National Association of Specialty Pharmacy

PRACTICE PARAMETERSPhase I Development

CALL FOR COMMENTSCOMMENTS DUE BY APRIL 14, 2014

Marina Kawaguchi-Suzuki, PharmD, BCPSClinical PharmacistUniversity of Florida

Vanthida Huang, PharmD, BSPHM, FCCPAssociate ProfessorMercer University College of Pharmacy

Hepatitis C

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National Association of Specialty Pharmacy (NASP) Practice Parameter Guidelines and Technical Standards define principles and technical parameters of specific specialty pharmacy clinical areas, which should generally produce desired health care outcomes. They describe a range of acceptable approaches for the diagnosis and/or treatment of disease for most patients in most circumstances. Given differences in training, experience, and local conditions, the NASP Practice Parameter Guidelines and Technical Standards acknowledge the need for health care providers to exercise their independent medical judgment in making decisions regarding the use and specific details of any procedure.

NASP Practice Parameter Guidelines and Technical Standards are educational tools designed to provide consensus-based scientifically valid and medically credible information to assist health care providers in delivering effective, efficient, consistent and safe medical care. They may be developed jointly with other professional organizations. It is expected that the NASP Practice Parameter Guidelines and Technical Standards will increase the likelihood that appropriate procedures will be performed in a safe and acceptable manner and will help reduce complications.

NASP Practice Parameter Guidelines and Technical Standards are intended to be Practicicing Standards that are regularly reviewed and revised to reflect changes in clinical practice parameter.

PRACTICE PARAMETER GUIDELINES describe recommended conduct in specific areas of clinical practice parameter. They are based on analysis of current literature, expert opinion, open forum commentary, and informal consensus. Guidelines are not intended to be legal standards of care or conduct and may be modified as determined by individual circumstances and available resources.

TECHNICAL STANDARDS describe technical parameters that are quantitative or measurable. They often include specific recommendations for patient management or equipment specifications or settings. Technical Standards are based on analysis of current literature, expert opinion, open forum commentary, and informal consensus. Technical Standards are intended to set a minimum level of acceptable technical parameters and equipment performance and may be modified as determined by individual circumstances and available resources.

Practice Parameter Guidelines & Technical StandardsPurpose & Intended Use

THISWAYIN »

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Below is a brief summary of instructions for the review process.

As you review, remember the goal of the project: » NASP has launched a project to develop practice parameters, specific to specialty

pharmacy, in a variety of therapeutic categories. » Each therapy area will have a different set of practice parameters, metrics, workflow,

reimbursement, reporting requirements. » Verify that the information is correct, current and accurate. » Identify missing topics. » Provide general feedback on the practice parameter including, but not limited to:

current treatment options, data points, guidelines, and any information related to best practices » In order to submit your review comments, please follow the link listed below.

PLEASE SUBMIT YOUR REVIEW COMMENTS BY ACCESSING THE FOLLOWING LINK

http://www2.nasprx.org/contact/practice-parameters/

Review Instructions

The Deadline to Submit your comments is April 14, 2014

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Marina Kawaguchi-Suzuki, PharmD, BCPSClinical PharmacistUniversity of Florida

Vanthida Huang, PharmD, BSPHM, FCCPAssociate ProfessorMercer University College of Pharmacy

NASP STAFF LIAISONS

CONTRIBUTING AUTHORS

ADVISORY COMMITTEE

Acknowledgements

Janique RiceDirector of EducationSpecialty Pharma Education Center

Cynthia AllenPresidentSeaCrest

Karim BandealyEducation CoordinatorSpecialty Pharma Education Center

Jeffrey Richard Gonneville, PharmDClinical PharmacistPharmaHealth Specialty Pharmacy

Andria Hornaday, PharmDClinical Pharmacy SpecialistEvolent Health

Courtney Kelly, PharmDDirector of Clinical PharmacyPharmaHealth Pharmacy

Laura J Walters, RPhSpecialty Pharmacy ManagerCareSource

Kendric Ware, PharmD, MBAAssistant Professor of Pharmacy PracticeSouth University

Gary Cohen, BSPharm, RPh, CSPCEONational Association of Specialty Pharmacy

Jim Smeeding, BSPharm, RPh, MBAExecutive DirectorNational Association of Specialty Pharmacy

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Practice ParameterDevelopment GuidelinesPROJECT OVERVIEW

One of the National Association of Specialty Pharmacy’s (NASP) primary goals is to improve patient outcomes. In support of this goal, NASP has launched a project to develop practice parameters, specific to specialty pharmacy, in a variety of therapeutic categories. The Practice Parameters Project is built on a foundation of collaboration among key opinion leaders, subject matter experts and industry stakeholders. NASP will engage specialty pharmacists, specialty pharmacy executives, payers, reimbursement consultants, disease-specific research organizations and patient advocacy groups to develop standards of practice for pharmacists in the targeted therapeutic areas. The foundation of the project is built on partnerships with other organizations to gain acceptance from key stakeholders. Each therapy area will have a different set of practice parameters, metrics, workflow, reimbursement, reporting requirements.

AREAS OF INTEREST

Phas

e I

Hepatitis C

Phas

e II

Crohn’s Disease Human Growth Hormone Oncology: Colorectal Cancer

Human Immunodeficiency Virus (HIV) Cystic Fibrosis Immune Deficiencies Oncology: Lung Cancer

Oncology: Breast Cancer Diabetes Infectious Disease Oncology: Multiple Myeloma

Oncology: Non-Hodgkin Lymphoma Gout Infertility Pulmonary Arterial Hypertension

Rheumatoid Arthritis Hemophilia Multiple Sclerosis

THREE-PART PRACTICE PARAMETER DEVELOPMENT

Part IWhite Paper Guidelines & Best Practices(recommendations for the diagnosis, management & treatment of the therapeutic category)

The white paper covers:

1. Current climate (disease rates diagnosis, management and fatalities, treatment costs and reimburse rates)2. Diagnosis best practices3. Assessment of disease activity4. Pharmacotherapy5. Goal of therapy

» Early therapy rationale and implications » Aggressive therapy

6. Therapy evaluation of top agents » Evaluation of upcoming pipeline

7. Summary and conclusion

Part IIDevelop patient decision pathway

The pathway includes decision-making factors in the following areas:

1. Quality of life/symptom control2. Disease progression3. Efficacy4. Joint damage (if applicable)5. Drug cost6. Safety7. Disease activity score8. X-ray imaging (if applicable)9. Health assessment questionnaire (if applicable)

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Part IIIAppendix of data points

Develop three sets of data points. The data points are metrics we collect and put into an algorithm to measure:

1. Clinical outcomes-goal measure patient longitudinally » Markers based on PP guidelines for management and follow up

» Identify » Provide range and scoring (algorithm) info

2. Economic Improvement » Site of care transition opportunities-medical benefit to Rx benefit » Prevention of hospital admission » Number of office visits

3. Humanistic improvement/ quality of life

DEVELOPMENT TIMELINE

The proposed timeline for the project is outlined below.

Milestone Timeline/Due By Responsibility

Draft #1 due from faculty• White paper• Decision pathway• Registry data points

January 31, 2014 Faculty

Review Draft #1 February 1-14, 2014 Advisory Group

Revise Draft #1 February 14-28, 2014 Faculty

Draft #2 due from faculty• White paper• Decision pathway• Registry data points

February 28, 2014 Faculty

Review Draft #2 March 1-15, 2014 Advisory Group

Final Draft• White paper• Decision pathway• Registry data points

March 16-24, 2014 Faculty

Publish Practice Parameters for public comment April 2014 NASP

Incorporate public comments / revisions April 14-25, 2014 Faculty

Publish May 1, 2014 NASP

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Practice Parameter Review & Approval GuidelinesOVERVIEW OF THE REVIEW AND APPROVAL PROCESS

NASP Advisory Groups are primarily responsible for reviewing the Practice Parameter Guidelines and Technical Standards and presenting a final draft for public comment and approval.

NASP included two reviews in the development schedule. After each review, NASP works with faculty members and compiles the comments into a revised draft that will be sent back to the faculty member responsible for the draft. The faculty member will be tasked with developing the next draft of the guidelines and reconciling any questions and/or concerns.

The finalized draft will be presented for public comment. NASP will accept comments from all stakeholders during the public comment period. All comments must be submitted electronically to ensure clarity and lessen the task of the Advisory Group. After the public comment period has closed, NASP will compile the comments and submit them to the Advisory Group and faculty for discussion and review. After resolving any questions/comments, NASP will publish the final, approved document.

NASP Staff will assist in scheduling the conference calls/virtual meetings to review the documents.

Following the call, all notes and additional drafts will be collated by NASP staff, who will prepare and format the next draft. The revised draft is circulated to the advisory group committee to verify that all the comments have been captured and accurately represent the decisions of the advisory group committee. If changes are required, the Chair will work with the advisory group committee and NASP staff to incorporate the revisions either by email or in rare cases, another call may be required.

Hepatitis CHepatitis C

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List of Abbreviations

AASLD American Association for the Study of Liver Disease

ALT Alanine transaminase

BCRP Breast cancer resistance protein

CDC Centers for Disease Control and Prevention

CYP Cytochrome P450

DAA Direct-acting antiviral

FDA Food and Drug Administration

HCV Hepatitis C virus

IDSA Infectious Disease Society of America

IU International units

NS Nonstructural protein

OATP Organic anion-transporting polypeptide

pegIFN Peginterferon alfa-2a or -2b

P-gp P-glycoprotein

RBV Ribavirin

RNA Ribonucleic acid

SVR Sustained virological response

U.S. United States

CURRENT CLIMATE

Approximately 160 million people, corresponding to 2.35% of the world’s population, are estimated to be chronically infected with hepatitis C virus (HCV).1 In 2007, only 849 cases of confirmed acute hepatitis C were reported in the United States (U.S.) due to asymptomatic infection and underreporting, and the Centers for Disease Control and Prevention (CDC) estimated that approximately 17,000 new HCV infections occurred that year.2 Approximately 75-85% of cases become chronic HCV infection.3 According to the current estimation, HCV chronically infects 3.2 million individuals in the U.S. with the infection most prevalent among “baby boomers” (those born between 1945-1965).2 In addition to the high prevalence, HCV has significant health burden to the society. Hepatitis C virus infection remains one of the most common blood-borne infections and is the leading cause of death from liver disease, being responsible for 8,000 to 10,000 deaths each year in the U.S.3,4 The HCV infection is also the primary indication for liver transplantation.4 The long-term

consequences of HCV infection include cirrhosis and hepatocellular carcinoma.5

Although an effective vaccine against HCV is currently unavailable, the use of pharmacological therapy has been the standard of practice for the treatment of HCV infection. The dual therapy of peginterferon alfa-2a or -2b (pegIFN) and ribavirin (RBV) has been used for the past decade, but a recent novel class of medication called direct acting antivirals (DAAs) have been approved. Boceprevir and telaprevir are first-generation DAAs approved by the U.S. Food and Drug Administration (FDA) in 2011, with the approval in 2013 of simeprevir and sofosbuvir as second-generation DAAs.6-8 The efficacy of HCV treatment has improved over time, and the uniqueness of each medication are discussed in details under pharmacotherapy section. Current concern is escalating financial cost with the approvals of DAAs.6 With the rising cost of the treatment, personalized medicine approach has been advocated particularly in this field to select most appropriate therapy. Factors which need to be considered are, but not limited to, host and HCV genotypes, chance of achieving viral eradication, likelihood of adverse drug reactions, potential drug interactions, early clinical response, and patient’s comorbidities.9,10 When healthcare providers treat patients infected with HCV, it is important to consider whether patients should be treated immediately or not, which DAA is most appropriate and preferable, and what duration the patient needs to be treated.

DIAGNOSIS BEST PRACTICES

Screening

Recently, the CDC recommended a one-time screening against HCV among persons born between 1945 and 1965.11 In addition to this population, clinical guidelines from the American Association for the Study of Liver Disease (AASLD) recommend screening the following individuals:12,13

» Persons who have ever injected illicit drugs or used intranasal illicit drugs » Persons infected with human

immunodeficiency virus (HIV) » Persons with hemophilia who received

clotting factor concentrates prior to 1987 » Persons who have ever been on

hemodialysis

» Persons with unexplained chronic liver disease and chronic hepatitis including elevated alanine transaminase (ALT) levels » Recipients of transfusions or organ

transplants prior to July 1992 » Recipients of transfusions or organ

transplants who were notified that the donor later tested positive for HCV infection » Recipients of transfusions or organ

transplants who were incarcerated » Children born to HCV-positive

mothers » Healthcare, emergency medical, and

public safety workers after needle stick injury or mucosal exposure to HCV-positive blood » Current sexual partners of HCV-

infected persons » Persons who received a tattoo in an

unregulated setting

Periodic testing is recommended in persons with ongoing risk factors for exposure to HCV, and annual testing is recommended in the following individuals:13

» Persons who inject illicit drugs » HIV-seropositive men who have

unprotected sex with men

Diagnosis

Diagnosis is made based on the presence of HCV ribonucleic acid (RNA) detected by a sensitive molecular method defined as the lower limit of detection being <15 international units (IU)/mL.5 Anti-HCV antibodies can be detected by enzyme immunoassay and is the first line diagnostic test.5 However, the test for anti-HCV antibodies may not be reliable in early acute HCV infection and in profoundly immunosuppressed patients, and HCV RNA testing should be incorporated in the initial evaluation in these situations.5 If an individual has suspected reinfection after previous spontaneous or treatment-related viral clearance, anti-HCV testing is expected to be positive, so initial testing should be performed with HCV RNA.13 When anti-HCV antibodies are positive, HCV RNA testing should be performed.5

The diagnosis of acute HCV infection can be most likely confirmed when seroconversion to anti-HCV antibodies is documented.5 Approximately 50% of patients already presents as anti-HCV positive at diagnosis, and if this is the case, acute

Practice Guidelines

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phase is suspected based on the following clinical signs and symptoms: alanine aminotransferase (ALT) >10 x the upper limit of normal and/or jaundice without a history of chronic liver disease or other causes of acute hepatitis.5 The diagnosis of chronic HCV is made based on the presence of both HCV antibodies and HCV RNA with elevated aminotransferases or with histology.5

Hepatitis C virus

Hepatitis C virus is a 9.6-kb positive-strand RNA virus encoding a polyprotein cleaved to 10 polypeptides.11,14 The HCV’s structural proteins consist of two envelope glycoproteins, the core protein, and nonstructural proteins (NS) include NS2, NS3, NS4A, NS5A, and NS5B.11 The recently approved telaprevir, boceprevir, and simeprevir are NS3/4A serine protease inhibitors whereas sofosbuvir targets NS5B polymerase.6

The HCV has been classified to seven genotypes (1 to 7) based on ~70% sequence homology, and to a number of subtypes (a, b, and more) based on ~80% sequence homology.14 In the Americas, Europe, and Japan, genotype 1 has been dominating, followed by genotypes 2 and 3.14 In South and Southeast Asia, genotypes 3 and 6 are most common while genotypes 4 and 5 are most prevalent in Africa.14 Recently discovered genotype 7 has not presented major clinical importance thus far.14 The HCV genotype is one of the most important diagnostic factors that need to be identified. The viral genotype is crucial in determining the treatment and the duration of therapy. Emerging data show that subtype 1a may be less susceptible than subtype 1b to some DAA drug combinations, therefore determination of the HCV subtypes may be desirable when selecting an appropriate DAA therapy.5

ASSESSMENT OF DISEASE ACTIVITY

It is recommended to assess liver disease severity prior to therapy, and especially identification of patients with cirrhosis is pertinent.5 Significant fibrosis of the liver may be present even with repeatedly normal ALT; therefore, evaluation of disease severity needs to be performed regardless of ALT levels.5 Liver biopsy remains the standard method of determination.5,12 However, the stages of fibrosis may be assessed initially by a more non-invasive method, such as liver stiffness measurement with the liver biopsy being reserved for cases where uncertainty or potential additional etiologies exist.5 Hepatitis C virus quantification or titer is also

indicated prior to antiviral treatment, and the measurement should be made by a sensitive assay with the lower limit of detection of <15 IU/mL.5

PHARMACOTHERAPY

The standard of treatment for patient with chronic hepatitis C infection has been dual therapy consisting of pegIFN plus RBV (pegIFN/RBV) in all genotypes.5,11,15 The ultimate goal of HCV treatment is the attainment of a sustained virologic response (SVR).4,16 This regimen achieved SVR of 40-50% among patients with HCV genotype 1 whereas patients with HCV genotype 2 or 3 achieved SVR of 70-80%.11,12,17-19 Duration of treatment with dual therapy had been 48 weeks and possibly up to 72 weeks in genotype 1 with genotypes 2 and 3 having a duration of 24 or 48 weeks (coinfected with HIV or delayed viral kinetics).16-18,20 Pharmacologic therapy for the treatment of HCV genotype 1 infection has changed since 2011 with the advent of DAAs.4 This led to triple therapy where a DAA, boceprevir or telaprevir, was added to the combination of pegIFN/RBV.4,5 The major advantage of triple therapy was the drastically improved SVR rates, which increased to about 70% in treatment-naïve patients with HCV genotype 1.4,5,21 The duration of treatment with the triple therapy was possibly reduced to 24 weeks from 48 weeks with the use of response-guided therapy.4,5,22 Furthermore, in January 2014, the AASLD and the Infectious Diseases Society of America (IDSA) published updated recommendations online to include simeprevir and sofosbuvir as a standard of treatment.13 The major change is to include sofosbuvir in the regimen as the first-line therapy due to the superior efficacy demonstrated in clinical trials.13 The SVR rates reached approximately 90% with sofosbuvir regimen in the hard-to-treat HCV genotype 1 infection.23,24 Other advantages include a simpler regimen (i.e. once-daily dosing for the second generation DAAs) and shorter durations of therapy.13,25,26 However, the treatment cost has significantly increased with the approvals of DAAs, and it should be noted that resistance is a future concern with the advent of DAAs.27-

29 The updated AASLD/IDSA guidelines also include recommendations for unique patient populations: patients coinfected with HIV/HCV, patients with cirrhosis, post-transplantation patients, and patients with impaired renal function.13 There is an additional guidance available for those special populations as well as pregnant women and the pediatric population.30-34 Treatment-naïve patients with compensated cirrhosis, with or without hepatocellular

carcinoma, can be treated in the same way as patients without cirrhosis.13 Treatment should be provided to patients with decompensated cirrhosis only by highly experienced HCV providers using the recommended therapy of sofosbuvir and RBV for up to 48 weeks.13 The patient’s creatinine clearance and hemoglobin level need to be evaluated and closely monitored.13

The recommended treatment algorithms based on the AASLD/IDSA guidelines are outlined in Part II. Table 1 summarizes the advantages and disadvantages of currently available therapies.

GOAL OF THERAPY

The primary goal in the treatment of HCV is the attainment of SVR.5 Therefore, patients can avoid developing complications and mortality.11 The endpoint of HCV therapy is determined by virologic parameters.4,5,12

Early therapy rationale and implications

Various factors, including current SVR rates, likelihood of adverse drug reactions, and availability of future treatments, need to be considered when deciding whether patients should be initiated on treatment or not. Initiating therapy including pegIFN/RBV combination has many adverse events, which can cause many patients to defer treatment. In addition, SVR is not achieved in all treated patients and will depend on many factors including HCV genotype, IFNL3 (previously called IL28B) genotype, chosen treatment, and other clinical factors.9,11 Considering the currently available treatment and the numbers of agents under development, waiting for new therapy can be an option, especially for patients infected with HCV non-genotype 1 who did not respond to prior therapy.11 However, initiation of treatment is generally recommended for patients with HCV genotype 1, 2, or 3 who have not received any prior therapy.11

THERAPY EVALUATION OF TOP AGENTS

Peginterferon alfa is a part of combination therapies and is used as a weekly injection in recommended regimens among interferon eligible patients.4,5,11-13,15 Peginterferon alfa is a long-acting interferon in the antiviral class.2,4,11 It is used in a combination with RBV in the treatment of chronic HCV infection including coinfected HIV and cirrhotic patients.5,22,30 The SVR rates were not significantly different between pegIFN-2a and pegIFN-2b in the IDEAL

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trial.35 The guidelines do not stress any particular preference between the two formulations.12,13,22,35 In addition, there was no difference regarding the frequency of adverse events with regard to headache, myalgia, neutropenia, and hemoglobin.22,35 However, there was a difference with depression which increased with pegIFN-2b compared to pegIFN-2a.22,35 Skin rash incidence decreased with pegIFN-2b compared to pegIFN-2a.22,35 Dose reduction or discontinuation of treatment may need to be considered if white blood cells, neutrophils, platelet counts, or hemoglobin decrease, if liver or renal function deteriorates, or if depression or suicidal ideation is observed as an adverse drug reaction.36 The cost of pegIFN is about $22,000 for 28-week treatment in the U.S.36

Ribavirin is a nucleoside analog which has a broad spectrum of antiviral activity.37 It inhibits the replication of RNA viruses.37 Ribavirin appears to decrease HCV infectivity in a dose-dependent manner. Higher doses

(1000-1400 mg/day) demonstrated higher SVR rates, compared to lower doses (800 mg/day), among patients receiving pegIFN.22,38,39 According to the AASLD/IDSA newly updated guidelines, RBV is recommended as weight-based dosing of 1000 mg (<75 kg) and 1200 mg (≥75 kg).13 Ribavirin is teratogenic in animals even at low doses and designated as U.S. pregnancy category X.33 Therefore, the use of any regimen including RBV is considered contraindicated in pregnant women.33 Monthly negative pregnancy tests are required during treatment and for 6 months after the discontinuation of treatment.36 Dose reduction, treatment discontinuation, or use of erythropoietin-stimulating agent may be necessary with significant decrease in hemoglobin, which is commonly seen with the use of RBV.36,40 RBV costs about $22,000 (Copegus 600 mg twice daily), $9,000 (Rebetol 1000 mg divided twice daily), $4,000 (Ribasphere 1000 mg divided twice daily) for a 28-week course of treatment in the U.S.36

First generation DAAs

Boceprevir is a HCV NS3/4A protease inhibitor indicated in combination with pegIFN and RBV for the treatment of chronic HCV genotype 1 infection in patients with compensated liver disease, null responders, partial responders, and relapsers.41,42 Boceprevir is recommended as an addition to pegIFN/RBV combination at treatment week 5 after 4 weeks of pegIFN/RBV lead-in phase. The triple therapy then continues for the remaining duration of treatment.43 The total duration of treatment can be 28 weeks (treatment-naïve patients with undetectable HCV RNA at weeks 8 and 24), 36 weeks (previous partial responders or relapsers with undetectable HCV RNA at weeks 8 and 24), or 48 weeks.43 The recommended dose of boceprevir is 800 mg (4 capsules of 200 mg) every 7-9 hours with food.42 The adverse events include anemia, neutropenia, hypersensitivity, fatigue, nausea

Drug Class Advantage Disadvantage

pegIFN/RBV • “Conventional” dual therapy • Regimen used for the long time before approval of DAAs

• Lower efficacy than DAAs, especially in HCV genotype 1 and 4 infections• Significant burden of toxicity• Long treatment duration

BoceprevirTelaprevir

• First generation DAA• protease inhibitor

• Improved efficacy compared to pegIFN/RBV• Shorter treatment duration than pegIFN/RBV with early response

• Complicated regimen, especially with the food (20 g of fat) requirement of telaprevir• Added toxicity to pegIFN/RBV• Potentials for drug interactions• Only indicated for treatment of HCV genotype 1infection• Financial cost

Simeprevir • Second generation DAA• protease inhibitor

• Improved efficacy compared to pegIFN/RBV• Simpler regimen than firs generation DAAs (once daily)• Shorter treatment duration than pegIFN/RBV• Lower anemia and rash incidences than first generation DAAs• Less drug interactions than first generation DAAs

• Added toxicity to pegIFN/RBV• Sulfonamide moiety• Financial cost

Sofosbuvir • Second generation DAA• polymerase inhibitor

• Improved efficacy compared to pegIFN/RBV and first generation DAAs• Shorter duration of therapy than pegIFN/RBV and protease inhibitors• Elimination of pegIFN injection for HCV genotypes 2 and 3 infections with better tolerability• Simpler administration (once daily regardless of food)• No significant CYP-mediated drug interactions• Higher resistance barrier than protease inhibitors

• Financial cost

Table 1. Advantages and disadvantages of currently available HCV therapies.

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and vomiting, and dysgeusia.43 Patients need to be carefully assessed especially for anemia due to the high incidence with this treatment.40,43 Boceprevir is a strong inhibitor of cytochrome P450 (CYP) 3A4/5 and is also partly metabolized by CYP3A4/5.43 Therefore, potential drug-drug interactions need to be considered. The cost is approximately $40,000 for 24-week treatment or $74,000 for 44-week treatment in the U.S.36

Telaprevir is another HCV NS3/4A inhibitor and the second DAA recommended as part of HCV triple therapy.44 Telaprevir is indicated for the treatment of genotype 1 chronic HCV infection with compensated liver disease, treatment-naïve, and previously treated patients with pegIFN/RBV dual therapy.44 Telaprevir is part of triple therapy for the first 12 weeks, followed by pegIFN/RBV dual therapy for an additional 36 weeks for a total of 48 weeks.44-48 The duration of treatment can be shortened to 24 weeks (12-week triple therapy plus 12-week dual therapy) if treatment-naïve patients achieved undetectable HCV RNA at weeks 4 and 12.44 The recommended dose for telaprevir is 1125 mg (3 tablets of 375 mg) every 12 hours given with food containing 20 g of fat. The common adverse events associated with telaprevir are rash, anorectal discomfort, anemia, fatigue, pruritus, nausea, and diarrhea.11,44 Telaprevir is a strong inhibitor of CYP3A; therefore, contraindicated when combined with drugs whose clearance is highly dependent on CYP3A.44 Telaprevir also inhibits certain drug transporters, such as P-glycoprotein (P-gp), organic anion-transporting polypeptide 1B1 (OATP1B1), and OATP2B1 with telaprevir itself acting as a substrate for CYP3A and P-gp.44 Any potential for drug-drug interactions needs to be considered carefully. The cost of telaprevir is about $66,000 for 12-week treatment in the U.S.36

The AASLD/IDSA guidelines, published in January 2014, does not recommend pegIFN/RBV with or without first generation DAAs (boceprevir or telaprevir) despite the 24- or 48-week treatment duration.13

Second generation DAAs

Simeprevir was approved by the FDA on November 22, 2013.7 Simeprevir is another HCV NS3/4A protease inhibitor indicated for chronic HCV genotype 1 infection.25 The treatment is initiated as triple therapy for the first 12 weeks and then continues as pegIFN/RBV dual therapy for 12 or 36 additional weeks.25,49 The total duration of treatment is 24 weeks for treatment-naïve and prior relapse patients and 48 weeks for prior non-responder patients.25,49 Baseline

testing for HCV NS3 Q80K polymorphism is recommended as simeprevir has shown limited efficacy in patients carrying this specific variant.25 Adverse events are similar with or without pegIFN/RBV with the incidence of photosensitivity and rash being higher in the simeprevir group. Simeprevir appears to have fewer incidences of anemia and rash than the first generation DAAs.50 The recommended dose is 150 mg 1 capsule once daily with food.25 Though simeprevir is another NS3/4A protease inhibitor, once daily dosing is a major advantage over the first generation DAAs. No dosage adjustment is required in patients with renal impairment, but simeprevir has not been studied in patients with end-stage renal disease or those who require hemodialysis.13 Simeprevir contains a sulfonamide moiety, but currently there is insufficient data linking this to risks in patients with sulfa allergy.25 Furthermore, simeprevir is a substrate of CYP3A, and concomitant use of moderate or strong inhibitors or inducers of CYP3A is not recommended.25 Simeprevir is also a weak intestinal CYP3A4 inhibitor, a weak CYP1A2 inhibitor, a P-gp inhibitor, and an OATP1B1/3 inhibitor; therefore, any potential for drug-drug interaction needs to be evaluated.25,36 However, simeprevir does not inhibit CYP3A4 at the liver and is considered to have less drug interactions than the first generation DAAs.25,50 The cost of simeprevir is about $66,000 for 12-week treatment in the U.S.36

Sofosbuvir is another second generation DAA which was approved by the FDA on December 6, 2013. This is the first HCV NS5B nucleotide polymerase inhibitor, which is a novel target for HCV therapy differing from all other current DAAs.24 It is indicated for the treatment of chronic HCV infection as part of antiviral combination therapy in genotypes 1-4 including hepatocellular carcinoma and coinfected HIV patients.8,11,26 Patients with genotype 1 or 4 will require 12 weeks of treatment in combination with pegIFN/RBV as triple therapy.26 Patients with genotype 2 will require 12 weeks of treatment in combination only with RBV as dual therapy. This is a major advantage of sofosbuvir which eliminates pegIFN injection, possibly leading to better patient’s compliance and tolerability.26 However, genotype 3 HCV infection will require 24 weeks of treatment, but these patients can also be treated without pegIFN injections.26 The recommended dose is 400 mg once daily regardless of food.26 No dosage adjustment is necessary for patients with mild to moderate renal impairment. The use is not recommended in patients with severe renal impairment or end-stage renal disease (CrCL < 30 mL/min) and in those who require hemodialysis due to the lack of data.13 The most common adverse

events are fatigue and headache.26 Sofosbuvir is a substrate for drug transporters, such as P-gp and breast cancer resistance proteins (BCRP), and drug-drug interaction may be possible with intestinal P-gp inducers (e.g., rifampin, St. John’s wort).26 Another advantage of sofosbuvir is that it is not metabolized by CYP enzymes, thus sofosbuvir have an advantage over other DAAs where drug interaction is a concern.51 In general, sofosbuvir seems to be better tolerated than the protease inhibitors. Moreover, unlike protease inhibitors against which HCV is showing resistance, sofosbuvir is reported to have high resistance barrier.27,52,53 The cost of sofosbuvir is $84,000 for 12-week treatment in the U.S.36

The recommended regimens including sofosbuvir and simeprevir by the AASLD/IDSA updated guidelines published in January 2014 are shown in the decision pathways (Part II).13 Laboratory parameters as well as adverse drug reactions, for which patients should be monitored, are listed as appendix of data points (Part III). As mentioned above, the cost of HCV treatment can be a significant burden, especially with the use of a DAA. Although combination therapy including sofosbuvir is considered the first-line, the use of alternative therapies may be justified based on patient characteristics, clinical prognosis factors, potentials for drug interactions, and toxicity profiles. The most appropriate therapy needs to be evaluated for patients on an individual basis.

Evaluation of upcoming pipeline

There are 6 investigational agents in chronic HCV infection to look forward to in the future. These compounds are faldaprevir, danoprevir, daclatasvir, asunaprevir, and tegobuvir.11,54,55 All these compounds are currently being investigated in the treatment of chronic HCV infection with or without combination with pegIFN/RBV.55 Fadaprevir was studied in treatment-naïve HCV genotype 1 patients (Phase III study) with the possibility of a pegIFN-free regimen.56,57 Danoprevir is an NS3/4A protease inhibitor in combination with pegIFN/RBV in treatment-naïve patients infected with HCV genotype 1 or 4.58,59 Daclatasvir is an NS5A replication complex inhibitor studied in combination with pegIFN/RBV in treatment-naïve HCV genotype 1 or 4 patients.60,61 Deleobuvir and tegobuvir are non-nucleoside inhibitors of NS5B polymerase.57,62 Asunaprevir is an NS3 protease inhibitor which is being studied in combination with daclatasvir.62

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SUMMARY AND CONCLUSION

Hepatitis C virus infection has a significant impact on our society due to the high incidence, the need for liver transplantation, the complications leading to cirrhosis and hepatocellular carcinoma, and the medical costs associated with these outcomes. In the U.S., the majority of patients are infected with HCV genotype 1 with HCV genotype 2 and 3 infections being reported in approximately 25% of cases. The HCV genotype is a crucial factor to determine the selection of an appropriate and effective therapy. Dual therapy with pegIFN and RBV has been the standard of care, but recent advancements have led to the incorporation of DAAs. First generation DAAs boceprevir and telaprevir were recommended by the AASLD 2011 clinical guidelines for the treatment of HCV genotype 1 infection as triple therapy in combination with pegIFN/RBV. However, the recently updated guidelines include simeprevir and sofosbuvir as the first line recommendation and alternative agents. More DAAs are currently being investigated. As newer agents are approved, the treatment cost is estimated to increase. The treatment regimen varies depending on which agent is chosen in addition to other patient/virus specific variables. It will be important to decide the best therapy for each patient by considering HCV genotype, patient’s genetic polymorphisms, concurrent medications, comorbidities, contraindications, and potential drug-drug interactions. Flu-like symptoms as well as hematologic and dermatologic side effects in particular are commonly reported. Due to the significant toxicity of the treatment, patient’s adherence to therapy should also be closely monitored.

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CLINICAL DECISION PATHWAY: DIAGNOSIS OF HCV

Early acute phase, profoundly

immunosuppresed, or suspected reinfection?

HCV RNA Testing Anti-HCV Antibodies

HCV Infection is not likelyDiagnosis of HCV Infection

YES NO

POSITIVE NEGATIVE

HCV Infection is not likely(If exposure to HCV occured

within 6 months, HCV RNA testing or follow-up testing for HCV antibody is recommended)

HCV RNA Testing

POSITIVE NEGATIVE

Repeat HCV RNA 3 months later to confirm a recovered infection

Diagnosis of HCV Infection

POSITIVE NEGATIVE

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CLINICAL DECISION PATHWAY: TREATMENT OF HCV, TREATMENT-NAÏVE PATIENTS

HCV Genotype

Genotype 2 Genotype 4Genotype 3Genotype 1 Genotype 5 / 6

SOF + RBV + pegIFN (12 wk)

If pegINF ineligible:SOF + SMV ± RBV

(12 wk)

SOF + RBV (12 wk) SOF + RBV (24 wk) SOF + RBV + pegIFN (12 wk)

If pegINF ineligible:SOF +RBV (24 wk)

SOF + RBV + pegIFN (12 wk)

AlternativeIf HCV-1b or HCV-1a with

undetected Q80K:SMV + RBV + pegIFN (24 wk; SMV 12 wk)If pegINF ineligible:

SOF + RBV (24 wk) - less effective in patients with

cirrhosis

AlternativeSOF + RBV + pegIFN

(12 wk)

AlternativeSMV + RBV + pegIFN

(24-48 wk; SMV 12 wk)

AlternativeRBV + pegIFN

(48 wk)

HCV genotype, patient’s genetic polymorphisms, concomitant medications, and other medical conditions are additional important factors in determining a particular treatment option. Potentials drug-drug interactions and contraindications should be assessed.

IFN ineligible: intolerance to pegIFN, autoimmune hepatitis, autoimmune disorders, hypersensitivity to pegIFN or its components, decompensated hepatic disease, history of depression, clinical features consistent with depression, baseline neutrophil < 1,500/μL, baseline platelet <90,000/μL, baseline hemoglobin < 10 g/dL, history of preexisting cardiac disease.

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CLINICAL DECISION PATHWAY: RETREATMENT OF HCV, TREATMENT-EXPERIENCED PATIENTS

HCV Genotype

Genotype 2 Genotype 4Genotype 3Genotype 1 Genotype 5 / 6

Nonresponder to pegIFN/RBV:

SOF + RBV + pegIFN (12 wk)

SOF + RBV (12 wk; 16 wk with cirrhosis)

SOF + RBV (24 wk) SOF + RBV + pegIFN (12 wk) SOF + RBV + pegIFN (12 wk)

AlternativeNonresponder to pefIFN/

RBV ± PI:SOF + RBV + pefIFN

(12-24 wk; SOF 12 wk)Nonresponder to

pegIFN/RBV:SIM + RBV + pegIFN (48 wk; SIM 12 wk)

AlternativeSOF + RBV + pegIFN

(12 wk)

AlternativeSMV + RBV (24 wk)

AlternativeSOF + RBV + pegIFN

(12 wk)

HCV genotype, patient’s genetic polymorphisms, concomitant medications, and other medical conditions are additional important factors in determining a particular treatment option. Potentials drug-drug interactions and contraindications should be assessed.

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CLINICAL DECISION PATHWAY: TREATMENT OF HCV, HIV/HCV-COINFECTED PATIENTS

HCV Genotype

Genotype 2 Genotype 4 / 5 / 6Genotype 3Genotype 1

Nonresponder to pegIFN/RBV:

SOF + RBV + pegIFN (12 wk)

SOF + RBV (12 wk; 16 wk if nonresponder or

cirrhosis)

SOF + RBV (24 wk) Treat as HCV-monoinfection

Treatment-naïve or relapser:SOF + RBV + pegIFN (12 wk)

Treatment-naïve and ineligible to pegIFN:

SOF + RBV (24wk)Treatment-naïve or relapser and

ineligible to pegIFN:SOF + SIM ± RBV (12 wk)

Nonresponse to pegIFN/RBVSOF + SIM ± RBV (12wk)

Nonresponse to pegIFN/RBV + BOC or TVR

Treat as HCV-monoinfection

AlternativeNonresponse to pegIFN/RBV

SOF + RBV + pegIFN (12 wk)

HCV genotype, patient’s genetic polymorphisms, concomitant medications, and other medical conditions are additional important factors in determining a particular treatment option. Potentials drug-drug interactions and contraindications should be assessed.

AlternativeHCV-1b or HCV-1a with

undetected Q80K:SIM + RBV + pegIFN (24wk)Nonresponse to pegIFN/RBVSOF + RBV + pegIFN (12wk)

SOF + RBV (24wk) - if ineligible

IFN ineligible: intolerance to pegIFN, autoimmune hepatitis, autoimmune disorders, hypersensitivity to pegIFN or its components, decompensated hepatic disease, history of depression, clinical features consistent with depression, baseline neutrophil < 1,500/μL, baseline platelet <90,000/μL, baseline hemoglobin < 10 g/dL, history of preexisting cardiac disease.

SIM should only be used with antiretroviral drugs: raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, and abacavir to avoid significant drug interactions.

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CLINICAL DECISION PATHWAY: TREATMENT OF RECURRENT HCV, POST-TRANSPLANTATION PATIENTS

HCV Genotype

Genotype 2 / 3Genotype 1

SOF + SIM ± RBV (12-24 wk) SOF + RBV (24 wk)

RBV initiated at 600 mg and increased monthly by 200 mg/day as tolerated to weight-based dose

These recommendation applies only to patients with compensated liver function

HCV genotype, patient’s genetic polymorphisms, concomitant medications, and other medical conditions are additional important factors in determining a particular treatment option. Potentials drug-drug interactions and contraindications should be assessed.

AlternativeSOF + SIM ± RBV (12-24 wk)

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LIST OF ABBREVIATIONS

BOC boceprevirCBC complete blood countDVR delayed virological responseEKG electrocardiogram eRVR extended rapid virological responseEVR early virological responseHCV hepatitis C virusIU international unitsLFT liver function testRNA ribonucleic acidRVR rapid virological responseSCr serum creatinineSMV simeprevirSOF sofosbuvirSVR sustained virological responseTSH thyroid stimulating hormoneTVR telaprevir

CLINICAL OUTCOMES-GOAL MEASURE PATIENT LONGITUDINALLY

» HCV RNA (IU/mL) at baseline » HCV RNA (IU/mL) at week 4 » HCV RNA (IU/mL) at week 8 (BOC) » HCV RNA (IU/mL) at week 12 » HCV RNA (IU/mL) at week 24 » HCV RNA (IU/mL) 12 weeks after therapy » HCV RNA (IU/mL) 24 weeks after therapy » RVR (dual therapy) » EVR (dual therapy) » DVR (dual therapy) » eRVR (TVR) » Early response (BOC) » Late response (BOC) » SVR 12 » SVR 24 » SVR 48 » Null response » Partial response » Breakthrough

ECONOMIC IMPROVEMENT

» Number of office visits » Number of hospital admission due to complication from the

liver disease » Number of hospital admission due to an adverse drug reaction » Use of erythropoietin-stimulating agent

HUMANISTIC IMPROVEMENT/QUALITY OF LIFE

» CBC at baseline » CBC at week 2 » CBC at week 4 (and periodically for pegIFN/RBV) » CBC at week 8 (BOC, TVR) » CBC at week 12 (BOC, TVR) » Blood chemistry (including electrolytes and SCr) at baseline » Blood chemistry at week 4 (and periodically for pegIFN/RBV) » Blood chemistry at week 8 (TVR) » Blood chemistry at week 12 (TVR) » LFT at baseline » LFT at week 2 (TVR) » LFT at week 4 (and periodically for pegIFN/RBV) » LFT at week 8 (TVR) » LFT at week 12 (TVR) » Thyroid function at baseline » TSH at week 2 (TVR) » TSH at week 4 (TVR) » TSH at week 8 (TVR) » TSH at week 12 (TVR) » Lipid profile at baseline (TVR) » EKG at baseline (if patients have cardiac disease) » Pregnancy test at baseline, then monthly during treatment

and for six months after discontinuation of RBV » Adverse drug reactions

• Flu-like symptoms (fatigue, pyrexia, myalgia, headache, and rigors)• Injection-site reaction• Arthralgias• Headache• Insomnia• Anemia• Nausea• Vomiting• Diarrhea• Hemorrhoids• Dysgeusia• Rash (TVR, SMV)• Pruritus • Anorectal discomfort (TVR)• Anal pruritus (TVR)• Psychiatric reaction (depression, irritability, anxiety, suicidal ideation etc.)• Bacterial infection• Alopecia• Any other side effects

Data Points for Algorithm

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1. Lavanchy, D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 17, 107-115, doi:10.1111/j.1469-0691.2010.03432.x (2011).2. Centers for Disease Control and Prevention. Hepatitis C Information for Health Professionals, <http://www.cdc.gov/hepatitis/hcv/> (2013).3. Yasin, T., Riley, T. R. & Schreibman, I. R. Current treatment of choice for chronic hepatitis C infection. Infect Drug Resist 4, 11-18, doi:10.2147/IDR.S4827 (2011).4. Ghany, M. G., Nelson, D. R., Strader, D. B., Thomas, D. L. & Seeff, L. B. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 54, 1433-1444, doi:10.1002/hep.24641 (2011).5. European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol, doi:10.1016/j.jhep.2013.11.003 (2013).6. Flisiak, R., Jaroszewicz, J. & Parfieniuk-Kowerda, A. Emerging treatments for hepatitis C. Expert Opin Emerg Drugs 18, 461-475, doi:10.1517/14728214.2013.847089 (2013).7. Traynor, K. Simeprevir approved for hepatitis C virus infection. Am J Health Syst Pharm 71, 6, doi:10.2146/news140001 (2014).8. Traynor, K. Sofosbuvir approved for chronic hepatitis C infection. Am J Health Syst Pharm 71, 90, doi:10.2146/news140006 (2014).9. Kawaguchi-Suzuki, M. & Frye, R. F. The Role of Pharmacogenetics in the Treatment of Chronic Hepatitis C Infection. Pharmacotherapy, doi:10.1002/phar.1349 (2013).10. Clark, P. J. & Thompson, A. J. Host genomics and HCV treatment response. J Gastroenterol Hepatol 27, 212-222, doi:10.1111/j.1440-1746.2011.06918.x (2012).11. Liang, T. J. & Ghany, M. G. Current and future therapies for hepatitis C virus infection. N Engl J Med 368, 1907-1917, doi:10.1056/NEJMra1213651 (2013).12. Ghany, M. G., Strader, D. B., Thomas, D. L. & Seeff, L. B. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49, 1335-1374, doi:10.1002/hep.22759 (2009).13. The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C, <http://www.hcvguidelines.org/> (2014).14. Scheel, T. K. & Rice, C. M. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 19, 837-849, doi:10.1038/nm.3248 (2013).15. Yee, H. S. et al. Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol 107, 669-689; quiz 690, doi:10.1038/ajg.2012.48 (2012).16. Naggie, S. Management of hepatitis C virus infection: the basics. Top Antivir Med 20, 154-161 (2012).17. Fried, M. W. et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347, 975-982, doi:10.1056/

NEJMoa020047 (2002).18. Manns, M. P. et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358, 958-965 (2001).19. Casey, L. C. & Lee, W. M. Hepatitis C virus therapy update 2013. Curr Opin Gastroenterol 29, 243-249, doi:10.1097/MOG.0b013e32835ff972 (2013).20. Berg, T. et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 130, 1086-1097, doi:10.1053/j.gastro.2006.02.015 (2006).21. Rosen, H. R. Clinical practice. Chronic hepatitis C infection. N Engl J Med 364, 2429-2438, doi:10.1056/NEJMcp1006613 (2011).22. Zhu, Y. & Chen, S. Antiviral treatment of hepatitis C virus infection and factors affecting efficacy. World J Gastroenterol 19, 8963-8973, doi:10.3748/wjg.v19.i47.8963 (2013).23. Soriano, V. et al. Hepatitis C therapy with HCV NS5B polymerase inhibitors. Expert Opin Pharmacother 14, 1161-1170, doi:10.1517/14656566.2013.795543 (2013).24. Herbst, D. A. & Reddy, K. R. Sofosbuvir, a nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus infection. Expert Opin Investig Drugs 22, 527-536, doi:10.1517/13543784.2013.775246 (2013).25. Janssen Therapeutics. Olysio (simeprevir) package insert. Titusville, NJ; 2013.26. Gilead Sciences, Inc. Sovaldi (sofosbuvir) package insert. Foster City, CA; 2013.27. Wu, S., Kanda, T., Nakamoto, S., Imazeki, F. & Yokosuka, O. Hepatitis C virus protease inhibitor-resistance mutations: Our experience and review. World J Gastroenterol 19, 8940-8948, doi:10.3748/wjg.v19.i47.8940 (2013).28. Palanisamy, N. et al. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res 99, 12-17, doi:10.1016/j.antiviral.2013.04.018 (2013).29. Cohen, J. Pharmaceuticals. Advocates protest the cost of a hepatitis C cure. Science 342, 1302-1303, doi:10.1126/science.342.6164.1302 (2013).30. Boccaccio, V. & Bruno, S. Management of HCV patients with cirrhosis with direct acting antivirals. Liver Int 34 Suppl 1, 38-45, doi:10.1111/liv.12391 (2014).31. Bourlière, M. et al. How to optimize HCV therapy in genotype 1 patients with cirrhosis. Liver Int 33 Suppl 1, 46-55, doi:10.1111/liv.12067 (2013).32. Coilly, A., Roche, B. & Samuel, D. Current management and perspectives for HCV recurrence after liver transplantation. Liver Int 33 Suppl 1, 56-62, doi:10.1111/liv.12062 (2013).33. Prasad, M. R. & Honegger, J. R. Hepatitis C virus in pregnancy. Am J Perinatol 30, 149-159, doi:10.1055/s-0033-1334459 (2013).34. El-Shabrawi, M. H. & Kamal, N. M. Burden of pediatric hepatitis C. World J Gastroenterol 19, 7880-7888, doi:10.3748/wjg.v19.i44.7880 (2013).35. McHutchison, J. G. et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 361, 580-593, doi:10.1056/NEJMoa0808010 (2009).36. Comparison of Hepatitis C Drugs.

Pharmacist’s Letter/ Prescriber’s Letter, Detail-Document #300204 (2014).37. Te, H. S., Randall, G. & Jensen, D. M. Mechanism of action of ribavirin in the treatment of chronic hepatitis C. Gastroenterol Hepatol (N Y) 3, 218-225 (2007).38. Hadziyannis, S. J. et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140, 346-355 (2004).39. Jacobson, I. M. et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 46, 971-981, doi:10.1002/hep.21932 (2007).40. Hynicka, L. M. & Heil, E. L. Anemia management in patients with chronic viral hepatitis C. Ann Pharmacother 47, 228-236, doi:10.1345/aph.1R513 (2013).41. Bacon, B. R. et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 364, 1207-1217, doi:10.1056/NEJMoa1009482 (2011).42. Kwo, P. Y. et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376, 705-716, doi:10.1016/S0140-6736(10)60934-8 (2010).43. MERCK & CO., INC. Victrelis (boceprevir) package insert. Whitehouse Station, NJ; 2013.44. Jesudian, A. B. & Jacobson, I. M. Optimal treatment with telaprevir for chronic HCV infection. Liver Int 33 Suppl 1, 3-13, doi:10.1111/liv.12079 (2013).45. Jesudian, A. B. & Jacobson, I. M. Telaprevir for chronic hepatitis C virus infection. Clin Liver Dis 17, 47-62, doi:10.1016/j.cld.2012.09.010 (2013).46. Hézode, C. et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 360, 1839-1850, doi:10.1056/NEJMoa0807650 (2009).47. Jacobson, I. M. et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364, 2405-2416, doi:10.1056/NEJMoa1012912 (2011).48. Fried, M. W. et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology 58, 1918-1929, doi:10.1002/hep.26641 (2013).49. You, D. M. & Pockros, P. J. Simeprevir for the treatment of chronic hepatitis C. Expert Opin Pharmacother 14, 2581-2589, doi:10.1517/14656566.2013.850074 (2013).50. Asselah, T. Sofosbuvir for the treatment of hepatitis C virus. Expert Opin Pharmacother 15, 121-130, doi:10.1517/14656566.2014.857656 (2014).51. Salvatierra, K., Fareleski, S., Forcada, A. & López-Labrador, F. X. Hepatitis C virus resistance to new specifically-targeted antiviral therapy: A public health perspective. World J Virol 2, 6-15, doi:10.5501/wjv.v2.i1.6 (2013).52. Keating, G. M. & Vaidya, A. Sofosbuvir: first global approval. Drugs 74, 273-282, doi:10.1007/s40265-014-0179-7 (2014).

REFERENCES

Page 21 of 21

53. Jesudian, A. B., de Jong, Y. P. & Jacobson, I. M. Emerging therapeutic targets for hepatitis C virus infection. Clin Gastroenterol Hepatol 11, 612-619.e611, doi:10.1016/j.cgh.2013.04.003 (2013).54. Barreiro, P., Vispo, E., Poveda, E., Fernández-Montero, J. V. & Soriano, V. Hepatitis C therapy: highlights from the 2012 annual meeting of the European Association for the Study of the Liver. Clin Infect Dis 56, 560-566, doi:10.1093/cid/cis915 (2013).55. Zeuzem, S. et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med 369, 630-639, doi:10.1056/NEJMoa1213557 (2013).56. Wendt, A. et al. Chronic hepatitis C: future treatment. Clin Pharmacol 6, 1-17, doi:10.2147/CPAA.S30338 (2014).57. Gane, E. J. et al. Efficacy and Safety of Danoprevir-Ritonavir plus Peginterferon Alfa-2a-Ribavirin in Hepatitis C Virus Genotype 1 Prior Null Responders. Antimicrob Agents Chemother 58, 1136-1145, doi:10.1128/AAC.01515-13 (2014).58. Marcellin, P. et al. Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection. Gastroenterology 145, 790-800.e793, doi:10.1053/j.gastro.2013.06.051 (2013).59. Lee, C. Daclatasvir: potential role in hepatitis C. Drug Des Devel Ther 7, 1223-1233, doi:10.2147/DDDT.S40310 (2013).60. Everson, G. T. et al. Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection. Gastroenterology 146, 420-429, doi:10.1053/j.gastro.2013.10.057 (2014).61. Schinazi, R., Halfon, P., Marcellin, P. & Asselah, T. HCV direct-acting antiviral agents: the best interferon-free combinations. Liver Int 34 Suppl 1, 69-78, doi:10.1111/liv.12423 (2014).

REFERENCES