational grant from
- 2. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
- 3. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Disclosures Marc Bourlière, MD, has disclosed that he has received consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, GlaxoSmithKline, and Roche. Graham R. Foster, FRCP, PhD, has disclosed that he has received funds for research support from Idenix and Spring Bank; consulting fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Idenix, Janssen, Merck, Novartis, and Roche; and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, and Roche The following planners and managers, Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; Jan Schultz, RN, MSN, CCMEP; Patricia Staples, MSN, NP-C, CCRN; and Eric D. Peterson, EdM, FACEHP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.
- 4. Which Cirrhotic Patients Should be Treated?
- 5. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Cirrhosis: A Continuous Spectrum of Disease ESLD Child-Pugh B Portal hypertension – high risk Cirrhosis – treatment candidate Liver disease is not optimally represented by Child-Pugh stage (A, B, or C) or MELD score
- 6. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Severity of Disease Increases Need for HCV Therapy but Also Impairs Response May not need immediate treatment BUT • Easier to treat • High likelihood of response Advanced disease/ cirrhosis Mild disease Greater need for treatment BUT • Response to current IFN- based therapy may be impaired
- 7. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Benefits and Challenges of Currently Approved HCV Therapies Currently approved HCV regimens are largely interferon-based – Genotype 1 – PegIFN/RBV + boceprevir – PegIFN/RBV + sofosbuvir – Genotype 2 or 3 – PegIFN/RBV or sofosbuvir + RBV – Genotype 4 – PegIFN/RBV ± sofosbuvir Combination of DAA agent with pegIFN/RBV has dramatically increased rates of SVR However, cirrhotic patients are at increased risk for hematologic side effects (eg, thrombocytopenia and anemia), other adverse effects of treatment, and worsening liver function – PegIFN/RBV + telaprevir – PegIFN/RBV + simeprevir
- 8. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Efficacy of Triple Therapy in Tx-Exp Patients: Clinical Trials vs Real Life* 1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Fontaine H, et al. EASL 2013. Abstract 60. 4. Fontaine H, et al. AFEF 2013. Abstract 26. 5. Vierling JM, et al. DDW 2013. Abstract 869c. Relapsers R EA LIZE[1] EAP[3] R EA LIZE[1] C U PIC[4] C U PIC[4] R ESPO N D 2[2] Null Responders R EA LIZE[1] EAP[3] R EA LIZE[1] C U PIC[4] C U PIC[4] PR O VID E[5] SVR(%) Telaprevir F0-4 F4 F3/4 F4 F0-4 F4 F3/4 F4 *Cross-comparison of studies cannot be carried out 100 80 60 40 20 0 Boceprevir 83 69 84 54 7453 29 41 28 29 19 0
- 9. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat CUPIC: High-Risk Patients Less Likely to Achieve SVR CUPIC enrolled treatment-experienced patients with compensated cirrhosis and notable risk factors – Patients achieved high SVR rates with TVR or BOC plus pegIFN/RBV Patients with cirrhosis who present with significant risk factors require careful monitoring when treated with pegIFN/RBV Factors Platelet Count ≤ 100,000/mm3 Platelet Count > 100,000/mm3 Albumin < 35 g/L N 37 31 Complications, n (%) 19 (51.4) 5 (16.1) SVR12, n (%) 10 (27.0) 9 (29.0) Albumin ≥ 35 g/L N 74 305 Complications, n (%) 9 (12.2) 19 (6.2) SVR12, n (%) 27 (36.5) 168 (54.9) Fontaine H, et al. AFEF 2013. Abstract 26.
- 10. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat HCV Decompensated Cirrhosis: Treatment With PegIFN/RBV Most in need of treatment (5-yr survival rate: 50%) SVR rates ranged: – 7% to 16% in genotypes 1-4[1,2] – 44% to 57% in genotypes 2/3 [1,2] Treatment limitation – Higher risk of infection and deaths related to infection[1] – More frequent adverse effects in Child-Pugh C (MELD > 18)[3] Treatment benefit – Lower rate of decompensation during follow-up[1,4] – Reduced mortality in responders[1,4] 1. Iacobellis A, et al. J Hepatol. 2007;46:206-212. 2. Iacobellis A, et al. Aliment Pharmacol Ther. 2009;27:1081-1085. 3. Forns X, et al. J Hepatol. 2003;39:389-396. 4. Fattovich G, et al. Gastroenterology. 1997;112:463-472.
- 11. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat 100 NEUTRINO: Virologic Response by Cirrhosis Status With Sofosbuvir + P/R Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Open-label, single-arm, phase III study Sofosbuvir 400 mg QD + PegIFN/RBV for 12 wks Treatment-naive patients with GT 1/4/5/6 HCV – 17% cirrhosis; platelets ≥ 90,000/mm3 – 89% GT 1, 9% GT 4, < 1% GT 5, 2% GT 6 SVR12(%) 92 80 252/ 273 43/54 80 60 40 20 0 n/N = GT 1/4/5/6 CirrhoticNoncirrhotic
- 12. clinicaloptions.com/hepatitis HCV Phase III Studies and Approved Agents QUEST-2: SVR12 by Subtype and Fibrosis Level With Simeprevir + PegIFN/RBV RGT Randomized, double-blind, placebo-controlled phase III trial in GT 1 treatment- naive patients Treatment regimens: – Placebo + pegIFN/RBV for 12 wks, followed by pegIFN/RBV for 36 wks – Simeprevir + pegIFN/RBV for 12 wks, followed by pegIFN/RBV for 12-36 wks (RGT) Manns M, et al. EASL 2013. Abstract 1413. No Cirrhosis Cirrhosis SMV + pegIFN/RBV PegIFN/RBV 189/ 231 61/ 119 11/ 17 6/ 15 n/N = 100 80 60 40 20 0 SVR12(%) 82 65 51 40
- 13. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat FISSION: SVR12 by GT and Cirrhosis Status With SOF + RBV vs PegIFN/RBV Randomized, controlled, open-label phase III noninferiority trial Sofosbuvir + RBV for 12 wks vs pegIFN + RBV for 24 wks Treatment-naive patients with GT 2/3 HCV – 20% to 21% cirrhosis; platelets > 75,000/mm3 ;28% GT 2, 72% GT 3 Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Gane E, et al. AASLD 2013. Abstract 5. GT 2 GT 3 SVR12(%) No Cirrhosis No CirrhosisCirrhosis Cirrhosis 58/59 44/54 10/11 8/13 •89/145 99/139 •13/38 11/37n/N = 100 80 60 40 20 0 98 82 91 62 61 71 34 30 Sofosbuvir + RBV PegIFN + RBV
- 14. clinicaloptions.com/hepatitis AASLD 2013: HCV Investigational Agents COSMOS: SVR12 in F3/4 GT 1 Pts Receiving Simeprevir + Sofosbuvir ± RBV Lawitz E, et al. EASL 2014. Abstract 165. Open-label, randomized phase IIa study of simeprevir + sofosbuvir with or without RBV for 12 or 24 wks in cirrhotic and noncirrhotic GT 1 treatment naive or previous null responders Primary endpoint: SVR12 SMV/SOF ± RBV SMV/SOF + RBV SMV/SOF + RBV SMV/SOF SMV/SOF 24 Wks 12 Wks Overall 16/16 12/12 6/6 9/9 15/16 10/11 7/7 6/7 44/45 37/39 F3 fibrosis F4 fibrosis SVR12(%) 100 80 60 40 20 0 100 100 100 100 100 94 91 98 86 95 n/N =
- 15. clinicaloptions.com/hepatitis AASLD 2013: HCV Investigational Agents Promising IFN-Free Regimens in Genotype 1 Cirrhotic Patients Regimen SVR12, % Tx Naive Tx Exp PI Failure Sofosbuvir + ledipasvir[1,2] --- 70 (N = 10) 91 (N = 11) Sofosbuvir + ledipasvir + RBV[1,2] --- 100 (N = 25) 100 (N = 11) Sofosbuvir + ledipasvir + GS-9669[1] --- 100 (N = 26) --- Daclatasvir + asunaprevir[3] * 90 (N = 203)† 82 (N = 205)† --- Daclatasvir + asunaprevir + BMS-791325 75 mg[4] 94 (N = 16) --- --- Daclatasvir + asunaprevir + BMS-791325 150 mg[4] 89 (N = 18) --- --- ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5] 94 (N = 86) 87-97 (N = 122) --- ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5] * 95 (N = 74) 95-100 (N = 98) --- 1. Gane EJ, et al. AASLD 2013. Abstract 73. 2. Lawitz. E et al. AASLD 2013, Abstract 215. 3. Manns M, et al. EASL 2014. Abstract 166. 4. Everson GT, et al. Gastroenterol. 2014;146:420-429. 5. Poordad F, et al. N Engl J Med. 2014;[Epub ahead of print]. *Treatment duration: 24 weeks; all others 12 weeks. † Genotype 1b HCV-infected patients only
- 16. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Take Home Points Cirrhotic patients are the most in need for HCV treatment Child-Pugh A patients should be strongly advised to undergo therapy More advanced cirrhosis should be treated with caution on a case-by-case basis Newest DAA + pegIFN/RBV combinations increase SVR in cirrhotic patients IFN-free DAA regimens demonstrate significant potency in cirrhotic patients
- 17. Ensuring Informed Decision-Making When Treating or Deferring in Cirrhotic Patients
- 18. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Ensuring Informed Decision Making for Cirrhotic Patients Patients should be fully informed of the potential risks of treatment or deferral Strategy Potential Benefits Potential Risks Immediate treatment SVR and prevention of disease progression Serious adverse events (death, infection, severe hepatic decompensation) Deferring treatment Achieving SVR with a future regimen with fewer adverse events Liver-related mortality Need for liver transplantation Liver failure Development of HCC
- 19. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Survival Outcomes in Pts With CHC and Advanced Fibrosis With/Without SVR Van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 30 20 10 0 0 All-Cause Mortality(%) 1 2 3 4 5 6 7 8 9 10 Yrs All-Cause Mortality P < .001 Without SVR With SVR Pts at Risk, n Without SVR With SVR 405 192 393 181 382 168 363 162 344 155 317 144 295 125 250 88 207 56 164 40 135 28 30 20 10 0 0 Liver-Related MortalityorLiver Transplantation(%) 1 2 3 4 5 6 7 8 9 10 Yrs Liver-Related Mortality or Liver Transplantation P < .001 Without SVR With SVR Pts at Risk, n Without SVR With SVR 405 192 392 181 380 168 358 162 334 155 305 144 277 125 229 88 187 56 146 40 119 28 30 20 10 0 0 Hepatocellular Carcinoma(%) 1 2 3 4 5 6 7 8 9 10 Yrs Hepatocellular Carcinoma P < .001 Without SVR With SVR Pts at Risk, n Without SVR With SVR 405 192 390 181 375 167 349 161 326 152 294 142 269 124 229 86 191 54 151 39 122 27 30 20 10 0 0 LiverFailure(%) 1 2 3 4 5 6 7 8 9 10 Yrs Liver Failure P < .001 Without SVR With SVR Pts at Risk, n Without SVR With SVR 405 192 384 180 361 166 337 160 314 152 288 141 259 123 216 88 184 56 143 40 113 28
- 20. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat CUPIC: Risk–Benefit of Achieving SVR12 vs Developing Serious Complications Platelet Count ≤ 100,000/mm3 Platelet Count > 100,000/mm3 Albumin < 35 g/L Serious AEs >> SVR SVR > Serious AEs Albumin ≥ 35 g/L SVR > Serious AEs SVR >> Serious AEs Fontaine H, et al. AFEF 2013. Abstract 26.
- 21. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Real-life Experience in Cirrhotic Patients 33 cirrhotic patients received TVR and 15 received BOC Almost all patients (22/23; 96%) with Child-Pugh score > 5 and/or baseline platelets < 110,000/µL (Group A/B) had either treatment failure or SAE Outcome, % Group A Platelets < 110,000/µL and Child-Pugh > 5 (n = 7) Group B Platelets < 110,000/µL or Child-Pugh > 5 (n = 16) Group C Platelets ≥ 110,000/µL and Child-Pugh = 5 (n = 20) Treatment failure 100 69 30 SAE 57 63 25 Treatment failure or SAE 100 94 50 Massoumy B, et al. EASL 2013. Abstract 857.
- 22. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Factors Associated With Hepatic Decompensation During P/R Therapy In retrospective cohort study, 68 pts with HCV-associated liver cirrhosis treated with pegIFN/RBV – Mean age: 51 yrs; baseline MELD: 9.2 (5-20) Hepatic decompensation observed in 36.8% of patients Baseline MELD score associated with hepatic decompensation in multivariate analysis: OR: 1.56 (1.18-2.07; P = .002) Dultz G, et al. PLoS One. 2013;8:e71262. 100 80 60 0 6 Frequencyof Decompensation(%) 40 20 8 10 12 14 16 18 20 MELD Score 22% 59% 83%
- 23. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Factors Associated With Greater Benefit or Greater Risk of Treatment in Cirrhotics Factors Associated With Greater Benefit of Therapy Factors Associated With Greater Risks of Therapy ↓ Child-Pugh score ↓ MELD score ↑ Platelet count ↑ Albumin level ↓ Age ↑ Child-Pugh score ↑ MELD score ↓ Platelet count ↓ Albumin level ↑ Age
- 24. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Take Home Points HCV treatment in cirrhotic patients is associated with high rates of treatment-related adverse events and lower response rates than in patients with less advanced disease However, immediate treatment could lead to SVR and prevent disease progression For every patient, an informed choice is critical
- 25. Optimizing Outcomes in Patients Who Wish To Be Treated
- 26. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Pretreatment Optimization Strategies Lifestyle changes Pretreatment initiation of eltrombopag Ultrasound to exclude ascites Check recent endoscopy report Consider antibiotics in cirrhotic patients with upper gastrointestinal bleeding[1] 1. Chavez-Tapia NC, et al. Cochrane Database Syst Rev. 2010;9:CD002907.
- 27. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat ENABLE: Eltrombopag Enables HCV Tx Initiation Through Higher Platelet Counts Patients with platelet counts < 75,000/µL received open-label eltrombopag in a dose-escalating fashion dependent on platelet response for 2-9 wks until platelet counts increased sufficiently to initiate antiviral therapy 773/ 805 694/ 715 ENABLE-1 (90,000/µL) ENABLE-2 (100,000/µL) 9697100 80 60 40 20 0 PatientsAchievingRequired PlateletThreshold(%) Afdhal NH, et al. Gastroenterology. 2014;146:442-452. Adverse Event, % ENABLE-1 (N = 715) ENABLE-2 (N = 805) Any 37 34 Grade ≥ 3 adverse events 2 3 Blood bilirubin level increased < 1 < 1 Hepatic neoplasm malignant <1 <1 Serious adverse events 1 1 Hepatic neoplasm malignant < 1 < 1
- 28. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat On-Treatment Optimization Strategies Anemia management – RBV dose reductions – Addition of erythropoietin – Transfusions Management of thrombocytopenia – On-treatment initiation of eltrombopag Monitoring of renal function
- 29. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Wk 2 Hb Level Predicts Subsequent Onset of Anemia (REALIZE: TVR + PegIFN/RBV) PtsWithAnemiaAfterWk2(%) 10/13 19/4832/60 15/59 7/5818/27 < 11 11 to < 12 12 to < 30 13 to <14 14 to 15 ≥ 15 Hb at Wk 2 (g/dL) Proportion of Patients With Occurrence of Hb < 10 g/dL After Wk 2 According to Hb Level at Wk 2 Zeuzem S, et al. J Hepatol. 2014;[Epub ahead of print]. 100 80 60 40 20 0 77 67 53 40 25 12
- 30. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat CUPIC: Anemia Management in Cirrhotics According to Age 22/ 221 Grade 3/4 Anemia Transfusions 10 100 80 60 40 20 0 Patients(%) Hezode C, et al. AASLD 2013. Abstract 1845. < 65 yrs ≥ 65 yrs 21 16/ 78 26/ 221 12 35 27/ 78 106/ 221 48 81 63/ 78 EPO P = .028 P < .001 P < .001 Grade 3/4 Anemia Transfusions 7 100 80 60 40 20 0 18 8/ 44 16/ 168 10 20 9/ 44 89/ 168 53 68 30/ 44 EPO P = .032 P ≤ .063 P = .088 Telaprevir Boceprevir 11/168
- 31. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat SVR by RBV Dose Reduction During First 4 Wks of Tx and HCV RNA Status Retrospective analysis of ADVANCE/ILLUMINATE studies of TVR + pegIFN/RBV SVR rates in pts with vs without RBV dose reduction between Wks 0-4 of Tx, analyzed by whether HCV RNA was detectable or undetectable 120/ 176 40/ 45 Undetectable HCV RNA Detectable HCV RNA 68 89 100 80 60 40 20 0 SVR(%) Sulkowski MS, et al. EASL 2012. Abstract 1162. 347/ 405 86 168/ 259 65 RBV dose reduction No RBV dose reduction
- 32. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Similar SVR When RBV Dose Modification or EPO Used to Manage Anemia on BOC 500/687 treatment-naive GT 1 pts on BOC-based therapy developed anemia (Hb ≤ 10 g/dL or expected to reach that nadir before next visit) Randomized to EPO (40,000 units/wk SC) or RBV dose reduction (by 200-400 mg/day) 178/ 251 178/ 249 RBV Dose Reduction EPO Use 71 72 100 80 60 40 20 0 SVR(%) Poordad F, et al. Gastroenterology. 2013;145:1035-1044.
- 33. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat ENABLE: Higher SVR Rates in Patients Receiving Eltrombopag vs Placebo Patients randomized 2:1 to either placebo or eltrombopag + pegIFN alfa-2a (ENABLE-1) or placebo or eltrombopag + pegIFN alfa-2b (ENABLE-2) Higher platelet counts in eltrombopag arms vs placebo by Wk 2 of treatment, enabling full dose of pegIFN to be maintained – ENABLE-1: 11,000/µL vs 79,000/µL 0 20 40 80 100 SVR(%) 60 32/ 232 14 ENABLE-1 ENABLE-2 103/ 449 33/ 252 96/ 506 23 13 19 Placebo Eltrombopag n/N = P = .0064 P = .0202 Afdhal NH, et al. Gastroenterology. 2014;146:442-452. – ENABLE-2: 124,000/µL vs 89,500/µL
- 34. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat ENABLE: Safety Considerations in Antiviral Phase Greater proportion of placebo pts D/C HCV treatment due to AEs (27% vs 19%) Cataracts more common in eltrombopag arm vs placebo for ENABLE-1 (8% vs 3%) but similar for ENABLE-2 (7% vs 6%) Hepatic decompensation (ascites, hepatic encephalopathy, variceal hemorrhage, or spontaneous bacterial peritonitis) more common in eltrombopag vs placebo-treated pts (10% vs 5%) Boxed warning: eltrombopag in combination with IFN + RBV may increase risk of hepatic decompensation 1. Afdhal NH, et al. Gastroenterology. 2014;146:442-452. AE, %[1] ENABLE-1 ENABLE-2 Placebo (n = 232) Eltrombopag (n = 449) Placebo (n = 252) Eltrombopag (n = 506) Any 97 96 93 94 Grade ≥ 3 AE 56 51 51 48 Serious AE 15 20 15 20
- 35. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Increased Risk of Renal Impairment With Triple Therapy Containing TVR or BOC Observational study of 1185 patients with GFR data at baseline Results emphasize that renal function must be assessed during treatment PR BOC PR 4.7 (10/211) 0.9 (1/109) 100 80 60 40 20 0 RenalImpairmentatWk12in PtsWithNormalRenal FunctionatBaseline(%) Mauss S, et al. EASL 2013. Abstract 872. 6.6 (38/575) TVR PR P = .0753 P = .0188 Risk Factor for Renal Insufficiency P Value Age < .001 Hypertension < .001 Diabetes < .05 Triple therapy < .05
- 36. clinicaloptions.com/hepatitis Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat Take Home Points Hb level should be frequently assess during treatment and anemia should be treated as early as possible – EPO and RBV dose reductions for anemia lead to similar SVR rates in BOC-treated patients In HCV patients with platelet counts < 70,000/µL, eltrombopag may increase platelet counts to levels that allow HCV therapy to be initiated and may allow for higher SVR rates with a reduced need for pegIFN dose reductions Renal function must be assessed during treatment
- 37. Go Online for More Insights Into the Management of Cirrhotic HCV Patients Downloadable slideset clinicaloptions.com/treatnow
Editor's Notes
- Graham R. Foster, FRCP, PhD: Hello, I’m Graham Foster and welcome to the CCO program on how to manage cirrhotic patients with hepatitis C. I’m Graham Foster from Queen Mary’s University of London, and I’m joined here today with Marc Bourlière.
- Graham R. Foster, FRCP, PhD: This slide summarizes our disclosures.
- Marc Bourlière, MD: So now we are going to move to first section.
- ESLD, end-stage liver disease; MELD, Model for End-Stage Liver Disease. Marc Bourlière, MD: And as you know, cirrhosis is a continuous spectrum of a disease coming from the totally inactive cirrhosis up to the Child‑B and end-stage liver disease. So this is not a homogenous disease.
- HCV, hepatitis C virus; IFN, interferon. Marc Bourlière, MD: And the severity of the disease increased the needs for HCV therapy but also decreased the response rate, as is shown on this slide.
- DAA, direct-acting antiviral; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: Thank you, Marc. It’s clearly a difficult decision as to when you should start treatment, and the continuity of the hepatitis C cirrhotic spectrum makes life very challenging. Let’s look at the current therapies. For genotype 1 patients, most recommendations include peginterferon, ribavirin, and a protease inhibitor, either boceprevir or telaprevir. In some markets, sofosbuvir and simeprevir are alternatives. Again, both combined with peginterferon and ribavirin. For genotype 2 or 3 patients, the alternatives include ribavirin plus pegylated interferon, or, indeed just sofosbuvir plus ribavirin, avoiding interferon altogether. For genotype 4, the data is less compelling, and most of the studies are still in progress. So, in most parts of the world, the recommendation would be peginterferon plus ribavirin, although sofosbuvir may be used in certain jurisdictions. So at the moment, for the vast majority of patients, the treatment for hepatitis C–associated cirrhosis would include pegylated interferon and ribavirin.
- SVR, sustained virologic response; Tx-Exp, treatment experienced. Graham R. Foster, FRCP, PhD: What I’m showing you here is the efficacy of some of the triple-therapy regimes in real-life studies. Bear in mind that the clinical trial data, by and large, included patients only with very well-compensated, relatively early cirrhosis; so, very much toward the bottom of Marc’s pyramid of cirrhotic disease. We can assess this by looking at the platelet counts, and in the majority of the clinical trials, patients with low platelet counts were excluded, and that means that the patients were, by and large, a well-compensated, relatively easy to treat, early cirrhotic population. You can see from this slide that in the trials that included more advanced patients with cirrhosis, in particular the CUPIC trial, which we’ll come to in a moment, the response rates were significantly lower than in patients with early disease. And a characteristic feature of all studies with peginterferon plus ribavirin and additional agents is that patients with more advanced cirrhosis do less well. So, the more cirrhotic your patient, the less well they will respond to treatment.
- BOC, boceprevir; SVR, sustained virologic response; TVR, telaprevir. Graham R. Foster, FRCP, PhD: One of the defining trials in this population was the French CUPIC study, which for the first time took a population of very advanced patients with cirrhosis and treated them with peginterferon-based treatments. And to talk you through this landmark study, I’m going to hand over to Marc. Marc Bourlière, MD: Thank you, Graham. And as you already underlined, what the real-life study demonstrated was to show us the limitations of the treatments. And in the CUPIC study, we enrolled treatment-experienced cirrhotic patients who were nonresponders to peginterferon and riba, and in this trial we were able to demonstrate that 2 baseline factors are very important in order to select the patients who need to be treated. And you can see on the slide that if you had a platelet count below 100,000 and an albumin level below 35 g/L, your chance of getting an SVR is low, but the chance, or the end chance, to get a complication is high, with serious adverse events as infections, death, liver decompensations, arising in around half of the patients. And clearly these populations are not candidates for triple therapy with first-generation PIs. However, in the vast majority of patients with a platelet count over 100,000 and an albumin level over 35 g/L, in this case, the SVR is high 55% with a very low rate of serious adverse events. And in the midterm, among those with only one bad baseline factor, we can demonstrate that SVR is high, and the serious adverse event is still moderate.
- HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Marc Bourlière, MD: So, now we are moving to the HCV decompensated cirrhosis, and this is a more tricky population, even if it’s the population which is the most in need of treatment because the 5-years survival rate is low—50%—we know that SVR rate with peginterferon and riba range from 7% to 16% in genotype 1 to 4, and from 44% to 57% in genotype 2 and 3. But they have a huge treatment limitation in these populations, because this population is at higher risk of infections and deaths related to infections, and there are more frequent side effects when you remove all the evaluations of liver disease, and there is more frequent side effect in Child-Pugh C patients or in patients with a MELD score over 18. So in these populations, the treatment’s benefit was demonstrated by a lower rate of decompensation when we follow up in those who reached SVR and a reduced mortality in responder. However, keep in mind that there are very few responders in this population, and this is a very difficult-to-treat population that can be only managed in a very high specialist center who have a liver transplants program among their centers.
- GT, genotype; HCV, hepatitis C virus; P, peginterferon; QD, once daily; R, ribavirin; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: Let’s move now to some of the next-generation therapies. You’ve heard very clearly the message from our current treatment regimens: that response rates in patients with cirrhosis are reduced, the risks of therapy are increased, and careful patient selection is the key to success. This is the data from an Eric Lawitz paper recently published in the New England Journal of Medicine, looking at treatment in well-compensated cirrhotic patients with peginterferon plus ribavirin plus sofosbuvir. You can see that as with previous treatment regimens, in this peginterferon- and riba-containing regimen, patients with cirrhosis do less well than patients without cirrhosis. So the trend is clearly the same, with the next generation of drugs combined with peginterferon and ribavirin. That is, patients with cirrhosis do a little less well.
- GT, genotype; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon alfa-2a; RBV, ribavirin; RGT, response-guided therapy; SMV, simeprevir. For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Amsterdam%202013/HCV%20Phase%20III/Capsules/1413.aspx Graham R. Foster, FRCP, PhD: This is yet another potent agent combined with pegylated interferon, this time simeprevir, and again it’s exactly the same story: In peginterferon plus ribavirin–containing regimens, the response rates in patients with cirrhosis are reduced. You can see that simeprevir adds a considerable benefit compared to peginterferon plus ribavirin in patients with cirrhosis, but notice that the response rates in patients with cirrhosis are reduced and continue to be reduced.
- GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin. Graham R. Foster, FRCP, PhD: In this study, I’m showing you patients with genotype 2 and genotype 3, looking at sofosbuvir plus ribavirin and peginterferon plus ribavirin. The take-home message here is exactly the same: Patients with cirrhosis do a little less well with peginterferon and ribavirin–containing regimens. Look firstly, please, at the genotype 2 patients. In the orange bars, you can see how patients treated with peginterferon and ribavirin with cirrhosis have a significant reduction in their sustained virologic response rate. Exactly the same is seen in patients with genotype 3. If we now turn to the interferon-free treatment regimens—this is sofosbuvir plus ribavirin—it’s clear that genotype 3 patients with cirrhosis respond rather poorly to interferon-free sofosbuvir–containing regimens. However, by contrast, for genotype 2, the response rates in patients with cirrhosis are sustained and, in fact, are a very impressive: greater than 90%. So pulling these data together, I think we can draw the conclusion that for peginterferon plus ribavirin–containing regimes, patients with cirrhosis have a reduced response rate. For direct-acting antiviral agents given without pegylated interferon, the picture is much more mixed. For genotype 3, clearly cirrhosis has a major impact; for genotype 2, it has much less of an impact. As the data emerges from ongoing clinical trials, I believe we’re going to see a trend to patients with cirrhosis responding much better to interferon-free regimens, and indeed the very latest data from interferon-free regimes does suggest that patients with cirrhosis can be treated with great success. So I do believe that the days of difficult to cure patients with cirrhosis are starting to come to an end. But at this moment in time, where interferon remains the main arm of treatment, it’s important to remember: If you allow your patient to develop cirrhosis, their chance of a response is going to be reduced.
- GT, genotype; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response. For more information about this study, please see the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/London%202014/Highlights/Capsules/165.aspx Graham R. Foster, FRCP, PhD: Let’s now move to interferon-free containing treatment regimens. It’s the COSMOS study involving simeprevir plus sofosbuvir with and without ribavirin. And although this is a pilot study, a relatively small-scale study, what it shows is that without interferon, the response rates in patients with advanced fibrosis may be equal to those response rates in patients who have earlier disease. So the trend to poorer responses in patients with cirrhosis that we see consistently in peginterferon plus ribavirin regimes may not hold true in the interferon-free era. Bear in mind, however, that this is a trial in which patients with cirrhosis had relatively high platelet counts. This is not a patient population with decompensated disease; this is not equivalent to the data that Marc showed you earlier on in the CUPIC study.
- IFN, interferon; RBV, ribavirin; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: These are a number of other studies making a similar point: that in interferon-free treatment regimens, patients with advanced fibrosis respond very well. So I believe, and I believe many clinicians believe, that interferon-free treatment will be highly effective in patients with cirrhosis. But—and the big but—is that most of these are relatively small-scale trials in very well-compensated patients with cirrhosis. So I think the take-home message that we’ve been telling people for many years—“Do not let your patient get cirrhosis”—is still true, even in the interferon-free era.
- DAA, direct-acting antiviral; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Marc Bourlière, MD: So. Looking at the take-home message point that we can draw from these cases, in this very moving time of new treatments, we can say that cirrhotic patients are the most in need for achieving treatments. Child-Pugh A patients should be strongly advised to undergo treatments. More advanced cirrhotic patients should be treated with caution on a case-by-case basis. Newest direct antiviral agents, plus peginterferon and riba combinations, increase SVR in cirrhotic patients, and there is now huge evidence that interferon-free DA regimens demonstrate significant potency in cirrhotic patients.
- Marc Bourlière, MD: So now let’s move to section 2: informed decision making when treating or deferring in cirrhotic patients.
- HCC, hepatocellular carcinoma; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: The most important issue is to make sure your patient is aware of the treatment choices. The treatment choices will clearly vary in the different areas of the world. We showed you a few moments ago that there are emerging treatments that are likely to allow effective treatment for patients with very advanced liver disease. However, the availability of these treatments will differ widely, and in some jurisdictions, the interferon-free regimens are already available and already funded. In others, the first-generation proteases have not yet been released. So, it’s very important to understand your own situation, your own drug availability, and discuss that with your patients. Patients should be told of the benefits and the risks. If you have cirrhosis, the benefits of immediate treatment are that you may achieve a sustained response and prevent disease progression. But there are risks, and the risks are that you may develop significant hepatic decompensation, and patients need to be aware that interferon-based treatments are not risk free. On the other hand, deferring treatment will not allow immediate benefits. Deferring treatment may provide access, in the future, to a much better tolerated, much more effective interferon-free regimen. Now, clearly the length of the delay will have a major impact on the advice you give your patient, and that requires informed decision making, both by the patient and the physician, as to the realistic probability of new regimens being available. There are risks to deferring treatment, and those risks relate to the development of liver cancer, the risks of liver-related mortality, and the risks for transplantation, and every patient needs to be informed of the benefits and the risks of the particular strategy that is being recommended.
- CHC, chronic hepatitis C; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: These data are compelling evidence showing the benefits of clearing hepatitis C. Across the board, mortality is reduced. The need for transplantation is reduced. The development of liver cancer is reduced. The development of liver failure is reduced. So there is absolute consensus that clearing hepatitis C provides very significant healthcare gains. But remember, in patients with cirrhosis, there are risks to therapy.
- SAE, serious adverse event; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: And, once again, we go back to the CUPIC data set, which is the most compelling data set in patients with advanced liver disease. Marc Bourlière, MD: CUPIC really allows us to select the patients in order to be treated among the cirrhotics. Platelet counts below 100,000 and albumin level below 35 g/L are the 2 key independent factors, which are predictive of the response and predictive of the complications. And clearly, as we have already stressed in the previous case, we are able to define population in which serious adverse complications are over SVR and another group of patients in which the SVR overcomes the complications.
- BOC, boceprevir; SAE, serious adverse event; TVR, telaprevir. Marc Bourlière, MD: These data were also confirmed in other real life clinical data, and coming from the German experience, you can see on this slide that if you have a platelet level below 110 and a Child‑Pugh score over 5, you have got 100% of either treatment failure or serious adverse event.
- HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease; OR, odds ratio; pegIFN, peginterferon; RBV, ribavirin. Marc Bourlière, MD: And that was already stressed before in the peginterferon and riba era. If you look to this German retrospective cohort study, you can see that the most important predictive factor of decompensations when you are treating patients with peginterferon and riba was the MELD score. And clearly on these slides you can see that, if you had a MELD score below 10, your chance of getting any complications during treatment is 22%. If you move from MELD 10 to MELD 14, your complications rise to 59%, and if you [move] over a MELD of 14, you have a very high chance to get complications with very few chances to get any SVR. So clearly this is not a population to be treated with peginterferon and riba.
- MELD, Model for End-Stage Liver Disease. Marc Bourlière, MD: So let’s now look at the factors associated with the greatest benefit and greatest risk in treating patients with cirrhosis. And this is the risk-benefit equation that needs to be evaluated for every patient in the context of available treatment. Factors associated with a greater benefit of therapy are those with a low Child-Pugh score, a low MELD score, patients with a high platelet count, a high albumin count. And, of course, patients who are younger tolerate treatments much better than patients who are elderly. Factors associated with a greater risk of therapy are those with a higher Child-Pugh score, a higher MELD score, thrombocytopenia, a low albumin, and advanced age.
- HCV, hepatitis C virus; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: So the take-home message is that hepatitis C treatment in patients with cirrhosis is associated with a high rate of treatment-related adverse events and, indeed, with decompensation and even death. The response rates are significantly reduced in treatments involving pegylated interferon and ribavirin. On the other hand, immediate treatment can lead to a sustained response, which has enormous benefits in the medium and long-term. For every patient, it’s important to make an informed choice. The critical factors to discuss with the patient are the chances of a response, the benefits of a response, and the risks of therapy. The background to that discussion should be information about alternatives which may be available in the foreseeable future, and clearly, for every jurisdiction, that information will differ.
- Graham R. Foster, FRCP, PhD: Let’s now move on to ways that we can reduce the risks in patients with cirrhosis who require treatment with interferon-based treatment regimens. Remember that we’re talking about treatments on interferon-based regimens. Let me hand over to Marc for some recommendations on what we can do to optimize treatment success.
- Marc Bourlière, MD: So looking back to the peginterferon and riba era, we know that there is a pretreatment optimization strategy. And the first one is we need to motivate lifestyle change, especially for those patients with overweight or alcohol consumption. So we can also make a pretreatment initiation of eltrombopag in those patients with low platelet counts without any liver decompensations. We need to do ultrasound to exclude ascites and hepatocellular carcinoma. We need to check for a recent endoscopy report, and we need, sometimes, to consider antibiotics earlier in the course of treatment.
- HCV, hepatitis C virus; Tx, treatment. Graham R. Foster, FRCP, PhD: One of the strategies that is widely used to improve patients’ prospects of responding and tolerating treatment is to raise the platelet count by the use of platelet-stimulating factors. Eltrombopag is an oral agent which stimulates thrombopoiesis and increases the platelet count. What I’m showing you here is the data from a very important pivotal trial, the ENABLE trial, in which patients with advanced cirrhosis were randomized to receive either platelet support therapy or no platelet support therapy. And what you can see is that in this study, patients treated with eltrombopag had a significant improvement in their platelet counts allow interferon treatment to be introduced.
- RBV, ribavirin. Marc Bourlière, MD: Here are the options. You can do ribavirin dose reductions, additions of erythropoietin transfusions, and for thrombocytopenia, you can use eltrombopag. And what we are going to do also is the monitoring of renal function, which is an thing that we need to take into account in the management of our patients.
- Hb, hemoglobin; pegIFN, peginterferon; RBV, ribavirin; TVR, telaprevir. Marc Bourlière, MD: Coming back to the anemia management, it is clear coming from the REALIZE phase III study that if a patient exhibits a hemoglobin level below 11 g/L at Week 2 on treatment with telaprevir, these patients had a very high chance to develop anemia with a hemoglobin level below 10 g/dL during the course of treatment; 77% will develop this severe anemia.
- EPO, erythropoietin. Marc Bourlière, MD: Another thing which is important coming from the CUPIC study is that the onset of anemia is more frequent in the aged patients over 65 compared to those below 55 years old, and this anemia requires more transfusions and more EPO use in these elderly populations compared to the young populations. So keep in mind that age is an important factor associated also to anemia and anemia risk.
- GT, genotype; pegIFN, peginterferon; RBV, ribavirin; TVR, telaprevir; Tx, treatment. Marc Bourlière, MD: Now let’s move to the management of this anemia. And what I’ve been demonstrating through the phase III study, contrary to what we know on the peginterferon and riba era, is that whether during the first 4 weeks of treatment, whether you are detectable or undetectable in terms of HCV RNA, the fact that you reduced the dose of ribavirin did not impair SVR. And this is nicely shown on the slide in which, in orange, you have the patients with no ribavirin dose reductions and in blue those who had ribavirin dose reductions during the first 4 weeks of treatments.
- BOC, boceprevir; EPO, erythropoietin; GT, genotype; Hb, hemoglobin; RBV, ribavirin; SC, subcutaneous; SVR, sustained virologic response. Marc Bourlière, MD: Moreover, you can say in this prospective trial published in Gastroenterology that among these naive G1 patients treated with boceprevir-based therapy, those patients who exhibited a hemoglobin level below 10 were treated either by EPO use and ribavirin dose reductions, and there is no difference in terms of SVR according to the management. So therefore, the recommended management now for anemia is really first to reduce ribavirin dose strongly and immediately when anemia arises.
- pegIFN, peginterferon; SVR, sustained virologic response. Graham R. Foster, FRCP, PhD: So for anemia, the recommendation is to dose reduce the drugs. The strategy for thrombocytopenia is the opposite; it’s to maintain the high dose of drugs and add in supporting agents. I showed you before that adding eltrombopag to patients with advance cirrhosis allowed the platelet count to increase, but that’s just a number on a blood test form. The critical question is whether adding eltrombopag to peginterferon- and ribavirin-based regimens increases the proportion of patients to achieve a sustained virologic response. These are the data from the ENABLE trial, which was powered to detect a change in sustained virologic response. The study involved both peginterferon alfa-2a and peginterferon alfa-2b, and you can see that there was a statistically significant increase in sustained virologic response in patients receiving eltrombopag. So, by contrast to the erythropoietin studies that Marc has just shown you, where adding EPO did not change sustained response rates, for eltrombopag, there is a properly powered, properly constituted study showing very clearly the benefits in terms of SVR. So, for patients with cirrhosis who are being considered for treatment, adding eltrombopag in those who develop, or are likely to develop, thrombocytopenia may significantly improve sustained response rates.
- AE, adverse events; D/C, discontinued; HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin. Graham R. Foster, FRCP, PhD: This slide summarizes the important safety considerations in the ENABLE study. You can see that, by and large, the drug was very well tolerated. It’s important to remember that this is a population of patients with very significant liver disease. These are patients who are at very high risk of side effects. It is important to remember that in this population of patients, there is a small but significant change in the number of patients who develop hepatic decompensation, and that’s a feature of pegylated interferon and ribavirin. There were a few more cataracts in patients taking eltrombopag and a few more hepatic decompensation events. So once again, we come back to the careful risk-benefit assessment in these patients.
- BOC, boceprevir; GFR, glomular filtration rate; PR, peginterferon/ribavirin; TVR, telaprevir. Graham R. Foster, FRCP, PhD: I’d now like to turn to our final issue to consider, which is renal impairment. Marc Bourlière, MD: So, renal impairment is a new issue that we have to deal with. If we look to the patients treated with triple therapy compared to those treated with peginterferon and riba in this large, German, real-life cohort, you can see the risk of renal impairment, characterized by a decrease of clearance creatinine compared to baselines, in 6.6% of patients treated with telaprevir and in 4.7% in patients treated with boceprevir. There is no clear evidence linking the use of a triple regimen with the occurrence of this renal impairment. But what we know is that there is a risk factor for this renal insufficiency that was characterized, and you may be more cautious for those patients with advanced age, with hypertensions, with diabetes, and this population should be really carefully followed for their renal insufficiency and renal assessment.
- BOC, boceprevir; EPO, erythropoietin; Hb, hemoglobin; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Marc Bourlière, MD: So the take-home message here regarding safety on triple regimen is that hemoglobin levels should be frequently assessed during treatments, and anemia should be treated as early as possible. EPO and ribavirin dose reductions for anemia lead to similar SVR rates in boceprevir-treated patients, and therefore for the community, ribavirin dose reductions is the first option to manage anemia, whatever the stage of the patient is. In HCV patients with platelet counts below 70,000, eltrombopag may increase platelet counts to a level that allows HCV therapy to be initiated and may allow for higher SVR rates with a reduced need for peginterferon dose reductions. And this is crucial in order to achieve high SVR. Last point: Renal functions must be assessed during treatment by doing creatinine clearance regularly in order to avoid renal impairment.