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Chronic Hepatitis C and Project ECHO State of Affairs Spring 2013

Chronic Hepatitis C and Project ECHO State of Affairs Spring 2013. 68 th Annual Ogden Surgical-Medical Society Conference May 15, 2013 Terry Box, MD. Disclosures. Research funding: Abbott, Boehringer-Ingelheim, Bristol Meyers Squibb, Gilead, Idenix, Merck, Roche, Salix, Sundise

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Chronic Hepatitis C and Project ECHO State of Affairs Spring 2013

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  1. Chronic Hepatitis C and Project ECHOState of Affairs Spring 2013 68th Annual Ogden Surgical-Medical Society Conference May 15, 2013 Terry Box, MD

  2. Disclosures • Research funding: • Abbott, Boehringer-Ingelheim, Bristol Meyers Squibb, Gilead, Idenix, Merck, Roche, Salix, Sundise • Speaker’s Bureau: • Genentech, Merck, Salix, Vertex • Consultant: • Kadmon

  3. Hepatitis C Virus InfectionMagnitude of the Problem • Nearly 4 million persons in United States infected • Approximately 35,000 new cases yearly • 85% of new cases become chronic • Leading cause of • Chronic liver disease • Cirrhosis • Liver cancer • Liver transplantation Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.

  4. Glossary of Terms • Viral Load- quantity of virus present in blood • Measured by assay of HCV RNA by polymerase chain reaction (PCR) • Genotype- different types of HCV virions (think of cousins) identified as 1,2,3,4,5,6 • Subtypes (think of siblings)- 1a,1b,2a,2b,3a,3b • Response to treatment • SVR- Sustained Virologic Response • Relapse and Breakthrough • Nonresponders- partial and null

  5. Hepatitis C VirusGenotypes in the USA Type 2 17% Type 3 10% Type 1 72% All others 1% McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.

  6. Determination of HCV GenotypeINNOLiPA Assay • HCV genotype • Best pretreatment predictor of response • Determines duration of therapy • All patients should have genotype determined prior to initiating therapy Illustration by Mitchell L. Shiffman, MD.

  7. Why Treat Chronic Hepatitis C? • The disease • Common, chronic, and potentially progressive • Complications are becoming more common[1,2] • Liver failure, HCC • The treatment • Viral cure, or SVR, is achievable • SVR associated with histologic improvement and gradual regression of fibrosis[3] • SVR reduces risk for liver failure and HCC, improves survival[4,5] 1. Kanwal F, et al. Gastroenterology. 2011;140:1182-1188. 2. Shaw JJ, et al. Expert Rev Gastroenterol Hepatol. 2011;5:365-370. 3. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 4. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 5. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.

  8. Milestones in Therapy of Genotype 1 HCV Direct-acting antivirals 100 2011 Peginterferon 2001 80 Ribavirin Standard interferon 70+ 1998 60 55 1991 SVR (%) 42 39 40 34 16 20 6 0 PegIFN 12 mos IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN/RBV 12 mos IFN 6 mos PegIFN/RBV/DAA Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.

  9. Primary Goal of HCV Therapy • SVR24: undetectable HCV RNA 6 mos after completion of treatment • Considered clinical cure • Measures of improved outcome • Histologic improvement • Inflammatory and fibrosis scores • Portal pressure reduction • Reduction in clinical complications including HCC • Survival

  10. We Understand the Rules of the Game With IFN-Based Treatment • Establishing patient candidacy • Assessing potential drug–drug interactions • Evaluating likelihood of SVR in treatment-naive and treatment-experienced patients • Applying response-guided treatment algorithms to maximize response and mitigate treatment failure • Optimally managing adverse events

  11. For Genotype 2 or 3, PegIFN/RBV Remains Standard of Care • Highly effective therapy with higher cure rates than genotype 1 • 24 wks of therapy is recommended[1,2] • Some patients (with RVR and low baseline HCV RNA) may be treated for 16 wks if therapy poorly tolerated, although relapse rates may be higher[2] • Future regimens may offer further improvements, such as • Shorter durations • All-oral therapy • Fewer adverse events 1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. EASL. J Hepatol. 2011;55:245-264.

  12. Two Protease Inhibitors Approved for GT1 HCV Infection Combined With PR 1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [US package insert]. October 2012.

  13. Addition of BOC or TVR to PegIFN/RBV Improves SVR in Genotype 1 Patients • BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV patients who are previously untreated or who have failed previous therapy 100 PegIFN + RBV 69-83 BOC/TVR + pegIFN* + RBV 80 63-75 40-59 60 SVR (%) 38-44 29-40 40 24-29 20 7-15 5 0 Treatment Naive[1,2] Relapsers[3,4] Partial Responders[3,4] NullResponders[4,5] *BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials. 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 5. Bronowicki JP, et al. EASL 2012. Abstract 11.

  14. Response Guided Therapy

  15. Patients Responding Early Can Achieve High SVR Rates With Shortened Therapy • Response-guided therapy:patients who achieve optimal virologic response at early time points can receive abbreviated therapy without reducing their chance of SVR • Patients eligible for RGT • Boceprevir: noncirrhotic treatment-naive patients, previous relapsers, and previous partial responders[1,2] • RGT criterion: must achieve undetectable HCV RNA at Wk 8 (ie, Wk 4 of triple therapy) and maintain it at Wk 24 • Telaprevir: noncirrhotic treatment-naive patients and previous relapsers*[2,3] • RGT criterion: must achieve undetectable HCV RNA at Wk 4 of triple therapy and maintain it at Wk 12 • Pts with cirrhosis are not eligible for RGT and should have 48 weeks of therapy *AASLD guidelines state that RGT may be considered with TVR in previous partial responders. 1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [US package insert]. October 2012.

  16. RGT Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients • Indicated for all noncirrhotic treatment-naive patients HCV RNA UndetectableUndetectable < 100 IU/mL PegIFN/RBV BOC + PegIFN/RBV Earlyresponse stop at Wk 28; f/u 24 wks 0 4 8 12 24 28 36 48 HCV RNA Detectable Undetectable < 100 IU/mL Slow response extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks PegIFN/RBV BOC + PegIFN/RBV PegIFN/RBV 0 4 8 12 24 28 36 48 Boceprevir [US package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Boceprevir [EU package insert]. July 2012.

  17. RGT With TVR + PegIFN/RBV in Tx-Naive Patients and Previous Relapsers • Indicated for all noncirrhotic treatment-naive pts and previous relapsers*[1,3] HCV RNA Undetectable Undetectable Undetectable TVR + PegIFN/RBV PegIFN/RBV eRVRstop at Wk 24, f/u 24 wks 0 4 12 24 48 HCV RNA Undetectable or detectable (≤ 1000 IU/mL) Detectable (≤ 1000 IU/mL) Undetectable No eRVR extend pegIFN/ RBV to Wk 48; f/u 24 wks TVR + PegIFN/RBV PegIFN/RBV 0 4 12 24 48 *AASLD guidelines say RGT “may be considered” for previous partial responders[2] but package inserts recommend 48 wks of therapy.[1,3] 1. Telaprevir [US package insert]. October 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [EU package insert]. March 2012.

  18. Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive and Tx-Exp’d Pts • All therapy should be discontinued in patients with the following: *Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL. 1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [US package insert]. October 2012.

  19. Adverse Effects

  20. BOC Plus PegIFN alfa-2b/RBV: Adverse Events • Higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs control *Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR). Boceprevir [US package insert]. July 2012.

  21. TVR Plus PegIFN alfa-2a/RBV: Adverse Events • Higher rates of rash, anemia, and anorectal signs and symptoms in TVR arms vs control *Pooled results from TVR arms. †Anemia was managed with RBV dose modification; epoetin alfa was not permitted. • In most subjects, rash was mild to moderate • Severe rash in 4%; discontinuation due to rash in 6% of subjects Telaprevir [US package insert]. October 2012.

  22. Higher Discontinuation Rates in Real-World Settings Than in Clinical Trials 40 30 174 GT1 Patients StartedTVR-Based Triple Therapy[2] 498 GT1 Patients Evaluated[1] 21 50 20 40 33[2] 10 30 21 Patients (%) 22 0 18 17 20 D/CBeforeWk 12 11 10 • 91/ • 498 69/ 407 89/ 407 43/ 407 58/ 174 36/ 174 n/N = 0 D/C TVR < 12 wks Due to AEs Started Therapy PatientChoice MildDisease Wait forBetterTherapies Did Not Start 1. Chen EY, et al. AASLD 2012. Abstract 133. 2. Bichoupan K, et al. AASLD 2012. Abstract 1755.

  23. Both BOC and TVR Have Potential for Many Drug–Drug Interactions • BOC • Strong inhibitor of CYP3A4/5 • Partly metabolized by CYP3A4/5 • Potential inhibitor of and substrate for P-gp • Most drug–drug interactions can be overcome by careful survey of the patient’s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy) • TVR • Substrate of CYP3A • Inhibitor of CYP3A • Substrate and inhibitor of P-gp

  24. Medicines That Are Contraindicated With BOC and TVR *Studies of drug–drug interactions incomplete. 1. Boceprevir [package insert]. July 2012. 2. Telaprevir [package insert]. October 2012.

  25. Cirrhotic Patients

  26. CUPIC: Interim Analysis of TVR and BOC Use in Cirrhotic Early Access Program • Interim results of 455 patients presented at 16-20 wks • Encouraging virologic responses with triple therapy • ~ 80% treated with TVR-based therapy had undetectable HCV RNA at end of 16 wks of ongoing therapy • ~ 65% treated with BOC-based therapy had undetectable HCV RNA at Wk 16 of ongoing therapy • High rate of serious adverse events • TVR: 48.6%; BOC: 38.4% • High rate of anemia • ~ 30% with grade 2 or higher with either drug • High rate of premature discontinuation • ~ 25% with either regimen Hezode C, et al. AASLD 2012. Abstract 51.

  27. Preliminary Real-World Safety Findings: CUPIC—PIs in Patients With Cirrhosis *Causes of death in patients treated with TVR: septicemia, septic shock, pneumopathy, esophageal varices bleeding, endocarditis; causes of death in patients treated with BOC: pneumopathy. Hezode C, et al. EASL 2012. Abstract 8.

  28. Summary • BOC- or TVR-based triple therapy increases SVR rates over pegIFN/RBV alone for all genotype 1 patient populations that have been evaluated • On-treatment management techniques including application of RGT algorithms and effective management of adverse events maximize treatment outcomes and mitigate treatment failure • In spite of significant progress using BOC- or TVR-based triple therapy there are several challenging impediments to universal application for HCV patients

  29. Regimens—Many Challenges For us—lead-in, response-guided therapy . . . For our patients . . . Pill Burden Food Requirement BOC = 12/day RBV = 4-7/day TVR = 6/day RBV = 4-7/day

  30. Challenges of Current PI-Based Therapy • Efficacy • Very dependent on the IFN response • Tolerability • Additional AEs beyond pegIFN/RBV • Regimens • Complicated (lead-in, RGT)/pill burden • DDIs • Many with both agents to common drugs • Genotype/special populations • Limited activity in non-GT1, limited data HIV/OLTx, ESRD

  31. Future of HCV Therapy

  32. Dosing and Regimens: Current Challenges and Future Solutions Challenge Investigational Strategies Dosing burden: 6-12 pills/day (TID dosing) with PIs + 4-7 pills/day RBV, food requirements QD, BID dosing;elimination of RBV;fixed-dose combinations; no food requirements RGT, lead-in,variable regimen based on treatment experience,up to 48 wks No RGT;no pegIFN/RBV lead-in; shorter regimens Different therapies based on HCV genotype DAA-based regimens effective across genotypes IFN containing; poor tolerability IFN sparing, alternative IFNs; agents with fewer adverse events

  33. What Are the Key Elements of an Ideal HCV Regimen? Easy Dosing Once daily, low pill burden Highly Effective High efficacy in traditionally challenging populations (ie, poor IFN sensitivity, cirrhosis) All Oral PegIFN/RBV replaced with alternate backbone with low chance of resistance Simple Regimen Short duration, simple, straightforward stopping rules Pan-Genotypic Regimen can be used across all genotypes Safe and Tolerable Few or easily manageable adverse effects

  34. HCV Life Cycle and DAA Targets Receptor bindingand endocytosis Transportand release Fusion and uncoating Translation andpolyprotein processing ER lumen Virionassembly (+) RNA LD LD LD Membranousweb RNA replication NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside ER lumen NS5A* inhibitors *Block replication complex formation, assembly Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  35. Investigational Agents for HCV Interferons Antiviral agents Therapeuticvaccines Hosttarget Cyclophilin miRNA-122 Cyp inhibitors Entry Replication, polyprotein processing and/or assembly NS5Bpolymerase inhibitors NS3protease inhibitors NS5Areplication complex inhibitors

  36. Comparison of DAA Profiles Good profile Average profile Least favorable profile Adapted from: Farnik H, et al. Antivir Ther. 2012;17:771-783.

  37. Investigational HCV Regimensin Phase III Clinical Trials Regimens With 1 DAA + PegIFN alfa/RBV Regimens With 2 DAAs + PegIFN alfa/RBV IFN-Free Regimens • Sofosbuvir + RBV • Sofosbuvir + GS-5885 (NS5A) (FDC) ± RBV • Asunaprevir (PI) + daclatasvir • ABT-450 (PI)/RTV/ABT-267 (NS5A) (FDC) + ABT-333 (NNI) + RBV • Faldaprevir (PI) + BI 207127 (NNI) + RBV • Daclatasvir + asunaprevir • Faldaprevir (BI 201335, PI) • Daclatasvir (BMS-790052, NS5A) • Sofosbuvir (GS-7977, NI) • Simeprevir (TMC-435, PI) • Alisporivir (CYP) • Vaniprevir (MK-7009, PI) New IFNs On Hold • PegIFN lambda-1a + RBV • PegIFN lambda-1a + daclatasvir + RBV • PegIFN lambda-1a + RBV + TVR Alternative Dosing • TVR BID (approved PI) ClinicalTrials.gov. November 27, 2012.

  38. Daclatasvir Plus Sofosbuvir ± RBV in Treatment-Naive GT1 or 2/3 Patients • No impact of RBV on viral response SVR24, % GT1 93 100 100 GT2/3 88 100 93 Wk 1 Wk 24 Sofosbuvir Daclatasvir + Sofosbuvir Treatment-naive, noncirrhotic patients Daclatasvir + Sofosbuvir GT1a or 1b (n = 44) GT2 or 3 (n = 44) Daclatasvir + Sofosbuvir + RBV Sobosbuvir dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 patients (1000-1200 mg/day); 800 mg/day for GT2/3 patients. Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

  39. Treat Now vs Wait: Many Issues to Consider Treat now • Triple therapy increases SVR • Earlier treatment has higher success rates • Successful treatment may arrest progression of liver disease • Uncertainty about timelines for approval and reimbursement Defer • First-generation PIs complex, associated with adverse events • Does current treatment failure affect future treatment? • Potential for higher SVR, including in challenging populations • Potential for simpler regimens, QD or BID, fewer adverse effects, eventually IFN-free • Activity in non–genotype 1

  40. Advantages of Future Therapies • Once-daily dosing • Shorter duration • Simpler regimens—no RGT • Fewer AEs • IFN free • High efficacy

  41. Caveats to Future Therapies • Very small studies • Potential for toxicity remains • Agents from multiple classes (nucs, nonnucs, PI, alisporivir) pulled for toxicity • Efficacy and safety in cirrhosis largely unknown • Minimal data—DDIs, special populations (OLTx, HIV, ESRD) • Timelines uncertain • Not just approval, but availability and reimbursement • Costs uncertain, but likely an issue in many regions

  42. If this stuff is so good, where are all the patients hiding? Hiding in plain sight

  43. Hepatitis C Virus (HCV) Infection HCV is approximately 4 times as prevalent as HIV and HBV in the United States A 2011 study estimated that as many as 5.2 million persons are living with HCV in the United States2 2.7 to 3.9 Million175% Unaware of Infection Undiagnosed Diagnosed 4 Total No. Infected (millions) ~800,000 to 1.4 Million165% Unaware of Infection 1.1 Million121% Unaware of Infection 3 2 HIV HBV HCV 1 0 HCV=hepatitis C virus; HIV=human immunodeficiency virus; HBV=hepatitis B virus. 1. Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC: The National Academies Press; 2010; 2. Chak E, et al. Liver Int. 2011;31(8):1090-101.

  44. You Are the First Line for HCV Screening x 2000patients (average patient load for PCP2) 2% (US prevalence of HCV1) Average PCP has 40 patients with HCVin his/her practice2* One in 30 baby boomers in the US has HCV (3.25%); however certain areas have a higher prevalence of the disease.3,4 • *Across the country HCV prevalence differs by region, state, and locality.ALT=alanine aminotransferase; HCV=hepatitis C virus; PCP=primary care provider; OR=odds ratio.1. Chak E, et al. Liver Int. 2011;31(8):1090-101; 2. Ferrante JM, et al. Fam Med. 2008;40(5):345-351; 3. Smith BD, et al. Abstract #394. Presented at: American Association for the Study of Liver Disease 2011 Annual Meeting; San Francisco, CA; November 5, 2011; 4. Institute of Medicine. Washington, DC: The National Academies Press; 2010.

  45. Chronic HCV Infection May Result in Liver Cirrhosis, HCC, and Liver-Related Death Liver transplant HCV is the #1 cause of liver transplant in the United States1 Up to 45% of patients awaiting liver transplant have HCV2 Liver cancer HCV is the leading cause of HCC1 Death 4% annual death rate postcirrhosis3 CDC has identified the number of deaths from HCV now exceed those from HIV4 Fibrosis Cirrhosis Hepatocellular Carcinoma (with cirrhosis) The rate of progression of liver fibrosis accelerates as fibrosis advances and can vary from patient to patient5,6 HCV = hepatitis C virus; HCC = hepatocellular carcinoma. 1. Rustgi VK. J Gastroenterol. 2007;42(7):513-21; 2. Gringeri E, et al. Transplant Proc. 2007;39(6):1901-1903; 3. Sangiovanni A, et al. Hepatology. 2006;43(6):1303-10. 4. The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 243. Presented November 8, 2011. 5. Thein HH, Yi Q, Dore GJ, et al. Hepatology. 2008;48(2):418-31. 6. Missiha SB, et al. Gastroenterology. 2008;134(6):1699–714.

  46. Although the Peak of Infections Occurred Decades Ago, Complications From HCV Will Continue to Increase as Chronic HCV Progresses 25% of patients with HCV currently have cirrhosis 1,200,000 1,000,000 800,000 Number of Patients 37% of patients with HCV are projected to develop cirrhosis by 2020, peaking at 1 million 600,000 400,000 200,000 Year 0 1990 2000 2010 2020 2030 An estimated 33% of undiagnosed baby boomers with HCV currently have advanced fibrosis (F3-F4, bridging fibrosis to cirrhosis)1 Adapted from Davis GL, et al. Gastroenterology 2010;138:513-21. 1. McGarry LJ. Hepatology. 2012;55(5):1344-55.

  47. Decrease in Life Expectancy With Chronic HCV Is Similar to the Decrease Due to Smoking 8 to 12 year reduction1 13 to 14 year reduction2 90 80 70 Life Expectancy (Years) 60 50 40 0 Average3 HCV Smoking HCV=hepatitis C virus. 1. Ryder SD. J Hepatol. 2007;47(1):4-6; 2. Centers for Disease Control and Prevention. MMWR. 2002;51:300-303; 3. Centers for Disease Control and Prevention. NVSS. 2010;58(19):1-135.

  48. Studies Have Shown a Decreased Rate of Liver Complications in Patients Who Achieved SVR With Peg-IFN/RBV* The HALT-C Trial was a multicenter study of 1145 subjects with advanced chronic HCV who were nonresponders to previous IFN-based treatment The trial found that achieving SVR with Peg-IFN/RBV therapy significantly reduced HCV-associated complications and mortality 20 18 Rates of Liver-Related Complications (%) Patients With SVR (n=140) Nonresponders (n=309) 16 13.9% 14 12 11.0% 9.1% Rates (%) 10 6.8% 8 6 4 1.4% 1.4% 0.7% 0.7% 2 DecompensatedLiver Disease† LiverTransplantation HCC Liver-RelatedDeath 0 *With pegylated interferon alfa and ribavirin; †Decompensated liver disease included variceal hemorrhage, ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. HALT-C = Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; IFN = interferon; Peg-IFN = pegylated interferon; RBV = ribavirin; SVR = sustained virologic response. Morgan TR, et al. Hepatology. 2010;52(3):833-44.

  49. CDC Guidelines for Screening Baby Boomers The Centers for Disease Control and Prevention (CDC) has created draft guidelines recommending a one-time anti-HCV antibody test for all baby boomers (those born from 1945 through 1965) in an effort to identify these undiagnosed individuals .

  50. Baby Boomers (Those Born From 1945 Through 1965) Account for 82% of HCV Cases in the United States1 Estimated Prevalence by Age Group2 1.6 Number With Chronic HCV Infection (millions) 1.4 1.2 1.0 0.8 0.6 0.4 <1920 1920s 1930s 1940s 1950s 1960s 1970s 1980s 1990+ 0.2 Birth Year Group 0 • Smith BD, et al. Hepatology. 2011; 54(4):554A. • Adapted from Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a baby boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; May 18, 2009. http://www.milliman.com/expertise/healthcare/publications/rr/consequences-hepatitis-c-virus-RR05-15-09.php Milliman report was commissioned by Vertex Pharmaceuticals.

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