Hepatitis C: Management of Previous Non-responders with First Line Protease Inhibitors Fred Poordad, MD The Texas Liver Institute Clinical Professor of Medicine University of Texas Health Science Center San Antonio, Texas
Concepts Using baseline predictors of response Utilizing on-treatment viral response and knowing when to quit Treating the most difficult patient population: the cirrhotic Getting the patient through treatment: On treatment management
Case 1: Treatment Failure Patient A 54 yo male was previously treated with pegylated interferon alfa-2b and ribavirin in 27 4 log decline by week 24, but never became undetectable through 48 weeks of therapy No week 12 data available Past medical history includes mild hypertension and hyperlipidemia, but neither have required therapy
Case 1: Labs and Imaging Viral Data and CBC HCV Genotype1a 3.4 million IU/mL WBC: 3,9/ L HB 14.6 g/dl Liver Panel and Ultrasound Total bilirubin.8 mg/dl ALT 118 IU/L; AST 97 IU/L Albumin 3.6 g/dl -Fetoprotein 2.4 ng/ml Platelets 135,/ L Ultrasound: 1 cm liver, spleen 13 cm ALT = alanine aminotransferase; AST = aspartate aminotransferase.
Concepts Using baseline predictors of response
Baseline Predictors Can Help Guide Us Past treatment experience Subtype Viral load Fibrosis Ethnicity IL-28B status
Baseline Predictors of SVR Vary in Naïve Versus Treatment Experienced Poordad F, et al. Gastroenterology 212;143(3):68-618
SVR (%) SVR Rates With BOC or TVR + PR According to Treatment History 1 8 Relapsers 69-83 Naive 63-75 Partial Responders Null Responders 6 4-59 4 29-4 2 Poordad F, et al. N Engl J Med. 211;364:1195-126. Jacobson IM, et al. N Engl J Med. 211;364: 245-2416. Bacon BR, et al. N Engl J Med. 211;364:127-1217. Zeuzem S, et al. N Engl J Med. 211;364: 2417-2428. Bronowicki JP, et al. EASL 212. Abstract 11.
SVR (%) REALIZE: SVR by Baseline Fibrosis Stage and Prior Response (TVR) 1 8 Prior Relapsers Prior Partial Responders Prior Null Responders 86 85 84 72 Pooled T12/PR48 PBO/PR48 6 56 4 32 34 41 39 2 18 2 13 13 14 1 6 n/n= 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 1/18 /5 11/32 1/5 24/59 1/18 15/38 /9 7/5 1/1 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Zeuzem, et al. N Engl J Med. 211 Jun 23;364(25):2417-28.
Does IL-28B Help?
SVR by IL-28B Genotype for (A) Previously Untreated Patients and (B) Previous Treatment-Failure Patients Poordad F, et al. Gastroenterology 212;143(3):68-618
Case 1: Week 4 PCR was <1 log decline Started on PegIFN and RBV At week 4, the PCR is 89, IU/mL This means the patient has poor IFN response What are his chances of responding?
Concepts Utilizing on-treatment viral response and knowing when to quit
SVR % Comparison of Lead-in Arms of Treatment-Experienced Trials 9 8 7 6 5 4 3 2 1 82 33 33 REALIZE (TVR) <1 log Decline 1 log Decline 76 RESPOND 2* (BOC) * Pooled data from Arm 2 (RGT) and Arm 3 Foster GR, et al. EASL 211. Abstract 6. Bacon BR, et al. NEJM. 211;364:127-1217.
% of Patients PROVIDE Final Results: SVR Rates by Prior Treatment Response 1 9 8 7 6 5 4 3 2 1 All patients treated with BOC + PEG/RBV 41 All includes: Nulls, Partials, Relapsers and Other Boceprevir is now labeled for null responders Vierling, et al. DDW 213 Nulls Partials Relapsers All 67 SVR (FAS) 96 65 2/49 57/85 27/28 16/164
Early Interferon Response (Lead-In) Further Defines Likelihood of Success for Non-CC Patients 1 9 8 7 6 5 4 3 2 1 2 67 2 3 SPRINT-2 and RESPOND-2 Combined 5 2 4 75 56 75 81 83 12 PR48 BOC RGT BOC/PR48 81 58 72 4 37 1 27 19 51 44 2 45 <1 log 1log <1log 1log <1log 1log 32 37 117 75 82 83 19 111 133 5 24 1 2 6 25 4 1 25 CC CT TT 5 13 26 82 23 28 76 26 34 Poordad F, et al. Gastroenterology 212;143(3):68-618
Futility Rules for BOC or TVR + PegIFN/RBV in Treatment-Experienced Patients Recommendation: All therapy should be discontinued in patients with the following: BOC [1,2] Time Point Criteria Action Wk 12 HCV RNA 1 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue all therapy TVR [2,3] Time Point Criteria Action Wk 4 or 12 HCV RNA >1 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue pegifn/rbv Assay should have a lower limit of HCV RNA quantification of 25 IU/mL and a limit of HCV RNA detection of approximately 1-15 IU/mL. 1. Boceprevir [package insert]. 2. Ghany MG, et al. Hepatology. 211;54:1433-1444. 3. Telaprevir [package insert].
% SVR SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL VL) (BOC Arms Combined) 1 8 91 79 83 6 5 48 49 4 2 16 38 3 8 21 6 28 1 2 <3 3-4 4-5 >5 1 11 28 9 2 23 33 23 7 15 31 23 29 44 16 5 31 3 29 98 25 51 <3 3-4 4-5 >5 <3 3-4 4-5 >5 33 4 RESPOND-2 SPRINT-2 Combined Studies Poordad F, et al. Gastroenterology 212;143(3):68-618
Potential Arguments for a Lead-in PEG-IFN + RBV Dosing Period Predict interferon responsiveness Can stop therapy and avoid side effects in face of likely futility Maintain patient s eligibility for trials of new direct-acting antivirals when few PI failure studies are available Assess hematologic response to pegifn/rbv therapy and make needed dose adjustments before starting PI Modified from Kwo PY, et al. Lancet 21;376(9742):75-16.
Concepts Treating the most difficult patient population: the cirrhotic
Meta-Analysis of Cirrhotic Patients in Boceprevir Trials Sources of data SPRINT-2 RESPOND-2 PEGASYS study EPO study Interim data from PROVIDE Total of 212 F4 patients (18 on BOC/PR, 32 on PR) Aims Dx by central reading of liver biopsies To consolidate results from SPRINT2/RESPOND2 in a larger population of patients To provide predictors of SVR by multiple logistic regression analysis To evaluate risk of severe AEs, as suggested by real-life study (CUPIC) To develop newer reliable futility which will enable sparing cost and risk of therapy To assess whether short treatment duration (i.e. 36 weeks) might be used in a subset of patients Vierling JM, et al. EASL 213
SVR % Overall SVR by F3 and F4 1 BOC PR PR 8 6 55 54 4 2 17 26 99/18 6/32 58/17 6/22 F4 F3 Vierling JM, et al. EASL 213
SVR (%, 95% CI) SVR According To Treatment Week 4 Virologic Response In F3 And F4 1 9 8 7 6 5 4 3 2 1 1 log HCV-RNA decline at TW4 <1 log HCV-RNA decline at TW4 67 66 29 21 47/7 1/35 85/128 1/48 F3 F4 Vierling JM, et al. EASL 213
Real World Cirrhotics: CUPIC Patient Baseline Demographics Characteristic Telaprevir N=295 Boceprevir N=19 Child-Pugh score A/B, n (%)* 28 (95) / 6 (2) 177 (93) /1 (1) MELD score, mean (range) 8.1 (6-22) 8.1 (6-28) Prothrombin time ratio, mean % (range) 86 (27 1) 87 (23 1) Serum albumin (g/l), mean (range) 4. (2.7 53.2) 4.7 (27. 5.3) Total bilirubin (μmol/l), mean (range) 15.5 (4. 73.) 15.2 (4. 78.) Hemoglobin (g/dl), mean (range) 14.5 (9. 19.7) 14.8 (1.8 18.4) Neutrophils (1 9 /mm 3 ), mean (range) 3.3 (.8-8.5) 3.2 (.5-8.5) Platelet count (1 3 /mm 3 ), mean (range) 151 (18 64) 144 (34 346) Esophageal varices, n (%) 51/145 (35.2) 37/97 (38.1) * Missing data : 21 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 213. Abst. 6
Patients with undetectable HCV RNA (Percentage) CUPIC Virological response (ITT): SVR12 1 TELAPREVIR 1 BOCEPREVIR 9 8 7 6 5 4 49% 79% 81% 77 % 68 % 56% 9 8 7 62% 6 51% 5 4 65% 67% 57% 4% 41% 3 3 2 2 16% 1 146 295 234 295 239 295 227 295 2 295 165 295 118 295 W4 W8 W12 W16 W24 W48 W6 1 31 19 97 19 118 19 124 19 128 19 18 19 79 19 W4 W8 W12 W16 W24 W48 W6 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 213. Abst. 6
CUPIC: Safety Findings Patients, n (% patients with at least one event) Serious adverse events (SAEs) Telaprevir n=295 Boceprevir n=19 535 in 16 patients (54.2%) 321 in 97 patients (51.%) Premature discontinuation / due to SAEs 139 (47.1%) / 63 (21.3%) 8 (42.1%) / 27 (14.2%) Death 7 (2.4%) 3 (1.6%) Infection (Grade 3/4) 27 (9.1%) 8 (4.2%) Hepatic decompensation (Grade 3/4 ) 15 (5.1%) 9 (4.7%) Anemia (Grade 3/4: Hb<8 g/dl) 38 (12.9%) 19 (1%) Rash (Grade 3/SCAR) 16 (5.4%) / 2 (.6%) 2 (1.%) / EPO use / blood transfusion 168 (57%) / 53 (18%) 119 (62.6%) / 26 (13.7%) GCSF use 8 (2.7%) 13 (6.8%) TPO use 6 (2%) 3 (1.6%) SCAR: severe cutaneous adverse reaction Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 213. Abst. 6
CUPIC: Predictors of Severe Anemia Multivariate analysis: Baseline factors related to anemia <8 g/dl or blood transfusion Predictors OR 95%CI p-value Gender: Female 2.19 1.11-4.33.23 No lead-in phase 2.25 1.15-4.39.18 Age 65 years 3.4 1.54-6.2.14 Hemoglobin level 12 g/dl for female 13 g/dl for male 5.3 2.49-11.25 <.1 Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 212. Abst. 51.
CUPIC: Risk of Occurrence of Death or Severe Complications Factors Platelet count >1,/mm 3 Platelet count 1,/mm 3 Albumin 3.5 mg/l 3.4% (1/298) 4.3% (3/69) Albumin <3.5 mg/l 7.1% (2/28) 44.1% (15/34) Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 212. Abst. 51.
Concepts Getting the patient through treatment: On treatment management of anemia
SVR Rates Similar Between Groups Regardless of Viremia Status at Start of Anemia Management SVR (%; 95% CIs) 1 9 8 86 86 All patients treated with BOC + PEG/RBV 7 6 5 56 56 4 3 RBV DR EPO RBV DR EPO 2 1 111 129 17 124 67 12 71 127 Undetectable Undetectable Detectable Detectable Poordad F et al, Abstract 154, AASLD 212
SVR (%, 95% CI) SVR Rates by Lowest RBV Dose Received for 14 Days* 1 9 8 7 6 5 4 3 2 1 92 11 12 6 3 5 7 28 4 75 58 77 2 4 6 8 1 12 14 77 43 56 67 3 45 Lowest RBV Dose (mg/day) for 14 days 36 4 11 33 1 3 *The lowest RBV dose (mg/day) received for at least 14 days during the treatment period based on information in patient diaries. Poordad F et al, Abstract 154, AASLD 212 31
SVR (%) SVR by Percent Total RBV Dose Received in Patients Who Received 8% of Treatment Duration 1 9 8 7 6 5 4 3 2 1 67 6 9 75 83 89 92 <5 5<6 6<7 7<8 8 % Total RBV Dose Received vs. Assigned Total RBV Dose* *Assigned Total RBV Dose = Per-protocol assigned total RBV dose for the entire treatment period Poordad F et al, Abstract 154, AASLD 212 9 12 2 24 34 38 1 19
Summary Treat previous relapsers since likelihood of SVR is very high Consider baseline predictors of response Cirrhosis Genotype 1b Non-black IL-28B CC variants Use on-treatment viral kinetics to predict outcome and also to stop therapy early when futile 4 week lead in (boceprevir and telaprevir) Week 8 log decline in poor interferon responders (boceprevir) Week 12 futility rule (boceprevir and telaprevir) Manage anemia aggressively with RBV dose reduction Weekly CBC in cirrhotics Can hold RBV if necessary Use secondary anemia management when needed