Clinical Therapeutics/Volume ], Number ], 2015

New Drug Review

Simeprevir and Sofosbuvir for Treatment of Chronic Hepatitis C Infection Lindsey M. Childs-Kean, PharmD, MPH, BCPS1; and Elizabeth O. Hand, PharmD, BCPS2 1

Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Seminole, Florida; and 2Department of Pharmacotherapy, The University of Texas at Austin College of Pharmacy, The University of Texas Health Science Center at San Antonio Pharmacotherapy Education and Research Center, San Antonio, Texas ABSTRACT Purpose: Chronic hepatitis C infection affects a large proportion of the world’s population and can lead to significant morbidity and mortality. The standard of care for treatment of hepatitis C infection has been peginterferon and ribavirin, with or without a first-generation protease inhibitor. In late 2013 and early 2014, sofosbuvir and simeprevir obtained regulatory approval, offering the first possibility for alloral treatment regimens. We provide a review of the clinical efficacy and safety of sofosbuvir- and simeprevir-containing regimens. Methods: Studies were identified in PubMed using the terms sofosbuvir and simeprevir in combination with hepatitis C. Abstracts of additional studies presented at professional meetings but not yet published were also reviewed. All Phase 3 trials published by August 1, 2014, as well as Phase 2 studies for which there was not a corresponding Phase 3 trial, were included in the review. Findings: Simeprevir was studied with peginterferon and ribavirin in 7 published Phase 3 trials, with overall efficacy rates of 59% to 100%. Sofosbuvir was studied with ribavirin and with or without peginterferon in 6 Phase 3 trials with overall efficacy rates of 50% to 93%. Patient groups with lower response rates tended to have cirrhosis and be older, men, and previous null responders. Simeprevir and sofosbuvir were studied in combination in 1 Phase 2a study with overall efficacy of 92%. Additional studies demonstrated the efficacy and safety of sofosbuvir regimens in patients before and after liver transplantation. Overall, the simeprevir- and sofosbuvir-containing regimens were tolerated better or as well as

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peginterferon and ribavirin regimens, with fatigue, headache, and nausea the most common adverse events. Implications: Results from numerous Phase 3 clinical trials indicate that sofosbuvir- and simeprevircontaining regimens are highly effective and safe for the treatment of chronic hepatitis C infection. The approval of these 2 agents has led to a complete overhaul of published guidelines, with sofosbuvir- and simeprevir-containing regimens included in preferred regimens. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: HCV, hepatitis C, simeprevir, sofosbuvir.

INTRODUCTION Chronic hepatitis C virus (HCV) infection is common worldwide, affecting approximately 185 million people globally, and is the cause of 350,000 deaths annually.1 In the United States, the Centers for Disease Control and Prevention estimates 3.2 million patients are chronically infected and more than 15,000 deaths are attributable to HCV each year.2 About 75% to 85% of all patients contracting HCV will progress to chronic infection, with 15% to 25% of patients spontaneously clearing the infection.2 The progression between various stages of fibrosis can take decades, and often patients are asymptomatic Accepted for publication December 14, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.12.012 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics until end-stage disease. Approximately one-third of patients with chronic HCV will develop cirrhosis or hepatocellular carcinoma.1 Complications of endstage liver disease include but are not limited to ascites, hepatic encephalopathy, and variceal hemorrhage. Due to the long latency period between contracting the disease and displaying clinical signs and symptoms, many patients remain unaware that they are infected, and infection rates are likely higher than what is reported. Unlike other chronic viral infections, HCV can be cured with treatment. The goals for treatment of chronic HCV are to reduce all-cause mortality and liver-related morbidity and mortality, which includes end-stage liver disease and hepatocellular carcinoma.3 Because those goals are not easily measurable, virologic response rates are used to assess treatment efficacy. Achieving sustained virologic response (SVR), defined as an undetectable viral load at the end of treatment and 24 weeks after the end of treatment, historically has been regarded as a virologic cure.4 SVR12, defined as an undetectable viral load at the end of treatment and 12 weeks after the end of treatment, has recently become the primary outcome of treatment studies after a high level of correlation between SVR12 and SVR was determined.5 For many years until 2011, the standard of care for treatment of all HCV genotypes was pegylated interferon (peginterferon) in combination with ribavirin for at least 24 weeks.4 In 2011, the first direct-acting antivirals, 2 protease inhibitors, boceprevir and telaprevir, were approved in many countries to be used in combination with peginterferon and ribavirin in patients with genotype 1 infection.6 Whereas the addition of boceprevir and telaprevir increased SVR rates up to 75% in certain genotype 1 subgroups, compared with those with just peginterferon and ribavirin (40%–50% for genotype 1 and 80% for genotypes 2 and 3), the SVR rates were still suboptimal.6 Patient factors that historically predicted decreased SVR rates with an interferoncontaining regimen included, but were not limited to HCV genotype (1 being worst), high viral load (4600,000 IU/mL), cirrhosis, and black race.4 IL28B genotype has also been identified as a pretreatment predictor: CC genotype is the favorable genotype and is associated with a higher SVR rate compared with CT or TT genotype.6 Additionally,

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interferon-based regimens subjected patients to weekly subcutaneous injections, numerous medication side effects, complicated dosing schedules, and food requirements, and long treatment durations (ie, 24–48 weeks). Therefore, there has been significant motivation to develop other direct-acting antiviral regimens with improved SVR rates, minimal side effects, oral route of delivery, once-daily administration, and shorter treatment durations. During late 2013 and early 2014, sofosbuvir and simeprevir gained regulatory approval in multiple countries.7,8 Simeprevir is a second-generation nonstructural protein 3A/4 (NS3A/4) protease inhibitor, and sofosbuvir is a nonstructural protein 5B (NS5B) polymerase inhibitor. The purpose of our article is to review the clinical data supporting the use of sofosbuvir and simeprevir for patients with chronic HCV.

METHODS All clinical trials of sofosbuvir and simeprevir used in the treatment of chronic HCV published before August 2014 were reviewed. Articles were identified by a search of PubMed using the terms sofosbuvir and/or simeprevir in combination with hepatitis C. All published Phase 3 trials were included in the review, as well as certain Phase 2 trials for which a Phase 3 trial is either ongoing or was not conducted. Additional articles were identified by a review of the published trials’ reference lists and the approved prescribing information. Abstracts from professional meetings were reviewed and included if the study had not had subsequent publication.

RESULTS Clinical Pharmacology Simeprevir is a second-generation inhibitor of the HCV NS3A/4 protease enzyme, which is essential in the viral life cycle.7 The absorption of simeprevir is increased at least 60% when taken with food; therefore, simeprevir is recommended to be taken with food.7 Simeprevir is highly protein bound, mostly to albumin. The metabolism of simeprevir is predominately through the cytochrome (CYP) P450 3A enzyme system in the liver, and simeprevir can inhibit intestinal, but not hepatic, CYP3A4 metabolism. The mean steady-state AUC of simeprevir is increased by 2.4-fold and 5.2-fold for patients with moderate liver impairment (Child-Turcotte-Pugh B)

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L.M. Childs-Kean and E.O. Hand and severe liver impairment (Child-Turcotte-Pugh C), and the clinical effects of these increases in drug exposure have not been studied. No dosage adjustment of simeprevir is required in patients with mild liver impairment (Child-Turcotte-Pugh A), and no dosage recommendation can be given for moderate to severe liver impairment.7 Simeprevir is eliminated almost entirely through biliary secretion with virtually no renal elimination; therefore, no dose adjustment is needed in patients with renal impairment.7 The structure of simeprevir contains a sulfonamide moiety. Although to date no patients with a history of a sulfa allergy experienced rash or photosensitivity when given simeprevir, the possibility of increased risk of adverse events in patients with a sulfa allergy cannot be ruled out.7 A test for baseline resistance to protease inhibitors, including simeprevir, at the Q80K polymorphism, is commercially available.7 Sofosbuvir is a nucleotide inhibitor of the HCV NS5B polymerase enzyme, terminating the chain of replicated viral RNA.8 Sofosbuvir bioavailability is not significantly altered by administration with food, and sofosbuvir is 61% to 65% bound to plasma proteins. Sofosbuvir is a prodrug and requires hepatic metabolism to form the active uridine analog triphosphate compound GS-461203. The metabolic pathway includes hydrolysis of the carboxyl ester moiety, phosphoramidate cleavage, and phosphorylation. Dephosphorylation can subsequently occur, producing an inactive nucleoside metabolite GS-331007. No dose adjustment is recommended for patients with any degree of liver impairment.8 About 80% of sofosbuvir is eliminated renally, with the majority being the inactive metabolite GS-331007. The sofosbuvir AUC0–1 is increased 61%, 107%, and 171% in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 50–80 mL/min/1.73 m2), moderate renal impairment (eGFR 30–50 mL/min/ 1.73 m2), and severe renal impairment (eGFR o30 mL/min/1.73 m2), respectively, compared with patients with normal renal function, and the GS331007 AUC0–1 is increased 55%, 88%, and 451%, respectively. For patients receiving hemodialysis, sofosbuvir and GS-331007 AUC0–1 are increased 28% and 1280% when sofosbuvir is administered 1 hour before the hemodialysis session and are increased 60% and 2070% when sofosbuvir is administered 1 hour after hemodialysis. About 18% of sofosbuvir is removed by a 4-hour hemodialysis

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session. No dose adjustment is recommended in patients with mild or moderate renal impairment.8 The safety and efficacy of sofosbuvir has not been established in patients with severe renal impairment or end-stage renal disease requiring hemodialysis; however, a study in this patient population is ongoing.9

Drug–Drug Interactions Due to the metabolism of simeprevir by the CYP3A4 system, inhibition of intestinal CYP3A4 metabolism, and inhibition of the p-glycoprotein (P-gp) transporter, many drug–drug interactions are possible. Strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, dexamethasone, St John’s wort, and efavirenz) can decrease the AUC of simeprevir and are not recommended to be given concomitantly.7 Strong CYP3A4 inhibitors (e.g., erythromycin, clarithromycin, itraconazole, milk thistle, and HIV protease inhibitors) can increase the AUC of simeprevir and are not recommended to be given concomitantly.7 Medication classes that may be given concomitantly with simeprevir but must be closely monitored either clinically or with therapeutic drug monitoring due to potential increased AUC from the simeprevir include antiarrhythmics, calcium channel blockers, statin drugs, and phosphodiesterase 5 inhibitors; similar individual drugs include digoxin and tacrolimus.7 Antiretroviral agents that appear to be safe to use with simeprevir include tenofovir, rilpivirine, raltegravir, emtricitabine, lamivudine, and abacavir.3 Sofosbuvir, but not GS-331007, is a substrate of the P-gp transporter as well as the breast cancer resistance protein. Therefore, inducers of P-gp, such as carbamazepine, phenytoin, rifampin, and St. John’s wort, may decrease the AUC of sofosbuvir, leading to possible therapeutic failure and should not be administered concomitantly.8 Because sofosbuvir and GS331007 neither inhibit nor induce the CYP enzyme system or the P-gp transporters, sofosbuvir and GS331007 are not expected to affect the concentrations of other coadministered medications metabolized or transported by these systems.8 Tipranavir appears to be the only antiretroviral that should be avoided with sofosbuvir because tipranavir can induce P-gp.3

Simeprevir Clinical Studies Simeprevir þ peginterferon þ ribavirin has been studied in 7 Phase 3 trials to date in various patient populations (Table I and Figure 1).10–15 All studies

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Trial/Design

Study Groups

394 patients randomized to QUEST-110 (Phase 3, simeprevir 150 mg orally randomized, doubledaily þ peginterferon blind, multicenter, alfa 2a 180 μg parallel-arm trial in HCV subcutaneously weekly þ treatment-naïve genotype ribavirin weight-based 1 patients aged at least dosing (n ¼ 264) or 18 y in Europe and placebo þ peginterferon North America) alfa 2a 180 μg subcutaneously weekly þ ribavirin weight-based dosing (n ¼ 130)

Treatment Duration

Outcome Measures

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Primary: Simeprevir group: SVR12 Simeprevir þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  12 or 36 wk, depending on responseguided therapy Placebo group: Placebo þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  36 wk Response-guided therapy: 24-wk duration if viral load at week 4 was o25 IU/ mL Stopping rules: Simeprevir or placebo stopped if Week-4 viral load was 41000 IU/ mL Peginterferon alfa and ribavirin stopped if Week-12 viral load was o2 log decline from baseline or if viral load was 425 IU/mL at Week 24 or 36

Key Finding: Efficacy Significant increase in SVR12 rate in simeprevir group (80% vs 50%; P o 0.0001) Significantly higher SVR24 rate in simeprevir group (83% vs 60%; P ¼ 0.0253) Significantly higher RVR rate in simeprevir group (80% vs 12%, 95% CI for difference, 60.5%–75.4%) On-treatment failure significantly lower in simeprevir group (9% vs 34%, 95% CI for difference, 33.7% to –16.0%) Viral relapse significantly lower in simeprevir group (9% vs 21%, 95% CI for difference, –22.1% to – 3.0%) Similar SVR12 rate in patients with genotype 1a and Q80K polymorphism receiving simeprevir compared with those with genotype 1a without the Q80K polymorphism receiving placebo (52% vs 53%; P ¼ 0.9199

Key Finding: Safety Most common AEs (simeprevir vs placebo): fatigue 42% vs 41%, headache 33% vs 39% AEs of interest (simeprevir vs placebo): rash 34% vs 32%, pruritus 30% vs 20%, photosensitivity 3% vs o1%, neutropenia 24% vs 18%, anemia 20% vs 21% Serious AEs (simeprevir vs placebo): 4% vs 6% AEs leading to permanent discontinuation of simeprevir or placebo (simeprevir vs placebo): o1% vs o1%

(continued)

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Table I. Phase 3 clinical studies of simeprevir.

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Table I. (continued). Trial/Design

Study Groups

QUEST-211 (Phase 3, 391 patients randomized to randomized, doublesimeprevir 150 mg orally blind, multicenter, daily þ peginterferon parallel-arm trial in HCV alfa 2a 180 μg (or treatment-naïve genotype peginterferon alfa 2b 1 patients aged at least weight-based dosing) 18 y in Europe, South subcutaneously weekly þ America, and North ribavirin weight-based America) dosing (n ¼ 257) or placebo þ peginterferon alfa 2a 180 μg subcutaneously weekly þ ribavirin weight-based dosing (n ¼ 134)

Treatment Duration

Outcome Measures

Significant increase in SVR12 rate in simeprevir group (81% vs 50%; P o 0.0001) Higher RVR rate in simeprevir group (79% vs 13%) On-treatment failure lower in simeprevir group (7% vs 32%) Viral relapse lower in simeprevir group (13% vs 24%) Similar SVR12 rate in patients with genotype 1a and Q80K polymorphism receiving simeprevir compared with those with genotype 1a without the Q80K polymorphism receiving placebo (75% vs 50%; P ¼ 0.2492)

Key Finding: Safety Most common AEs (simeprevir vs placebo): headache 39% vs 37%, fatigue 37% vs 42%, pyreia 31% vs 40%, influenzalike illness 26% vs 26% AEs of interest (simeprevir vs placebo): rash 27% vs 20%, pruritus 26% vs 27%, photosensitivity 4% vs o1%, neutropenia 21% vs 27%, anemia 21% vs 28% Serious AEs (simeprevir vs placebo): 6% vs 7% AEs leading to permanent discontinuation of simeprevir or placebo (simeprevir vs placebo): o1% vs o1%

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(continued)

L.M. Childs-Kean and E.O. Hand

Primary: Simeprevir group: SVR12 simeprevir þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  12 or 36 wk, depending on responseguided therapy Placebo group: placebo þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  36 wk Response-guided therapy: 24 week duration if viral load at Week 4 was o25 IU/ mL and undetectable at Week 12 Stopping rules: Simeprevir or placebo stopped if Week-4 viral load was 41000 IU/ mL Peginterferon alfa and ribavirin stopped if Week-12 viral load was o2 log decline from baseline or if viral load was 425 IU/mL at Week 24 or 36

Key Finding: Efficacy

Trial/Design

Study Groups

PROMISE12 (Phase 3, 393 patients randomized to randomized, doublesimeprevir 150 mg orally blind, multicenter, daily þ peginterferon parallel-arm trial in HCV alfa 2a 180 μg genotype 1 patients aged subcutaneously weekly þ at least 18 y in Europe, ribavirin weight-based Asia-Pacific region, and dosing (n ¼ 257) or North America who have placebo þ peginterferon had a prior relapse to alfa 2a 180 μg peginterferon alfa and subcutaneously weekly þ ribavirin) ribavirin weight-based dosing (n ¼ 134)

Treatment Duration

Outcome Measures

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Primary: Simeprevir group: SVR12 Simeprevir þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  12 or 36 wk, depending on responseguided therapy Placebo group: Placebo þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  36 wk Response-guided therapy: 24-week duration if viral load at Week 4 was o25 IU/ mL and undetectable at Week 12 Stopping rules: Simeprevir or placebo stopped if Week-4 viral load was 41000 IU/ mL Peginterferon alfa and ribavirin stopped if Week-12 viral load was o2 log decline from baseline or if viral load was 425 IU/mL at Week 24 or 36

Key Finding: Efficacy Significant increase in SVR12 rate in simeprevir group (79.2% vs 36.1%; P o 0.001) Significantly higher RVR rate in simeprevir group (77.2% vs 3.1%; P o 0.001) On-treatment failure significantly lower in simeprevir group (3.1% vs 21.7%; P o 0.001) Viral relapse significantly lower in simeprevir group (18.5% vs 48.4%; P o 0.001) Similar SVR12 rate in patients with genotype 1a and Q80K polymorphism receiving simeprevir compared with those with genotype 1a without the Q80K polymorphism receiving placebo (46.7% vs 30%, 95% CI for difference –7.5% to 44.7%)

Key Finding: Safety Most common AEs (simeprevir vs placebo): fatigue 32.3% vs 43.6%, headache 33.1% vs 36.1%, influenza-like illness 30.0% vs 20.3% AEs of interest (simeprevir vs placebo): rash 23.1% vs 22.6%, pruritus 27.7% vs 27.8%, photosensitivity 3.5% vs 0%, neutropenia 17.7% vs 21.8%, anemia 16.9% vs 20.3% Serious AEs (simeprevir vs placebo): 6% vs 7% AEs leading to permanent discontinuation of simeprevir or placebo (simeprevir vs placebo): o1% vs o1%

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Table I. (continued).

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Table I. (continued). Trial/Design

Study Groups

CONCERTO-113 (Phase 3, 183 patients randomized to simeprevir 100 mg orally randomized, doubledaily þ peginterferon blind, placebo-controlled alfa 2a 180 μg trial in HCV genotype 1 subcutaneously weekly þ treatment-naïve patients ribavirin weight-based aged 20–70 y in Japan) dosing (n ¼ 123) or placebo þ peginterferon alfa 2a 180 μg subcutaneously weekly þ ribavirin weight-based dosing (n ¼ 60)

Treatment Duration

Outcome Measures

Significant increase in SVR12 rate in simeprevir group (88.6% vs 61.7%; P o 0.0001) Significantly higher SVR24 rate in simeprevir group (88.6% vs 56.7%; P o 0.0001) Higher RVR rate in simeprevir group (84.4% vs 13.3%) Viral breakthrough lower in simeprevir group (0.8% vs 3.3%) Viral relapse lower in simeprevir group (7.6% vs 30.6%)

Key Finding: Safety Most common AEs (simeprevir vs placebo): pyrexia 61.0% vs 51.7%, anemia 56.9% vs 60.0%, rash 23.1% vs 22.6%, headache 43.9% vs 45.0%, malaise 42.3% vs 46.7%, alopecia 35.8% vs 46.7% AEs of interest (simeprevir vs placebo): pruritus 28.5% vs 30.0%, photosensitivity 1.6% vs 0%, neutropenia 6.5% vs 1.7% Serious AEs (simeprevir vs placebo): 3.3% vs 10.0% AEs leading to permanent discontinuation of simeprevir or placebo (simeprevir vs placebo): 0% vs 1.7%

(continued)

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L.M. Childs-Kean and E.O. Hand

Primary: Simeprevir group: SVR12 Simeprevir þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  12 or 36 wk, based on responseguided therapy Placebo group: Placebo þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  36 wk Response-guided therapy: 24-wk duration if viral load at Week 4 was o1.2 log IU/mL detectable or undetectable and undetectable at Week 12 Stopping rules: Simeprevir or placebo stopped if Week-4 viral load was 41000 IU/ mL Peginterferon alfa and ribavirin stopped if viral load was 41.2 log IU/ mL at Week 36

Key Finding: Efficacy

Trial/Design

Study Groups

CONCERTO-214 (Phase 3, 106 patients randomized to simeprevir 100 mg orally randomized, open-label, daily þ peginterferon parallel-arm trial in HCV alfa 2a 180 μg genotype 1 patients aged subcutaneously weekly þ 20–70 y in Japan who ribavirin weight-based had a prior nonresponse dosing  12 wk (n ¼ 53) to interferon-based or simeprevir 100 mg treatment) daily þ peginterferon alfa 2a 180 μg subcutaneously weekly þ ribavirin weight-based dosing  24 wk (n¼53)

Treatment Duration

Outcome Measures

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SMV12/PR: Simeprevir þ Primary: SVR12 peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  12 or 36 wk, based on responseguided therapy SMV24/PR: Simeprevir þ peginterferon alfa þ ribavirin  24 wk with possible extension of peginterferon alfa þ ribavirin  24 wk, based on response guided therapy Response-guided therapy: 24-wk duration if viral load at Week 4 was o1.2 log IU/mL detectable or undetectable and undetectable at Week 12 Stopping rules: Simeprevir or placebo stopped if Week-4 viral load was 41000 IU/ mL Peginterferon alfa and ribavirin stopped if viral load was 41.2 log IU/ mL at Week 36

Key Finding: Efficacy Significant increase in SVR12 rate in simeprevir groups compared with null hypothesis proportion (52.8%, 35.8% vs 14%; P o 0.0001) Significantly higher SVR24 rate in simeprevir groups compared with null hypothesis proportion (50.9%, 35.8% vs 14%; P o 0.0001) High RVR rates in both groups (58.5% vs 50.9%) Viral breakthrough similar in both groups (13.2% vs 11.3%) Viral relapse similar in both groups (38.6% vs 51.1%)

Key Finding: Safety Most common AEs (SMV12/PR vs SMV24/PR): pyrexia 62.3% vs 58.5%, anemia 52.8% vs 58.5%, malaise 56.6% vs 45.3%, headache 43.4% vs 43.4%, rash 37.7% vs 43.4%, alopecia 39.6% vs 28.3% Serious AEs (SMV12/PR vs SMV24/PR): 3.8% vs 5.7% AEs leading to permanent discontinuation of simeprevir (SMV12/PR vs SMV24/PR): 0% vs 0%

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Table I. (continued).

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Table I. (continued). Trial/Design

Study Groups

CONCERTO-314 (Phase 3, 49 patients received simeprevir 100 mg orally open-label, single-arm daily þ peginterferon trial in HCV genotype 1 alfa 2a 180 μg patients aged 20–70 y in subcutaneously weekly þ Japan who had relapsed ribavirin weight-based to interferon-based dosing treatment)

Outcome Measures

Primary: Simeprevir þ SVR12 peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  12 or 36 wk, based on responseguided therapy Response-guided therapy: 24-wk duration if viral load at Week 4 was o1.2 log IU/mL detectable or undetectable and undetectable at Week 12 Stopping rules: Simeprevir or placebo stopped if Week 4 viral load was 41000 IU/mL Peginterferon alfa and ribavirin stopped if viral load was 41.2 log IU/ mL at Week 36 Primary: Treatment-naïve and SVR12 prior relapse patients: Simeprevir þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  12 or 36 wk, based on responseguided therapy

Key Finding: Efficacy

Key Finding: Safety

Significant increase in SVR12 rate in simeprevir group compared with historical control (95.9% vs 50%; P o 0.0001) Significantly higher SVR24 rate in simeprevir group compared with null hypothesis proportion (89.8% vs 50%; P o 0.0001) High RVR rate (81.6%) Viral breakthrough low (0%) Viral relapse low (8.2%)

Most common AEs: pyrexia 73.5%, headache 51.0%, malaise 46.9%, anemia 44.9%, alopecia 34.7%, rash 32.7% Serious AEs: 12.2% AEs leading to permanent discontinuation of simeprevir: 2.0%

SVR12 rates for treatment-naïve, relapse, and nonresponse patients: 91.7%, 100%, 38.5% SVR24 rates for treatment-naïve, relapse, and nonresponse patients: 91.7%, 96.6%, 38.5%

Most common AEs: pyrexia 84.8%, anemia 50.6%, malaise 48.1%, headache 45.6%, rash 38.0%, lopecia 35.4%, alopecia 35.4% Serious AEs: 2.5% AEs leading to permanent discontinuation of

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(continued)

L.M. Childs-Kean and E.O. Hand

CONCERTO-415 (Phase 3, 79 patients received simeprevir 100 mg orally open-label, multicenter, daily þ peginterferon single-arm trial in HCV alfa 2b 1.5 μg/kg genotype 1 treatmentsubcutaneously weekly þ naïve or treatmentribavirin weight-based experienced patients dosing aged 20–70 y in Japan)

Treatment Duration

Trial/Design

Study Groups

Treatment Duration

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Prior nonresponders: Simeprevir þ peginterferon alfa þ ribavirin  12 wk followed by peginterferon alfa þ ribavirin  36 wk Response-guided therapy: 24-wk duration if viral load at Week 4 was o1.2 log IU/mL detectable or undetectable and undetectable at Week 12 Stopping rules: All medications stopped if Week 12 viral load was o2 log drop from baseline (for treatmentnaïve and prior relapse patients), if Week 12 viral load 42 log10 IU/ mL (for prior nonresponders) Peginterferon alfa and ribavirin stopped if viral load was 41.2 log IU/ mL at Week 24 or 36

Outcome Measures

Key Finding: Efficacy

Key Finding: Safety

SVR4 rates for treatment-naïve, relapse, and nonresponse patients: 91.7%, 100%, 42.3% RVR rate for treatmentnaïve, relapse, and nonresponse patients: 79.2%, 86.2%, 60.0% Viral breakthrough for treatment-naïve, relapse, and nonresponse patients: 0%, 0%, 23.1% Viral relapse for treatment-naïve, relapse, and nonresponse patients: 8.3%, 3.4%, 26.7%

simeprevir: 0%

AEs ¼ adverse events; HCV ¼ hepatitis C virus; PROMISE ¼ the PROtease inhibitor TMC435 In patientS who have previously rElapsed on IFN/RBV trial; CONCERTO ¼ the Clinical Optimization of New treatment strategy with TMC435 in Combination with pEginterferon plus Ribavirin for Treatment-naive and treatment-experienced patients infected with HCV genotype One trials; PR ¼ Peginterferon þ Ribavirin; RVR ¼ rapid virologic response; SVR4 ¼ sustained virologic response 4 wk after end of treatment; SVR12 ¼ sustained virologic response at 12 wk after end of treatment; SVR24 ¼ sustained virologic response 24 wk after end of treatment.

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Table I. (continued).

L.M. Childs-Kean and E.O. Hand

100% 80% 60% 40%

CONCERTO-4 (non-response)

CONCERTO-4 (relapse)

CONCERTO-4 (naïve)

CONCERTO-3

CONCERTO-2 (24 weeks)

CONCERTO-2 (12 weeks)

CONCERTO-1

PROMISE

QUEST-2

0%

QUEST-1

20%

SVR12: Sustained Virological Response 12 weeks after end of treatment

Figure 1. Sustained virologic response 12 weeks after end of treatment rates in Phase 3 trials with simeprevir. PROMISE ¼ the PROtease inhibitor TMC435 In patientS who have previously rElapsed on IFN/RBV trial; CONCERTO ¼ the Clinical Optimization of New treatment strategy with TMC435 in Combination with pEginterferon plus Ribavirin for Treatment-naive and treatment-experienced patients infected with HCV genotype One trials.

had similar designs, including a possibility for response-guided therapy (RGT) for those patients whose viral load declined rapidly on treatment. The simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection trial (QUEST-1) and the simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection trial (QUEST-2) were randomized, double-blind, placebo-controlled, multicenter trials conducted in Europe and the Americas in genotype 1 treatment-naïve patients.10,11 The patients received simeprevir 150 mg daily or matching placebo with peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin alone for 12 or 36 weeks, dependent on the RGT algorithm. The majority of patients in the QUEST-1 trial receiving simeprevir had genotype 1a infection (56%), whereas most patients in the QUEST-2 trial receiving simeprevir had genotype 1b (58%). Additionally, most patients in both studies were male, aged in their mid-40s, and had an unfavorable IL28B genotype (CT or TT). SVR12 rates were significantly higher for patients who received simeprevir with peginterferon and ribavirin than those who received placebo with peginterferon and ribavirin ( 80% vs 50%; P o 0.0001 in each study). The PROtease inhibitor TMC435 In patientS who have previously rElapsed on IFN/RBV (PROMISE) trial

] 2015

was a randomized, double-blind, placebo-controlled, multicenter trial conducted in Europe, the Americas, and the Asia-Pacific region and enrolled genotype 1 patients who were prior relapsers to peginterferon and ribavirin.12 Most patients had genotype 1b infection (57% in the simeprevir arm), were male (69% in the simeprevir arm), and had an unfavorable IL28B genotype (76% in the simeprevir arm). The patients received simeprevir 150 mg daily or matching placebo with peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin alone for 12 or 36 weeks, dependent on the RGT algorithm. SVR12 rates were significantly higher for patients who received simeprevir with peginterferon and ribavirin than those who received placebo with peginterferon and ribavirin ( 80% vs 36%; P o 0.001). One notable trend across these three trials is the diminished SVR12 rate in patients with genotype 1a and the presence of a baseline Q80K polymorphism. Simeprevir-receiving patients with genotype 1a without the Q80K polymorphism had an SVR12 rate of 78% to 84%, whereas patients with genotype 1a and the Q80K polymorphism had an SVR12 rate of 47% to 58%. This reduced SVR12 rate was similar to the SVR12 rates of the placebo þ peginterferon þ ribavirin groups. Of note, patients with genotype 1b had SVR12 rates of about 85%. The Clinical Optimization of New treatment strategy with TMC435 in Combination with pEginterferon plus Ribavirin for Treatment-naive and

11

Trial/Design NEUTRINO16 (Phase 3, single-group, open-label trial in treatment-naïve genotype 1, 4, 5, or 6 patients aged at least 18 y in the United States)

Study Groups 327 patients received Sofosbuvir 400 mg orally daily þ weight-based ribavirin þ peginterferon alfa-2a 180 μg subcutaneously weekly

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499 patients randomized to FISSION16 (Phase 3, sofosbuvir 400 mg orally randomized, open-label, daily þ weight-based active control ribavirin or peginterferon noninferiority study in alfa 2a 180 μg treatment-naïve genotype subcutaneously weekly þ 2 and 3 patients aged at ribavirin 400 mg orally least 18 y in the United twice daily States, Europe, Australia, and New Zealand)

Outcome Treatment Duration Measures 12 wk

Primary: SVR12

12 wk (sofosbuvir Primary: þ ribavirin arm) SVR12 24 wk (peginterferon þ ribavirin arm)

Key Finding: Efficacy Significantly improved SVR rates (90%) compared with historical response rate of 60% (P o 0.001) Rates of response did not differ greatly by genotype: 89% for genotype 1, 96% for genotype 4 Multivariable logistic regression: Cirrhosis and non-CC IL28B genotype strongly associated with reduced response 92% of patients without cirrhosis with SVR vs 80% with cirrhosis 98% with CC genotype vs. 87% with non-CC genotype SVR12: 67% in both sofosbuvir þ ribavirin and peginterferon þ ribavirin arms (difference of 0.3%, 95% CI, –7.5 to 8; P o 0.001) At Week 2, 92% with genotype 2 or 3 had

Key Finding: Safety Most common AEs: fatigue 59%, headache 36%, and nausea 34% Early treatment discontinuation due to AEs: 2% Serious AEs: 1%

Most Common AEs (sofosbuvir arm vs peginterferon arm): Fatigue 36% vs 55%, headache 25% vs 44%, nausea 18% vs 29% AEs of interest (sofosbuvir arm vs peginterferon arm): (continued)

Clinical Therapeutics

12

Table II. Phase 3 clinical studies of sofosbuvir.

] 2015

Table II. (continued). Trial/Design

Study Groups

Outcome Treatment Duration Measures

HCV viral loads o 25 IU/mL By Week 4, 99.6%

Stratification based on viral load, genotype, and presence of cirrhosis

POSITRON17 (Phase 3, randomized, blinded, placebo controlled study in interferon ineligible or interferon unwilling genotype 2 and 3 patients aged at least 18 y in North America, Australia, and New Zealand)

Key Finding: Efficacy

278 patients randomized to sofosbuvir 400 mg orally daily þ weightbased ribavirin or placebo 57% had psychiatric illnesses, 19% with autoimmune disorders, 16% with cirrhosis

Primary: SVR12

SVR12: 78% (0% placebo; P o 0.001) Genotype 3 significantly associated with reduced response (61%) compared with 93% of genotype 2 patients Overall 81% without cirrhosis had SVR, 61% with cirrhosis

12 wk vs 16 wk

SVR12

Based on a historical response rate for population of 25%, significant increase in SVR12 for both 12-wk group (50%) and 16-wk group (73%; P o 0.001 for each comparison)

anemia 9% vs 14%, neutropenia 0% vs 12%, thrombocytopenia 0% vs 7% Discontinuation due to AEs (sofosbuvir arm vs peginterferon arm): 1% vs 11% Serious AEs (sofosbuvir arm vs peginterferon arm): 3% vs 1% Most common AEs (sofosbuvir arm vs placebo): fatigue 44% vs 24%, nausea 22% vs 18%, headache 21% vs 20% Discontinuation due to AEs (sofosbuvir arm vs placebo): 2% vs 4% Serious AEs (sofosbuvir arm vs placebo): 5% vs 3% Most common AEs (16 wk vs 12 wk): fatigue 47% vs 45%, headache 33% vs 25%, nausea 20% vs 21% Discontinuation due to AEs (16 wk vs 12 wk): 0% vs 1%

13

(continued)

L.M. Childs-Kean and E.O. Hand

201 patients randomized to FUSION17 (Phase 3, receive sofosbuvir 400 blinded, active control mg daily þ weight-based study in treatmentribavirin  12 wk then experienced genotypes 2 continuation of and 3 patients aged at sofosbuvir þ ribavirin  least 18 y in North 4 wk or placebo  4 wk America and New Zealand) Patients

12 wk

Key Finding: Safety

Trial/Design

Study Groups

Outcome Treatment Duration Measures

stratified by genotype and presence of cirrhosis

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VALENCE18 (Phase 3, 419 patients randomized to initially randomized, sofosbuvir 400 mg orally placebo controlled study daily þ weight-based in treatment-naïve and dosing of ribavirin vs experienced genotype 2 placebo and 3 patients aged at least 18 y in Europe. Study design changed to a descriptive study following publication of FUSION study)

24 wk (genotype 3) 12 wk (genotype 2)

SVR12

Key Finding: Efficacy SVR12 rates for genotype 2 not significantly different for 12 vs 16 wk (86% vs 94%) 16 wk significantly better than 12 wk for genotype 3 patients (62% vs 30%, 95% CI for difference, 48 to 15) Lowest response was seen with genotype 3, with cirrhosis, and 12 wk of treatment (19%). This improved to 61% with 16 wk of treatment SVR12 (genotype 2 vs genotype 3): 93%, 85% 99% with HCV viral load o25 IU/mL at Week 4 SVR12 rates in patients with no prior treatment: 92% (cirrhosis) and 95% (no cirrhosis) SVR12 rates in patients who received prior treatment: 62% (cirrhosis) and 87% (no cirrhosis)

Key Finding: Safety Serious AEs (16 wk vs 12 wk): 3% vs 5%

Most common AEs (placebo vs 12 wk vs 24 wk): headache 27%, 29%, 30%, fatigue 19%, 23%, 30%, pruritus 9%, 24%, 27% Discontinuation due to AEs (placebo vs 12 wk vs 16 wk): 1%, 1%, o1% Serious AEs (placebo vs 12 wk vs 16 wk): 2%, 0%, 4% (continued)

Clinical Therapeutics

14

Table II. (continued).

] 2015

Table II. (continued). Trial/Design

Study Groups

12 wk for genotypes 2 and 3 NOT previously treated 24 wk for all others

SVR12

Key Finding: Efficacy Overall, 68% of genotype 3 with cirrhosis had SVR12 compared with 91% without cirrhosis Multivariable logistic regression: 4 factors associated with improved SVR12baseline HCV RNA 6 log10 IU/mL, female gender, absence of cirrhosis, age o50 y SVR12: genotype 1 (76.3%), genotype 2/3, treatment naive (75%), genotype 2/3, treatment experienced (92.7%) SVR12, genotype 2 treatment experienced: 92% SVR12, genotype 3, treatment experienced: 94% By Week 4, 96.5%, 98.5%, and 100% of treatment-naïve genotype 1 patients, treatment-naïve genotype 2/3 patients, and treatment

Key Finding: Safety

Most commonAEs (genotype 1 vs treatment-naïve genotype 2/3 vs treatment-experienced genotype 2/3): fatigue 36%, 35.3%, 46.3%, insomnia 13.2%, 20.6%, 19.5%, nausea 15.8%, 17.6%, 14.6% Discontinuation due to AEs (genotype 1 vs treatment-naïve genotype 2/3 vs treatment-experienced genotype 2/3): 2.6%, 4.4%, 4% Serious AEs (genotype 1 vs treatment-naïve

15

(continued)

L.M. Childs-Kean and E.O. Hand

224 patients received PHOTON19 (Phase 3, sofosbuvir 400 mg orally multicenter, open-label daily þ weight-based trial in treatment-naïve ribavirin genotype 1, 2, 3, or treatment-experienced genotype 2 or 3 HIV coinfected patients aged at least 18 y in the United States and Puerto Rico)

Outcome Treatment Duration Measures

Clinical Therapeutics

16 Table II. (continued). Trial/Design

Study Groups

Outcome Treatment Duration Measures

Key Finding: Efficacy experienced genotype 2/3 patients had viral loads below the lower limit of detection, respectively Among genotype 1 patients, multivariable logistic regression analysis showed that nonblack race, genotype 1a, and completing 24 wk of treatment were associated with achieving SVR12

Key Finding: Safety genotype 2/3 vs treatment-experienced genotype 2/3): 7%, 7.4%, 2.4% No clinically significant changes in HIV RNA in patients not on ART; 2 patients on ART were nonadherent to ART and had HIV viral breakthrough

AEs ¼ adverse events; ART ¼ antiretroviral therapy; HCV ¼ hepatitis C virus; SVR12 ¼ sustained virologic response at 12 wk after end of treatment.

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L.M. Childs-Kean and E.O. Hand

100% 80% 60% 40%

PHOTON (genotype 2/3, experienced)

PHOTON (genotype 2/3, naïve)

PHOTON (genotype 1)

VALENCE (genotype 3)

VALENCE (genotype 2)

FUSION (16 weeks)

FUSION (12 weeks)

POSITRON

FISSION

0%

NEUTRINO

20%

SVR12: Sustained Virological Response 12 weeks after end of treatment

Figure 2. Sustained virologic response 12 weeks after end of treatment rates in Phase 3 trials with sofosbuvir.

treatment-experienced patients infected with HCV genotype One (CONCERTO)-1, -2, -3, and -4 trials were all conducted in Japan with almost all patients having genotype 1b infection. CONCERTO-1 was a randomized, double-blind, placebo-controlled trial that included only treatment-naïve patients;13 CONCERTO-2 was a randomized, open-label, multicenter, multiarm study that enrolled only patients with prior nonresponse to peginterferon and ribavirin;14 CONCERTO-3 was an open-label, single arm trial that studied only patients with prior relapse to peginterferon and ribavirin;14 CONCERTO-4 was an open-label, multicenter study that enrolled both treatment-naïve and treatment-experienced patients.15 Patients with liver cirrhosis, HIV, hepatitis B virus coinfection, or liver disease from any non-HCV cause were excluded from all the CONCERTO studies. Treatment regimens were similar to those in the QUEST-1, QUEST-2, and PROMISE trials, except that the dose of simeprevir used was 100 mg daily. Patients in CONCERTO-1, CONCERTO-2, CONCERTO-3, and treatment-naïve and prior relapse patients in CONCERTO-4 were eligible for RGT. Prior nonresponse patients in CONCERTO-4 were required to complete 48 weeks of treatment. Across the 4 studies, SVR12 rates were very high for treatment-naïve and prior relapse patients ( 90% to 100%; P o 0.0001 for the placebo arm comparison in CONCERTO-1) and lower for prior null response patients ( 40%–50%).

] 2015

Across all Phase 3 trials, the adverse event profile of simeprevir þ peginterferon þ ribavirin was similar to that of peginterferon þ ribavirin alone, including fatigue, headache, flu-like symptoms, alopecia, and hematologic abnormalities.10–15 The side effects of interest in patients receiving simeprevir included rash, pruritus, and photosensitivity, and these tended to occur more frequently in patients receiving simeprevir than those receiving placebo. Despite the high percentage of patients experiencing adverse effects in the clinical trials (425% for each adverse event), rates of serious adverse effects and study discontinuations due to adverse effects were relatively low and were similar to patients receiving placebo with peginterferon and ribavirin. Some patients receiving simeprevir did experience elevated total bilirubin (6%–9%); however, this resolved both with continued treatment and when treatment was discontinued. The 7 Phase 3 trials with simeprevir in combination with peginterferon and ribavirin showed significant efficacy for a wide range of patients with genotype 1 infection. These significant improvements in SVR12 rates over peginterferon and ribavirin included patients with known negative predictive factors to responding to peginterferon and ribavirin alone: IL28B genotype CT and TT, high baseline HCV viral load, and compensated cirrhosis. Important patient populations that were not studied in these trials were HIV coinfected patients, hepatitis B virus coinfected patients, liver transplant recipients, and patients with decompensated liver disease.

17

Clinical Therapeutics

Sofosbuvir Clinical Studies Six Phase 3 trials have been published to date evaluating the efficacy of sofosbuvir þ ribavirin with or without peginterferon for treatment of chronic HCV (Table II and Figure 2).16–19 The first 2 studies, FISSION and NEUTRINO assessed a 12-week regimen of therapy with sofosbuvir þ ribavirin ⫾ peginterferon for previously untreated patients.16 NEUTRINO was a single group, open-label study that included patients with genotypes 1, 5, and 6 and included peginterferon, whereas FISSION was a larger, randomized, active control noninferiority study of patients with genotypes 2 or 3 treated without peginterferon. The primary outcome of each study was SVR12, which was 89% and 96% for genotypes 1 and 4, respectively, in the NEUTRINO study and significantly improved from the historical response rate of 60% (P o 0.001). SVR12 rates in the FISSION study were lower, approximately 67% for both patients who received sofosbuvir þ ribavirin and those who received standard peginterferon þ ribavirin, concluding that sofosbuvir þ ribavirin was noninferior to peginterferon þ ribavirin (P o 0.001). A simultaneous publication evaluated sofosbuvir þ ribavirin alone in patients with genotypes 2 or 3 for whom peginterferon had failed or in whom interferon therapy was contraindicated.17 The POSITRON study, a blinded, placebo-controlled study, evaluated 12 weeks of sofosbuvir þ ribavirin compared with matching placebo.17 Of the 278 patients treated, the majority had a psychiatric illness (57%) that precluded therapy with peginterferon. SVR12 was 78% overall, with genotype 2 patients having an improved response over genotype 3 patients (93% vs 61%). Patients without cirrhosis also had improved SVR12 rates compared with cirrhotics (81% vs 61%). The FUSION study compared a 16-week sofosbuvir þ ribavirin regimen to the previously studied 12-week regimen in treatmentexperienced patients, and found SVR12 rates of 75% and 50% for 16 weeks and 12 weeks, respectively.17 Both were significantly higher than the historical response rate of 25% with peginterferon þ ribavirin (P o 0.001). Of note, 16 weeks of therapy was not significantly better than 12 weeks for patients with genotype 2; however, 16 weeks was better for patients with genotype 3. The lowest SVR12 rates occurred for patients with genotype 3 and cirrhosis who received 12 weeks of treatment (19%), and this number improved to 61% with 16 weeks of treatment.

18

In response to the findings of FUSION that patients with genotype 3 may have higher SVR12 rates with longer treatment durations, the VALENCE study protocol was amended. The purpose of the VALENCE study was to assess the efficacy of 24 weeks of sofosbuvir þ ribavirin for genotype 3 and to confirm the efficacy rates noted for 12 weeks of therapy in genotype 2 patients.18 Patients could be included in the study whether or not they had received prior interferon-based therapy. The initial study design was placebo-controlled, but following publication of the FUSION study, the placebo arm was terminated, and the patients in the placebo arm were offered to enroll in an open-label clinical trial using sofosbuvir þ ribavirin. More than 400 patients were treated, including a large number that had been previously treated (58%), and a significant portion of patients who had no prior response to HCV therapy (30%). Patients with genotype 2 had high SVR12 rates (93%). SVR12 rates were slightly lower but still quite high in patients with genotype 3 receiving 24 weeks of treatment (85%). Notably patients with cirrhosis who had been previously treated had SVR12 rates of 62%. The highest SVR12 rates were seen in patients without cirrhosis who had not previously been treated (95%). Multivariable logistic regression identified baseline HCV viral loads o6 log10 IU/mL, female gender, absence of cirrhosis, and age o50 years as predictors of improved likelihood of SVR12 in patients with genotype 3. The most recently published Phase 3 study of sofosbuvir, PHOTON, was a multicenter, open-label, nonrandomized study of sofosbuvir þ ribavirin for treatment of genotypes 1, 2, or 3 in patients with HIV coinfection.19 Patients with genotypes 2 or 3 could be included if they had been previously treated. To be included, patients on antiretroviral (ART) therapy had to be stable on the current regimen for 8 weeks before starting HCV therapy, have an HIV viral load o50 copies/mL, and a CD4 count 4200 cells/mL. Treatment duration was 12 weeks for patients with genotypes 2 and 3 who had not previously been treated, and 24 weeks for all others. SVR12 rates for genotype 1 patients and previously untreated genotype 2 or 3 patients were both 75% or greater. In treatment-experienced genotype 2 or 3 patients, the reported SVR12 rate exceeded 90%. No clinically significant changes in HIV viral loads were identified for patients not currently receiving ART, and of the

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L.M. Childs-Kean and E.O. Hand 2 patients who had HIV virologic breakthrough, both had undetectable serum levels of ART indicating nonadherence. Rates of serious adverse events and early discontinuation were low in all Phase 3 studies (Table II). The most common adverse events were fatigue, insomnia, diarrhea, headache, and anemia, and most were considered mild-moderate in severity. The 24-week treatment duration was associated with higher rates of diarrhea and mood irritability than the 12-week duration in the VALENCE study, but all other adverse events occurred at similar rates despite prolonging therapy. The above Phase 3 trials give a significant amount of data for patients with compensated liver disease (compensated cirrhosis and lesser degrees of fibrosis) without hepatocellular carcinoma and without a history of liver transplant. In a Phase 2 open-label, multicenter study, 61 patients who met Milan criteria for liver transplant received sofosbuvir and ribavirin for up to 48 weeks or until the time of transplant, whichever duration was shorter, to prevent posttransplantation HCV recurrence.7,20 The primary end point was a HCV viral load below the lower limit of quantitation (LLOQ) (HCV RNA o25 IU/mL) 12 weeks after transplant, referred to as the posttransplant virological response (pTVR). Most patients had genotype 1 infection, were male, and had ChildTurcotte-Pugh Scores of less than 7 (Child-TurcottePugh Class A). Of the 61 patients in the study, 41 had undergone transplant at the time of abstract presentation, 37 had a HCV viral load less than the LLOQ at the time of transplant, and 36 had reached the point where pTVR could be assessed. The pTVR rate was 64% (23 out of 36), and all but 1 patient with HCV recurrence had a viral load below the LLOQ for less than 30 days before receiving the liver transplant, indicating that at least 30 days of a suppressed HCV viral load could lead to better outcomes. The adverse effects reported in these patients were comparable to those in the patients with compensated liver disease in the Phase 3 trials. In a compassionate use program, 63 patients with severe recurrent HCV infection after liver transplantation, including fibrosing cholestatic hepatitis, received sofosbuvir and ribavirin, with or without peginterferon for up to 48 weeks; 45 patients received at least 4 weeks of treatment.21 Most (33 patients) were genotype 1 patients, male, with an average age of

] 2015

55 years. At Week 4 of treatment, 78% of patients had a HCV viral load below the limit of quantitation or detection, and 2 patients who received only 12 weeks of treatment achieved SVR12. The clinical condition of 71% of patients improved in the first 4 weeks of treatment, including normalization of alanine transferase (ALT) and/or bilirubin and resolution of ascites and/or encephalopathy. Another 13% of patients were reported to have clinically stabilized. Seven patients died after starting treatment, and all deaths were attributed to liver disease progression or complications. Forty-seven serious adverse events were reported that were consistent with the known adverse event profile of ribavirin and/or peginterferon (eg, fatigue, diarrhea, and headache); none were attributed to sofosbuvir.

Simeprevir-Sofosbuvir Combination Study Simeprevir and sofosbuvir have been studied as a combination therapy in the COmbination of SiMeprevir and sOfoSbuvir in HCV-infected patients (COSMOS) study, a Phase 2a, randomized, openlabel, multicenter trial (Table III).22 The study enrolled 2 cohorts with varying degrees of fibrosis, including compensated cirrhosis, and treated with simeprevir 150 mg daily þ sofosbuvir 400 mg daily ⫾ weight-based ribavirin for 12 or 24 weeks (Table III). Most patients were men (64%), white (81%), had genotype 1a (78%), had IL28B genotype CT or TT (86%), and were aged 58 years on average. High SVR12 rates were seen in every arm of the trial, exceeding 90% in the overall study population. Despite small numbers in the different treatment arms, there appeared to be no significant effect on SVR12 rates when ribavirin was added to the combination or the duration was extended to 24 weeks. Additionally, the difference in SVR12 rate between patients with genotype 1a and the Q80K polymorphism and patients with genotype 1a without the polymorphism was numerically low (6%). The regimens were overall well tolerated, with fatigue, headache, and nausea being the most common adverse events. Two percent of patients experienced serious adverse events, and 2% withdrew from the study due to adverse events. The very high SVR12 rates seen in COSMOS prompted a Phase 3 trial to confirm the results. In COSMOS, SVR12 rates in excess of 90% were seen in patients with a prior null response to peginterferon

19

Trial/Design COSMOS22 (Phase 2a, randomized, openlabel, multicenter, parallel arm trial in HCV genotype 1 patients aged at least 18 y in the United States. Cohort 1: Nonresponse patients with Metavir fibrosis stage 0-2 Cohort 2: Nonresponse or treatment-naïve patients with Metavir fibrosis stage 3–4)

Study Groups

Treatment Duration

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Cohort 1: 81 patients 12 or 24 wk, randomized to depending simeprevir 150 mg on randomizatiorally daily þ on assignment sofosbuvir 400 mg orally daily þ ribavirin weightbased dosing (n ¼ 51) or simeprevir 150 mg orally daily þ sofosbuvir 400 mg orally daily (n ¼ 29) Cohort 2: 87 patients randomized to simeprevir 150 mg orally daily þ sofosbuvir 400 mg orally daily þ ribavirin weightbased dosing (n ¼ 57) or simeprevir 150 mg orally daily þ sofosbuvir 400 mg orally daily (n ¼ 30)

Outcome Measures Primary: SVR12 Secondary: SVR4, SVR24, RVR, ontreatment failure, viral relapse

Key Finding: Efficacy 92% of patients overall achieved SVR12 and SVR4, 90% (95% CI, 81%–96%) in Cohort 1, 94% (95% CI, 87%– 98%) in Cohort 2 No significant effect on SVR12 by use of ribavirin, treatment duration, or past treatment use RVR overall 81% On-treatment failure 0% Viral relapse 3.5%

Key Finding: Safety Most common AEs (overall study population): fatigue (31%), headache (20%), nausea (16%) AEs of interest (overall study population): rash 17%, pruritus 11%, anemia 14%, photosensitivity 5%, neutropenia 1% Serious AEs (overall study population): 2% AEs leading to permanent discontinuation of study drugs (overall study population): 2%

AEs ¼ adverse events; COSMOS ¼ the COmbination of SiMeprevir and sOfoSbuvir in HCV-infected patients trial; HCV ¼ hepatitis C virus; RVR ¼ Rapid Virological Response, undetectable viral load after 4 weeks of treatment; SVR12 ¼ sustained virologic response at 12 wk after end of treatment.

Clinical Therapeutics

20 Table III. Clinical study of simeprevir þ sofosbuvir.

L.M. Childs-Kean and E.O. Hand and ribavirin as well as compensated cirrhosis, arguably the most difficult HCV patient population to treat. Important patient populations that were not studied in COSMOS were HIV coinfected patients, hepatitis B virus coinfected patients, liver transplant recipients, and patients with decompensated liver disease.

Resistance No patients receiving sofosbuvir in the Phase 3 clinical studies we reviewed experienced viral breakthrough while on treatment, suggesting that sofosbuvir has a high barrier to resistance. The mutations L159F and V321A in the NS5B region were isolated in genotype 3 patients in Phase 3 trials (6 and 5 patients for the respective substitutions).8 Neither of these substitutions altered the overall susceptibility of HCV to sofosbuvir. The S282T substitution in the NS5B region, which had previously been isolated in cell culture from strains that showed a reduced susceptibility to sofosbuvir, was not detected in any patients in the Phase 3 trials; however, it was isolated in a genotype 2b patient who relapsed after sofosbuvir monotherapy in a Phase 2 trial. For this patient, the S282T substitution was no longer detected 12 weeks after treatment had finished. In the trial enrolling patients awaiting liver transplant, several patients experienced relapse, breakthrough, or partial response; the substitutions detected were L159F, C316N, S282R, and/or L320F. However, the clinical significance of these substitutions is not clear. There appears to be no cross-resistance between sofosbuvirresistant HCV strains and other currently available direct-acting antiviral-resistant strains. Simeprevir appears to have a lower barrier to resistance than sofosbuvir. Of the patients who experienced viral relapse or breakthrough with simeprevir þ peginterferon þ ribavirin in the Phase 3 trials, the majority (91%) of patients had substitutions in the NS3 region at Q80, S122, R155, and/or D168.7 The most common substitutions were R155K, predominately in genotype 1a patients, and D168V, predominately in genotype 1b patients. Patients with genotype 1a and a baseline Q80K polymorphism were likely to have virologic failure if a R155K substitution also was present at the time of failure. Patients with treatment-emergent substitutions were followed after treatment ended for a median of 28 weeks (range ¼ 0– 70 months). 48% of patients with the R155K

] 2015

substitution still had detectable levels of the substitution at the end of follow-up; 33% of patients with the D168V substitution continued to have detectable levels until the end of follow-up. Clinical concerns for simeprevir resistance are 2fold: baseline presence of Q80K polymorphism in genotype 1a patients and cross-resistance with other HCV protease inhibitors. As described earlier, a marked decreased SVR12 rate was seen in genotype 1a patients with a baseline Q80K polymorphism who received simeprevir þ peginterferon þ ribavirin.10–12 This decrease was not seen in the patients given simeprevir þ sofosbuvir ⫾ ribavirin in COSMOS.22 The Q80K baseline polymorphism was detected in 30% of the overall genotype 1a patient populations in the Phase 2b and Phase 3 trials and was 48% in US genotype 1a patient populations in the trials. The simeprevir package insert as well as published guidelines recommend screening for Q80K polymorphism at baseline if a patient is to receive the simeprevir þ peginterferon þ ribavirin regimen, and to choose an alternative regimen if the polymorphism is detected.3,7 Guidelines state that a Q80K polymorphism test may be considered for a patient who is to undergo simeprevir þ sofosbuvir ⫾ ribavirin treatment, but even the presence of a Q80K polymorphism does not preclude treatment with this regimen.3 Cross-resistance is expected across the HCV protease inhibitor class. HCV strains with the simeprevirassociated substitutions R155K and I170T have shown reduced susceptibility to both boceprevir and telaprevir. Substitutions that emerged in patients who failed boceprevir- or telaprevir-containing regimens, most notably R155K, A156T, and A156V, are expected to reduce susceptibility to a simeprevircontaining regimen.7 Therefore, patients who have experienced virologic failure to a boceprevir- or telaprevir-containing HCV regimen should not be treated with a simeprevir-containing regimen.3

Postmarketing Findings Since the approval of simeprevir and sofosbuvir, there has been 1 important change in regard to drug– drug interactions with simeprevir. Steady-state simeprevir was studied in combination with single-dose cyclosporine in healthy volunteers before approval, and there was found to be no significant change in the simeprevir levels.23 However, during an ongoing

21

Clinical Therapeutics Phase 2 study of simeprevir with ribavirin and daclatasvir (an NS5A replication complex inhibitor) in patients after liver transplant taking cyclosporine at steady state, the AUC of simeprevir was increased approximately 6-fold.3,7 Therefore, simeprevir and cyclosporine coadministration is no longer recommended. These data seem to suggest that there may be a difference in the drug interaction potential of hepatically targeted and metabolized drugs in patients with healthy livers and those with liver disease, and more drug–drug interaction studies are needed in patients with liver disease. Widespread use of sofosbuvir has not identified any additional drug interactions. The adverse events of interest during the Phase 3 trials with simeprevir included rash and photosensitivity. Most of these symptoms were mild-moderate in nature and did not necessitate HCV therapy discontinuation. Practical considerations for treatment and prevention of rash and photosensitivity include limiting sun exposure and using sun protective clothing and sunscreen, use of over-the-counter topical steroids and oral antihistamines, and monitoring for rash progression. If the rash becomes severe, medical care is recommended, and the simeprevir should be discontinued.24 More widespread use of simeprevir and sofosbuvir has not identified additional safety signals.

Influence on Clinical Practice The approval of sofosbuvir- and simeprevircontaining regimens has prompted significant revisions to the hepatitis C treatment guidelines put out jointly by the American Association for the Study of Liver Disease (AASLD), the Infectious Disease Society of America (IDSA), and the International Antiviral Society-USA (IAS-USA)3 as well as those released by the European Association for the Study of the Liver (EASL).25 The standard of care as recently as 2013, peginterferon þ ribavirin with or without boceprevir or telaprevir, is no longer recommended in both sets of updated guidelines.3,25 Whereas the revised AASLD/ IDSA/IAS-USA guidelines divide recommendations among 4 major groups (treatment-naïve patients, treatment-experienced patients, HIV coinfected patients, and other unique patient populations), the treatment recommendations are generally similar regardless of treatment experience and HIV coinfection status.3 These guidelines also divide the recommendations for interferon-eligible and interferon-ineligible patients. The

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preferred regimens for genotype 1 patients are sofosbuvir þ peginterferon þ ribavirin  12 weeks for interferon-eligible, treatment-naïve patients and simeprevir þ sofosbuvir with or without ribavirin for interferon-ineligible patients regardless of treatment experience. Alternatives for genotype 1 patients include sofosbuvir þ ribavirin  24 weeks and simeprevir þ peginterferon þ ribavirin  24 to 48 weeks. The preferred regimen for all genotype 2 patients is sofosbuvir þ ribavirin  12 weeks, with consideration of adding peginterferon to the regimen as an alternative. The preferred regimen for genotype 3 is sofosbuvir þ ribavirin  24 weeks with sofosbuvir þ peginterferon þ ribavirin  12 weeks as an alternative. Additional unique patient populations included in the AASLD/IDSA/IAS-USA guidelines are patients with cirrhosis, HCV recurrence following liver transplantation, and renal impairment.3 The guidelines recommend patients with decompensated cirrhosis be referred to a specialist, preferably a transplant center, with the recommended treatment regimen being sofosbuvir þ ribavirin for up to 48 weeks. The same regimen (or until the time of transplant, whichever duration is shorter) is recommended for patients meeting Milan criteria and awaiting liver transplant. Patients after liver transplant with genotype 1 are recommended to receive simeprevir þ sofosbuvir ⫾ ribavirin  12 to 24 weeks (preferred) or sofosbuvir þ ribavirin ⫾ peginterferon  24 weeks (alternative). Genotype 2 or 3 patients after liver transplant should receive sofosbuvir þ ribavirin  24 weeks. The EASL guidelines differ from the AASLD/IDSA/ IAS-USA guidelines in that they list treatment options for various patient populations with levels of recommendation, instead of listing a preferred regimen and 1 or more alternative regimens.25 For genotype 1 patients, the options in the EASL guidelines include sofosbuvir þ peginterferon þ ribavirin, simeprevir þ peginterferon þ ribavirin, daclatasvir þ peginterferon þ ribavirin (for genotype 1b), sofosbuvir þ ribavirin, sofosbuvir þ simeprevir ⫾ ribavirin, and sofosbuvir þ daclatasvir ⫾ ribavirin. The genotype 2 and 3 options include sofosbuvir þ ribavirin ⫾ peginterferon and sofosbuvir þ daclatasvir ⫾ ribavirin (for genotype 3 only). Daclatasvir is available in Europe but not yet in the United States. One concern with the use of these medications is access to them, particularly due to their cost. At the time of US Food and Drug Administration approval,

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L.M. Childs-Kean and E.O. Hand sofosbuvir had a wholesale acquisition cost of $28,000 per bottle of 28 pills ($1000 per pill and $84,000 for 12 weeks), and simeprevir had a wholesale acquisition cost of $66,360 for 12 weeks.26 It is important to note that these costs do not include the additional costs for ribavirin ⫾ peginterferon or laboratory monitoring. The implications for payers are significant because there are millions of patients with chronic HCV infection in the United States alone. The pricing of the medications in more resource-limited countries is expected to be less. As future HCV regimens become available, pricing will likely continue to be a factor in treatment regimen choice.

study results reveal very high SVR12 rates (more than 91% for 12 weeks regardless of treatment experience or presence of cirrhosis). A third such regimen is sofosbuvir with daclatasvir, an NS5A replication complex inhibitor, with or without ribavirin, for 12 to 24 weeks.34 This regimen is already available to patients and providers in Europe. High SVR12 rates were seen in patients with genotypes 1, 2, and 3 (89%–98%). Additionally, other drugs from many direct-acting antiviral classes, including but not limited to NS3A/4 protease inhibitors, NS5A replication complex inhibitors, NS5B non-nucleoside polymerase inhibitors, and NS5B nucleoside polymerase inhibitors, are being studied in combination regimens for no longer than 12-week durations.

FUTURE DIRECTIONS Future studies involving simeprevir and sofosbuvir should include more data in “real-life” patients. This includes evaluating SVR12 rates and safety in patients with multiple comorbidities, including but not limited to hepatitis B coinfection and decompensated cirrhosis. SVR12 rates appear to not be as high in genotype 3 patients compared with other genotypes with the new regimens; more studies are needed to identify additional treatment options for this group of patients. Additionally, there is the need to evaluate drug– drug interactions in patients with HCV infection rather than only healthy volunteers in the event that HCV-related liver disease plays a role in the interaction. Further data on sofosbuvir use in patients with severe renal impairment is expected soon as well. One other area that will need further inquiry is the role of sofosbuvir and/or simeprevir in the treatment of acute HCV infection. Additional Phase 3 studies have been completed for other HCV drug regimens. One regimen is a combination of sofosbuvir and ledipasvir, an NS5A replication complex inhibitor, in a fixed dose combination pill for genotype 1 patients. The Phase 3 studies for this regimen indicate very high SVR12 rates (94%– 99% for 12 weeks regardless of treatment experience and 93% for 8 weeks in treatment-naïve patients without cirrhosis) with 1 pill per day dosing.27–29 Another regimen with Phase 3 data published is a combination of ABT 450/ritonavir/ombitasvir (NS3A/ 4 protease inhibitor/pharmacokinetic booster/NS5A replication complex inhibitor) with dasabuvir (NS5B non-nucleoside polymerase inhibitor) with or without ribavirin for genotype 1 patients.30–33 The Phase 3

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CONCLUSIONS The approvals of simeprevir and sofosbuvir are supported by clinical evidence from multiple trials. These approvals have improved the chances of virologic cure (SVR12) with a shorter duration of treatment; possibly fewer adverse events; and the option of all oral, interferon-free treatment for chronic HCV infection. Sofosbuvir and/or simeprevir are now a component of all standard-of-care regimens in multiple sets of published guidelines.

REFERENCES 1. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guide lines/en/. April 2014. Accessed August 1, 2014. 2. Centers for Disease Control and Prevention. Hepatitis C FAQs for Healthcare Professionals. http://www.cdc.gov/ hepatitis/HCV/HCVfaq.htm#section1. July 2014. Accessed August 1, 2014. 3. AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguide lines.org. August 2014. Accessed August 11, 2014. 4. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatol. 2009;49:1335–1374. 5. Chen J, Florian J, Carter W, et al. Earlier sustained virological response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterol. 2013; 144:1450–1455. 6. Ghany MG, Nelson DR, Strader DB, et al. An update on the treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guidelines from the American

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Clinical Therapeutics

7. 8. 9.

10.

11.

12.

13.

14.

15.

Association for the Study of Liver Diseases. Hepatol. 2011;54:1433– 1444. Olysio [package insert]. Janssen Therapeutics. November 2013. Sovaldi [package insert]. Gilead Sciences, Inc. December 2013. ClinicalTrials.gov. Sofosbuvir plus ribavirin in subjects with HCV infection and renal insufficiency. http://clinical trials.gov/ct2/show/NCT01958281? term=sofosbuvirþANDþrenal&rank= 1. Accessed August 15, 2014. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384:403–413. Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomized, doubleblind, placebo-controlled phase 3 trial. Lancet. 2014;384:414–426. Forns X, Lawitz E, Zeuzern S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterol. 2014;146:1669–1679. Hayashi N, Izumi N, Kumada H, et al. Simeprevir with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial. J Hepatol. 2014;61:219–227. Izumi N, Hayashi N, Kumada H, et al. Once-daily simeprevir with peginterferon and ribavirin for treatmentexperienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies. J Gastroenterol. 2014;49:941–953. Kumada H, Hayashi N, Izumi N, et al. Simeprevir (TMC435) once daily with peginterferon α-2b and ribavirin in patients with genotype-1 hepatitis-C

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16.

17.

18.

19.

20.

21.

22.

23.

24.

virus infection: the CONCERTO-4 study. Hepatol Res. 2014. http://dx. doi.org/10.1111/hepr.12375. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878–1887. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. New Engl J Med. 2013;368:1867–1877. Zeuzern S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin for genotypes 2 and 3. N Engl J Med. 2014;370:1993–2001. Sulkowski MS, Naggie S, Lalezari J, et al. Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. JAMA. 2014;312:353– 361. Curry M, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatol. 2013;58:313A–317A. Forns X, Fontana RJ, Moonka D, et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. Hepatol. 2013;58:730A–760A. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014. http://dx.doi.org/10.1016/ S0140-6736(14)61036-9. Ouwerkerk-Mahadevan S, Simion A, Mortier S, et al. No clinically significant interaction between the investigational HCV protease inhibitor TMC435 and the immunosuppressives cyclosporine and tacrolimus. Hepatol. 2012;56:191A–1144A. U.S. Department of Veterans Affairs National Hepatitis C Resource Center Program and the Office of Public Health. Adverse Effects.

25.

26.

27.

28.

29.

30.

31.

32.

33.

http://www.hepatitis.va.gov/provider/ guidelines/2014hcv/adverse-effects. asp. Accessed November 10, 2014. European Association for the Study of the Liver. EASL Recommendations on the treatment of hepatitis C. http://www.easl.eu/assets/appli cation/files/easl_recommendations_ hcv_2014_full.pdf. Accessed August 1, 2014. Owens GM. Hepatitis C: New treatments emerge in 2014 that will have profound implications for payers. Am J Manag Care. http://www. ajmc.com/payer-perspectives/0314/ Hepatitis-C-New-Treatments-Emer ge-in-2014-That-Will-Have-Profoun d-Implications-for-Payers. Accessed August 1, 2014. Afdahl N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. New Engl J Med. 2014; 370:1483–1493. Afdahl N, Zeuzern S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889–1898. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370: 1879–1888. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/ r-ombitasvir and dasabuvir with ribavirin. New Engl J Med. 2014;370: 1594–1603. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. New Engl J Med. 2014;370: 1983–1992. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. New Engl J Med. 2014;370: 1973–1982. Zeuzern S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT450/r-ombitasvir and dasabuvir with ribavirin. New Engl J Med. 2014; 370:1604–1614.

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Address correspondence to: Lindsey M. Childs-Kean, PharmD, MPH, BCPS, Clinical Assistant Professor, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, 9200 113th St, N, PH 102, Seminole, FL 33772. E-mail: [email protected]fl. edu

] 2015

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