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Current strategies for the management of treatment naïve and treatment-experienced patients Mark S. Sulkowski, MD Medical Director, Viral Hepatitis Center.

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Presentation on theme: "Current strategies for the management of treatment naïve and treatment-experienced patients Mark S. Sulkowski, MD Medical Director, Viral Hepatitis Center."— Presentation transcript:

1 Current strategies for the management of treatment naïve and treatment-experienced patients Mark S. Sulkowski, MD Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology Johns Hopkins University School of Medicine Baltimore, Maryland

2 Treatment-Naive Data and Regimens Treatment-Experienced Data and Regimens Overview Futility Rules Adverse Effects

3 SVR in Treatment-Naive HCV Genotype-1 Infection PEG IFN + RBV + PI 4,5 70%–79% IFN 1 IFN + RBV 1 PEG IFN + RBV 2,3 SVR (%) 10% 30% 45% Abbreviations: IFN, interferon; PEG IFN, peginterferon; PI, protease inhibitor; RBV, ribavirin. 1. McHutchison JG, et al. Semin Liver Dis. 1999;19: Manns MP, et al. Lancet. 2001;358: Fried MW, et al. N Engl J Med. 2002;347: Jacobson IM, et al. N Engl J Med. 2011;364: Poordad F, et al. N Engl J Med. 2011;364: Graphic courtesy of Dr. David R. Nelson.

4 Standard of Care for HCV Genotype 1 Boceprevir or Telaprevir in combination with PEG IFN/RBV Adults with compensated liver disease, including cirrhosis –Treatment-naive –Failed previous interferon-based therapy Must not be used as monotherapy Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

5 Resistance Develops Rapidly During Monotherapy with Protease Inhibitor Telaprevir Dosing Kieffer TL, et al. Hepatology 2007; 46: Log 10 HCV RNA (IU/mL) HCV RNA (>100 IU/mL) Wild-type T54A V36A/M R155K/T 36/155 A156V/T 36/156 Days Patient 1002Patient 1018 LOD 114 1

6 Treatment-Naive Data and Regimens Treatment-Experienced Data and Regimens Overview Futility Rules Adverse Effects

7 Boceprevir—RGT in Treatment-Naive Patients with No Cirrhosis PEG IFN/RBV for 4 weeks, followed by boceprevir 800 mg TID + PEG IFN/RBV Abbreviations: RGT, response-guided therapy; TW, treatment week. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; HCV RNA Recommendation TW8TW24 Undetectable Administer all 3 drugs through TW28 DetectableUndetectableAdminister all 3 drugs through TW36, then administer PEG IFN/RBV through TW48

8 HCV RNA Assays—“Not Detected” Is Required for Shortened Therapy Below lower limit of quantification (LLOQ) but still “detectable” is not sufficient to shorten therapy—ie, patient should continue for 48 weeks Harrington P, et al. Frequency and Clinical Relevance of Detectable/

9 SPRINT-2—BOC/PR: Overall SVR and Relapse Rate by Cohort and Treatment Arm SVRRelapse 211/ / / / / / 162 3/ 25 6/ 35 2/ 14 22/ 52 29/ 55 12/ 52 Abbreviations: RGT, response-guided therapy; SVR, sustained virologic response. Nonblack N = 938; black N = 159. Poordad F, et al. N Engl J Med. 2011;364:

10 Poordad F, et al. N Engl J Med. 2011;364: SPRINT-2—BOC/PR: SVR According to HCV RNA Response at Week 8 HCV RNA Undetectable Wk 8 HCV RNA Detectable Wk 8 170/ / / 56 38/ / / 233 8/ 25 8/ 29 8/ 38 14/ 18 18/ 22 3/ 4 44% of all patients eligible for 28 weeks

11 Boceprevir—Treatment-Naive Non-RGT Regimens 1. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; Poordad F, et al. N Engl J Med. 2011;364: Poor Interferon Responsiveness 1 Compensated Cirrhosis 1 4 weeks of P/R followed by 44 weeks of B + P/R Consideration should be given to extending treatment for treatment-naive patients with poor interferon responsiveness (< 0.5 or 1-log drop 2 ) at week 4: 4 weeks of P/R followed by 44 weeks of B + P/R

12 Poordad F, et al. N Engl J Med. 2011;364: SPRINT-2—BOC/PR: SVR Based on Week 4 Lead-In Response Nonblacks Blacks IFN Responsiveness* Poor IFN Response † *Undetectable or ≥1-log decline. †<1-log decline. 187/ / / / 24 6/ 24 22/ 36 5/ 16 12/ 26 31/ / 234 3/62

13 SPRINT-2—BOC/PR: SVR in Advanced Fibrosis/Cirrhosis Poordad F, et al. N Engl J Med. 2011;364: / / / / 34 22/ 42 9/ 24

14 Baseline predictors of SVR: SPRINT-2 EffectOdds Ratio (95% CI) P value Baseline HCV-RNA: ≤400,000 vs. >400, (1.5, 87.8) 0.02 IL-28B rs genotype: CC vs. TT 2.6 (1.3, 5.1)0.006 IL-28B rs genotype: CC vs. CT a 2.1 (1.2, 3.7)0.01 IL-28B rs genotype: CT vs. TT 1.2 (0.7, 2.2)0.48 Cirrhosis no vs. yes4.3 (1.6, 11.9)0.004 Genotype: 1b vs. 1a2.0 (1.2, 3.4)0.005 Race: non-black vs. black2.0 (1.1, 3.7)0.03 BMI ≤ 30 vs. > (1.0, 2.5) 0.07 Poordad et al. Gastroenterology 2012 in press

15 SVR Rate according to IL28B: Boceprevir - SPRINT-2 Poordad F et al. EASL 2011

16 BOC/PegIFN/RBV: IL-28B polymorphism is a strong predictor of TW8 response % Patients with undetectable HCV-RNA by TW8 CC CT + TT SPRINT-2 RESPOND

17 Predictors of SVR include HCV RNA decline at week 4: SPRINT-2 EffectOdds Ratio (95% CI) P value Baseline HCV-RNA: ≤400,000 vs. >400, (1.0, 68.6)0.046 Decline in HCV-RNA at week 4 (≥ 1 vs. < 1 log 10 decline) 8.2 (4.5, 15.0)<.0001 Cirrhosis no vs. Yes3.5 (1.1, 11.3)0.04 BMI ≤ 30 vs. >302.5 (1.4, 4.2)0.001 Genotype: 1b vs. 1a/other/missing2.1 (1.2, 3.6)0.01 Race: non-black vs. black1.8 (0.9, 3.6)0.08 IL-28B rs genotype: CC vs. TT 1.2 (0.6, 2.7)0.59 IL-28B rs genotype: CC vs. CT a 1.1 (0.6, 2.1)0.76 IL-28B rs genotype: CT vs. TT 1.1 (0.6, 2.2)0.73 Poordad et al. Gastroenterology 2012 in press

18 SPRINT-2: SVR Based on Early Interferon Response Vierling JM, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011: Abst Log 10 Viral Load Decrease After 4 week of P/R Lead-in All Patients (Cohort 1 + Cohort 2) % of Patients With SVR PR48BOC/RGTBOC/PR48

19 HCV RNA suppression after 4 weeks of PegIFN/RBV according to IL28B genotype Poordad et al. Gastroenterology 2012 in press

20 Telaprevir—RGT in Treatment-Naive Patients Telaprevir 750 mg TID, PEG IFN, and RBV starting on day 1 Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; HCV RNARecommendation Undetectable at TW4 and TW12 Administer all 3 drugs through TW12, then administer PEG IFN/RBV through TW24 Detectable (≤1000 IU/mL) at TW4 and/or TW12 Administer all 3 drugs through TW12, then administer PEG IFN/RBV through TW48

21 ADVANCE—TVR/PR: Overall RVR, eRVR, and SVR Rates 246/ / / / / / / / /361 (Wk 4) (Wk 4 and 12) (Wk 24 postEOT) P <.001 Patients eligible to receive 24 wks of total treatment 246/ / / / / / / / /361 Abbreviations: EOT, end of treatment; eRVR, extended rapid virologic response; P, peginterferon; R, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; T, telaprevir. Jacobson IM, et al. N Engl J Med. 2011;364:

22 ILLUMINATE—TVR/PR: SVR and Relapse Rates SVRRelapse 388/ / / /469 9/159 4/154 Abbreviations: ITT, intent-to-treat; SVR, sustained virologic response. Sherman KE, et al. N Engl J Med. 2011;365:

23 ADVANCE: Week 4 HCV RNA not detected according to IL28B genotype

24 SVR according to IL28B: Telaprevir - ADVANCE Jacobson et al. EASL 2011

25 Telaprevir—Treatment-Naive NonRGT Regimens Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; Compensated Cirrhosis Treatment-naive patients with cirrhosis and undetectable HCV RNA at weeks 4 and 12 may benefit from continuing PEG IFN/RBV through week 48

26 ADVANCE—TVR/PR: Impact of Host and Viral Factors *<800,000 IU/mL vs ≥800,000 IU/mL. Jacobson IM, et al. N Engl J Med. 2011;364: Results from the T12/PR24 Group Low * High * 1b1aNon- black BlackF0-2F3-4 Viral LoadGenotypeRaceFibrosis 64/ / / / / / / 52 16/ 26

27 Treatment-Naive Data and Regimens Treatment-Experienced Data and Regimens Overview Futility Rules Adverse Effects

28 Treatment-Experienced Patients are Heterogeneous Prior relapsers 1 –Undetectable HCV RNA at the end of therapy but detectable during follow-up Prior partial responders 1 –≥2-log drop HCV RNA at week 12 but never undetectable Prior null responders –<2-log drop HCV RNA at week 12 2,3 Included in telaprevir trials 2 Excluded from boceprevir trials; Interferon responsiveness assessed with 4 week lead-in 3 1. Ghany MG, et al. Hepatology. 2009;49: Zeuzem S, et al. N Engl J Med. 2011;364: Bacon BR, et al. N Engl J Med. 2011;364:

29 PEG IFN/RBV for 4 weeks, followed by boceprevir 800 mg TID + PEG IFN/RBV Boceprevir—RGT in Prior Partial Responders or Relapsers Without Cirrhosis HCV RNA Recommendation TW8TW24 Undetectable Complete 3-medicine regimen at TW36 DetectableUndetectableContinue all 3 medicines through TW36, then administer PEG IFN/RBV through TW48 Abbreviations: RGT, response-guided therapy; TW, treatment week. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

30 Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN  -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy; Bacon BR, et al. N Engl J Med. 2011;364: RESPOND-2—BOC/PR: Relapsers and Partial Responders 95/ / / 80 23/ 57 30/ 58 2/29 72/ / / 51

31 Boceprevir—Treatment-Experienced Non-RGT Regimens Compensated Cirrhosis 4 weeks of P/R followed by 44 weeks of B + P/R Null Responders 4 weeks of P/R followed by 44 weeks of B + P/R Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

32 RESPOND-2—BOC/PR: SVR by Week 4 Lead-In Response to Peginterferon/Ribavirin Change in HCV RNA from Baseline 15/ 46 15/ 44 80/ / / 67 Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN  -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy. With permission from Bacon BR, et al. N Engl J Med. 2011;364:

33 RROVIDE: SVR and Relapse Rates, by Prior Treatment Response 19/4753/78 3/229/62 1/6 5/981/13813/94 SVR was also achieved in all 4 patients with ‘other’ prior non-response.

34 Telaprevir—RGT in Prior Relapsers Telaprevir 750 mg TID, PEG IFN, and RBV starting on day 1 Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; HCV RNARecommendation Undetectable at TW4 and TW12 Administer all 3 drugs through TW12, then administer PEG IFN/RBV through TW24 Detectable (≤1000 IU/mL) at TW4 and/or TW12 Administer all 3 drugs through TW12, then administer PEG IFN/RBV through TW48

35 Recommendation Administer all 3 drugs through TW12, then administer PEG IFN/RBV through TW48 Telaprevir—Non-RGT in Prior Partial or Null Responders Telaprevir 750 mg TID, PEG IFN, and RBV starting on day 1 Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

36 REALIZE: SVR by Baseline Fibrosis Stage and Prior Response Prior relapsers Prior partial responders Prior null responders 2/15 n/N= 53/62144/16712/380/510/1834/473/170/915/3811/321/5 No, minimal or portal fibrosis Cirrhosis Stage Pooled T12/PR48 Pbo/PR48 SVR (%) 2/1548/5724/591/187/501/10 Bridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis Zeuzem S, et al. N Engl J Med 2011;364:

37 SVR by Response at Week 4 in Lead-In Arm of REALIZE: HCV RNA at Week 4 in Nonresponders Decline in HCV RNA at week Foster G et al, EASL 2011 %

38 Treatment-Naive Data and Regimens Treatment-Experienced Data and Regimens Overview Futility Rules Adverse Effects

39 Boceprevir—Futility (Stopping) Rules Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; Week 24 HCV RNA confirmed detectable Week 12 HCV RNA ≥100 IU/mL OR STOP ALL DRUGS

40 Retrospective Analysis of SPRINT-2 Underscores Validity of BOC Futility Rules Jacobson IM, et al. AASLD Abstract 954. Earliest 100% negative predictive time point for SVR which spared largest number of patients from continuing failing regimen was HCV RNA ≥ 100 IU/mL at Week 12 Stopping RuleStopped by TW12 Rule, n Additional stopped by TW24 rule, n Total Stopped, nSVR missed using TW12 rule, n > LLD, 9.3 IU/mL > LLQ, 25 IU/mL ≥ 50 IU/mL ≥ 100 IU/mL ≥ 1000 IU/mL < 2 log decline < 3 log decline

41 Telaprevir—Futility (Stopping) Rules Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; Week 24 HCV RNA confirmed detectable Week 4 and/or Week 12 HCV RNA >1000 IU/mL OR STOP ALL DRUGS

42 Retrospective Analysis of TVR Ph III Trials Underscores Validity of TVR Futility Rules No pt with HCV RNA > 1000 IU/mL at Wk 4 (n = 25) or Wk 12 (n = 12) had SVR Viral kinetic analysis of pts with HCV RNA > 1000 IU/mL at Wk 4 –23 of 25 reached HCV RNA nadir before Wk 4 –In most pts, HCV RNA already increasing from nadir by Wk 4 Emergence of TVR-resistant variants in most pts with HCV RNA > 1000 IU/mL at Wk 4 Jacobson IM, et al. EASL Abstract 55. HCV NS3/4A Variant Level of TVR Resistance Tx-Naive Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 14) Tx-Exp’d Pts With HCV RNA > 1000 IU/mL at Wk 4, n (n = 11) V36M + R155KHigh 12 8 A156S/T/VHigh 1 0 R155KLow 0 2 Wild typeNone 1 1 Tx Experienced (n = 11)Tx Naive (n = 14) Wks on Treatment HCV RNA, IU/mL Wks on Treatment

43 Treatment-Naive Data and Regimens Treatment-Experienced Data and Regimens Overview Futility Rules Adverse Effects

44 Drug Interactions with Telaprevir and Boceprevir BOC and TVR are CYP3A4 inhibitors Drug interactions may affect blood levels of either PI or co-administered drug Caution is needed with ALL co-administered medications –Review package inserts for interaction lists –Reconcile patient medication list –Patient needs to communicate new meds started by other health care providers –Other resource: hcvadvocate.org; hep-druginteractions.org Boceprevir [package insert]. May Telaprevir [package insert]. March Ghany MG, et al. Hepatology. 2011;54: Figure adapted from: Back D. Drug-drug interactions (in relation to HCV). Presented at: 7th International Workshop on HIV & Hepatitis Co-infection; June 1-3, 2011; Milan, Italy. Lecture. Inhibitor blocks the function of the CYP enzyme P450 Inhibitor  AUC Drug + Inhibitor Inducer  AUC

45 Drug-Drug Interaction Resource

46 Boceprevir Triple Therapy— Adverse Effects Adverse Effect Boceprevir + PEG IFN/RBV (n = 1225) PEG IFN/RBV (n = 467) Anemia * 50%30% Neutropenia25%19% Dysgeusia35%16% * Anemia was managed with erythropoiesis-stimulating agents, with or without RBV dose reduction (boceprevir + PEG IFN/RBV, 43%; PEG IFN/RBV, 24%). Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; Pooled Data from Treatment-Naive Population (SPRINT-1, SPRINT-2)

47 Randomized controlled trial: RBV dose reduction Vs. EPO for anemia during BOC + PegIFN/RBV 687 HCV genotype 1, treatment naïve patients enrolled Hb at screening < 15 g/dL for men and women 500 met protocol defined anemia and were randomized: RBV DR, n=249; EPO, n=251

48 End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms Patients, % 205/251203/249 19/196 19/ / /251  (95% CI) –0.7% (– 8.6, 7.2)* CI, confidence interval; DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response. *The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort. Poordad F et al. 47th EASL; Barcelona, Spain; April 18-22, Abst Anemia Management: Erythropoietin vs Ribavirin Dose Reduction - Primary and Key Efficacy End Points

49 Anemia Management: Erythropoietin vs Ribavirin Dose Reduction - SVR by Secondary Anemia Intervention DR, dose reduction; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response. Poordad F et al. 47th EASL; Barcelona, Spain; April 18-22, Abst Patients, % Secondary Anemia Intervention

50 BOC/PR: Exposure-Response Relationships for Anemia % of Pts with Anemia from P05101 and P05216 vs Boceprevir % of Pts with Anemia from P05101 and P05216 vs RBV steady-state AUC Observations were binned as quartiles and plotted at the median quartile value. The total number of subjects with hemoglobin <10 g/dL for each quartile and total number of subjects per quartile bin (in parentheses) are shown along the x-axis. US Food and Drug Administration; April 27, Committee/UCM pdf. Accessed April 26, 2011.

51 Telaprevir Triple Therapy— Adverse Effects Adverse Effect Telaprevir + PEG IFN/RBV (n = 1797) PEG IFN/RBV (n = 493) Rash56%34% Anemia*36%17% Anorectal Effects29%7% *Anemia was managed with RBV dose reduction; ESA not permitted. (Telaprevir + PEG IFN/RBV, 32%; PEG IFN/RBV, 12%). Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; Pooled Data from Treatment-Naive and -Experienced Populations (ADVANCE, ILLUMINATE, REALIZE)

52 Nadir Hemoglobin, Discontinuation for Anemia, and Median Hemoglobin Levels 0 Median Hemoglobin (g/dL) Weeks TVR …. TVR T12PR (n=363) T8PR ( (n=364) PR (control) (n=361) % of Patients with T12PR N=363 T8PR N=364 PR N=361 Hemoglobin <10 g/dL Hemoglobin <8.5 g/dL 992 Per protocol, anemia was to be managed with RBV dose modifications and ESAs were not allowed 1%, 3% and 1% of patients in T12PR, T8PR and PR, respectively discontinued all drugs due to anemia events 4%, 2% and 0% of patients in T12PR, T8PR and PR, respectively discontinued telaprevir/placebo only Hemoglobin nadir during TVR/Pbo PhaseMedian Hemoglobin Jacobson IM, et al.N Engl J Med 2011;364:

53 Telaprevir Treatment-Naïve Studies: RBV dose reduction was common Treatment-naïve Patients From ADVANCE and ILLUMINATE During the Overall Treatment Phase (T12PR, N=885)

54 SVR According to Minimum Ribavirin Dose/Day During Telaprevir Treatment Phase

55 Ribavirin dose reduction: Proportion of Patients who Achieved SVR 0-4 Weeks Post First Dose 160/221 >4-12 Weeks Post First Dose 171/237 >12-24 Weeks Post First Dose 85/99 >24-48 Weeks Post First Dose 36/43 n/N = Sulkowski M et al. 47th EASL; Barcelona, Spain; April 18-22, Abst Treatment Naïve (T12PR) Timing of First Ribavirin Dose Reduction

56 Advisory Committee Briefing Materials for Telaprevir: RBV Effect on Hemoglobin Toxicity Effect of Ribavirin (RBV) Exposure on Hemoglobin Toxicity Hemoglobin toxicity of Grade 2+ (Grade 2+ Hgb Tx) was defined as Hgb 3.5 g/dL. Vertical bars represent rates of Hgb toxicity in each quartile of AUC. The horizontal bar along the AUC axis represents the distribution of AUC 3rd (5%-95%, 1st to 3 rd quartile, mean, median). Advisory Committee Briefing Document for NDA Telaprevir 375 mg tablets. Silver Spring, MD; April 1, AdvisoryCommittee/UCM pdf. Accessed April 26, 2011.

57 Telaprevir—Rash Summary from Pooled Safety Database Rash was primarily eczematous –Mild to moderate in most –Severe rash in 4% –May occur at any time during telaprevir exposure Led to discontinuation of telaprevir in 6% –Serious skin reaction in <1%, including Stevens-Johnson Syndrome or DRESS Treat with oral antihistamines and/or topical corticosteroids –Systemic steroids are not recommended Abbreviation: DRESS, Drug Rash with Eosinophilia and Systemic Symptoms. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

58 Severe Rash on Telaprevir

59 Rash Management Rash descriptionManagement Mild: Localized, limited distribution, with or without pruritus Continue all drugs Monitor for rash progression or development of systemic symptoms TVR dose should not be reduced or interrupted Oral antihistamines and /or topical corticosteroids Systemic corticosteroids not recommended Good skin care practices Moderate: Diffuse (up to 50% BSA) with or without superficial skin peeling, pruritus, or mucous membrane involvement with no ulceration Severe: Generalized rash involving either >50% BSA or any of the following: Vesicles or bullae Superficial ulceration of mucous membranes Epidermal detachment Atypical or typical target lesions Palpable purpura, non-blanching erythema Discontinue TVR; continue Peg-IFN/RBV If no improvement within 7 days (or earlier if indicated), consider discontinuation of Peg-IFN and/or RBV Good skin care practices Refer to dermatologist Oral antihistamines and/or topical corticosteroids Systemic corticosteroids not recommended Serious skin reactions: Toxic epidermal necrolyosis, SJS, DRESS, acute generalized exanthematous pustulosis, rash that requires therapy with systemic corticsteroids, erythema multiforme (not life- threatening) Discontinue all medications immediately Refer for urgent medical care Cacoub P, et al. J Hepatol. 2012;56:

60 Adherence is critical Triple therapy presents challenges [143] –TID dosing –Food requirements Data show pegIFN/RBV adherence decreases over time [5] –Addition of PIs may exacerbate this trend 1. Telaprevir [package insert]. May Boceprevir [package insert]. May EMA. Boceprevir [package insert] EMA. Telaprevir [package insert] Lo Re V 3rd, et al. Ann Intern Med. 2011;155:


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