Grazoprevir/Elbasvir for the Treatment of Hepatitis C Application for Inclusion on the WHO Model List of Essential Medicines (EML) Contents

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Grazoprevir/Elbasvir for the treatment of Hepatitis C Application for inclusion on the WHO Model List of Essential Medicines (EML) Contents

Table of Tables ...... 3 Table of Figures ...... 3 General Items ...... 4 Summary statement of the proposal for inclusion, change or deletion ...... 4 Name of the WHO technical department and focal point supporting the application (where relevant) ...... 4 Name of organization(s) consulted and/or supporting the application ...... 4 International Non-proprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine ...... 5 Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate) ...... 5 Whether listing is requested as an individual medicine or as representative of a pharmacological class ...... 5 Treatment details, public health relevance and evidence appraisal and synthesis ...... 6 Grazoprevir/elbasvir treatment details ...... 6 WHO Guidelines ...... 6 US Guidelines (AASLD/IDSA) ...... 6 European Guidelines (EASL) ...... 7 Summary ...... 8 Additional requirements associated with treatment ...... 8 Information supporting the public health relevance ...... 9 Review of benefits: summary of comparative effectiveness in a variety of clinical settings ...... 10 Overview of grazoprevir/elbasvir efficacy...... 10 Genotype 1 ...... 11 Phase 3 trials ...... 11 Phase 2 trials ...... 13 Genotype 1 summary...... 14 Genotype 2 ...... 14 Phase 3 trials ...... 14 Phase 2 trials ...... 14 Genotype 2 summary...... 15 Genotype 3 ...... 15 Phase 3 trials ...... 15 Phase 2 trials ...... 15 Genotype 3 summary...... 15 Genotype 4 ...... 16 Phase 3 trials ...... 16 Phase 2 trials ...... 17 Genotype 4 summary...... 17 Genotype 5 ...... 17

Phase 3 trials ...... 17 Phase 2 trials ...... 18 Genotype 5 summary...... 18 Genotype 6 ...... 18 Phase 3 trials ...... 18 Phase 2 trials ...... 19 Genotype 6 summary...... 19 Special populations ...... 20 HCV-HIV coinfection...... 20 Drug-drug interactions ...... 20 Severe renal impairment ...... 20 Intravenous drug users receiving Opioid Agonist Therapy ...... 21 Efficacy conclusion ...... 21 Review of harms and toxicity: summary of evidence on safety ...... 22 Phase 3 trials ...... 22 Phase 2 trials ...... 23 Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group ...... 24 United States pricing ...... 24 Non-United States pricing ...... 24 Cost-effectiveness analyses ...... 24 Regulatory information ...... 26 Summary of regulatory status of the medicine ...... 26 Availability of pharmacopoeial standards ...... 26 References ...... 27

Table of Tables

Table 1 Formulations and strengths proposed for inclusion ...... 5 Table 2 Product presentation and posology ...... 6 Table 3 AASLD/IDSA grazoprevir/elbasvir treatment recommendations in individuals with or without compensated cirrhosis ...... 7 Table 4 Summary of grazoprevir/elbasvir trials by genotype ...... 10 Table 5 Completed Phase 3 clinical trials in HCV genotype 1 infected individuals (intent-to-treat analyses) ..... 11 Table 6 Completed Phase 2 clinical trials in HCV genotype 1 infected individuals (intent-to-treat analyses) ..... 13 Table 7 Completed Phase 2 clinical trials in HCV genotype 2 infected individuals (intent-to-treat analyses) ..... 14 Table 8 Completed Phase 2 clinical trials in HCV genotype 3 infected individuals (intent-to-treat analyses) ..... 15 Table 9 Completed Phase 3 clinical trials in HCV genotype 4 infected individuals (intent-to-treat analyses) ..... 16 Table 10 Completed Phase 2 clinical trials in HCV genotype 4 infected individuals (intent-to-treat analyses) ... 17 Table 11 Completed Phase 2 clinical trials in HCV genotype 5 infected individuals (intent-to-treat analyses) ... 18 Table 12 Completed Phase 3 clinical trials in HCV genotype 6 infected individuals (intent-to-treat analyses) ... 18 Table 13 Completed Phase 2 clinical trials in HCV genotype 6 infected individuals (intent-to-treat analyses) ... 19 Table 14 Safety data from Phase 3 trials of grazoprevir/elbasvir ...... 22 Table 15 Safety data from Phase 2 trials of grazoprevir/elbasvir ...... 23 Table 16 Original US market prices of interferon-free regimens (adapted from Bell et al. 2016) ...... 24 Table 17 Standard of care regimens for non-cirrhosis, treatment-naive patients with HCV genotype 1, and cost per SVR (adapted from Rosenthal et al. 2016) ...... 25 Table 18 Regulatory status according to stringent regulatory authorities ...... 26

Table of Figures

Figure 1 Overall proportion of patients achieving SVR when combining trials for each genotype. Confidence intervals are represented by error bars at 95% confidence ...... 11

General Items

Summary statement of the proposal for inclusion, change or deletion

Grazoprevir with elbasvir is a combination product with US-FDA approved indication for the treatment of chronic hepatitis C (HCV) genotypes 1 and 4 in adults. [1] Grazoprevir is a protease inhibitor of HCV NS3/4A that prevents cleavage of the polyprotein necessary for replication. Elbasvir is an NS5A inhibitor, preventing HCV viral RNA replication and virion assembly. [2]

The regimen is included in current HCV guidelines as a first-line option for the treatment of HCV genotype 1 or 4 treatment-naïve and treatment-experienced individuals, with or without cirrhosis. It is also recommended for individuals with human immunodeficiency virus (HIV) coinfection and those with severe renal impairment. The regimen is tolerated well and has a good side effect profile with few individuals discontinuing treatment because of adverse events.

Given this efficacy and safety data, grazoprevir/elbasvir is a potent regimen in the fight against chronic HCV and should supplement the current HCV regimens included in the WHO Essential Medicines List (EML).

Name of the WHO technical department and focal point supporting the application (where relevant)

WHO Global Hepatitis Programme, Department of HIV/AIDS

Name of organization(s) consulted and/or supporting the application

Department of Pharmacology and Therapeutics University of Liverpool 70 Pembroke Place Liverpool L69 3GF

International Non-proprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine

 Grazoprevir (J05AX)  Elbasvir (J05AX)

Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate)

Grazoprevir/elbasvir (trade name, Zepatier) is available as a fixed-dose film-coated tablet produced by the manufacturer Merck Sharp & Dohme Corp. Each tablet contains 100 mg of grazoprevir and 50 mg of elbasvir. The recommended dose of the combination is one tablet taken orally once daily with or without food.

This information is shown in Table 1. The safety and effectiveness of grazoprevir/elbasvir have not been established in paediatric patients and as such, no paediatric formulations are included.

Table 1 Formulations and strengths proposed for inclusion

Medicine Formulation Market availabilitya Grazoprevir 100 mg - Elbasvir 50 mg - Fixed-dose combinations Zepatier; Merck Sharp & Grazoprevir + Elbasvir Tablet: 100 mg + 50 mg Dohme Corp. aNo known market availability of individual formulations of grazoprevir and elbasvir

Whether listing is requested as an individual medicine or as representative of a pharmacological class

The listing is requested as Individuals medicines.

Treatment details, public health relevance and evidence appraisal and synthesis

Grazoprevir/elbasvir treatment details

Grazoprevir 100 mg in combination with elbasvir 50 mg should be provided as per the recommendations from international/national guidelines as detailed in the sections below. Grazoprevir/elbasvir is given with or without ribavirin for 12-16 weeks, depending on genotype, treatment experience, and presence of baseline resistance polymorphisms. [1]

Table 2 Product presentation and posology

Product Presentation Posology Grazoprevir/elbasvir Tablet containing 100 mg One tablet one daily grazoprevir and 50 mg elbasvir (morning)

WHO Guidelines

Grazoprevir in combination with elbasvir was not considered in the updated 2016 WHO Guidelines as it had not received stringent regulatory (SRA) approval at the time of writing. [3] The Guidelines Development Group included that initial available data suggests that the combination is efficacious in a variety of situations, including in those with HIV coinfection, and with later stage chronic kidney disease.

US Guidelines (AASLD/IDSA)

The 2016 AASLD/IDSA guidelines for treating HCV have been updated to include grazoprevir/elbasvir as a recommended regimen in treatment-naïve or experienced patients with genotype 1 or 4 with or without compensated cirrhosis. [4] AASLD/IDSA treatment indications and quality of recommendations are shown in Table 3.

In addition, the regimen is recommended in AASLD/IDSA guidelines for individuals co- infected with HIV, however there are limitations on with which antiretrovirals it can be co- administered (Class IIa, Level B). Antiretrovirals that cannot be used with grazoprevir/elbasvir include cobicistat, efavirenz, etravirine, nevirapine, and all HIV protease inhibitors.

A 12-week regimen of grazoprevir/elbasvir is recommended for use in individuals with genotype 1a, 1b, or 4 with severe renal impairment (creatinine clearance of <30 mL/min)

(Class IIb, Level B). The regimen is not recommended for patients with decompensated cirrhosis.

Table 3 AASLD/IDSA grazoprevir/elbasvir treatment recommendations in individuals with or without compensated cirrhosis

Patient population Treatment Duration Quality Genotype 1a: Treatment- Grazoprevir/elbasvir 12 weeks Class I, Level naïve or Peg-IFN/RBV A experienced, no baseline NS5A RAVs Genotype 1a: Treatment- Grazoprevir/elbasvir + WB 16 weeks Class IIa, naïve or Peg-IFN/RBV ribavirin Level B (TN); experienced, baseline Class I, Level NS5A RAVs B (TE) Genotype 1b: Treatment- Grazoprevir/elbasvir 12 weeks Class I, Level naïve or Peg-IFN/RBV A experienced Genotype 1: NS3 inhibitor Grazoprevir/elbasvir + WB 12 weeks Class IIa, experienced ribavirin Level B Genotype 4: Treatment- Grazoprevir/elbasvir 12 weeks Class IIa, naïve or relapse after Level B Peg-IFN/RBV Genotype 4: Peg-IFN/RBV Grazoprevir/elbasvir+ WB 16 weeks Class IIa, experienced ribavirin Level B

Abbreviations: WB RBV, weight-based ribavirin; RAV, resistance-associated variants; TN, treatment-naïve; TE, Peg-IFN/RBV exposed

European Guidelines (EASL)

The latest EASL guidelines mirror AASLD guidelines, with grazoprevir/elbasvir recommended for use in individuals with genotype 1 or 4 infection. [5] Treatment-naïve and treatment- experienced patients infected with genotype 1 or 4 with or without compensated cirrhosis should receive grazoprevir/elbasvir for 12 weeks. In genotype 1a infected individuals with a high baseline HCV RNA level (>800,000 IU/mL) or with baseline RAVs, treatment should include WB RBV and be extended to 16 weeks.

As with US guidelines, EASL guidelines recommend the use of grazoprevir/elbasvir for 12 weeks in patients with genotype 1 or 4 infection with HIV coinfection or severe renal impairment/end-stage renal disease.

Summary

 Not yet included in WHO guidelines but recommended in US and European guidelines;  Recommended for use in patients with genotype 1a, 1b, or 4 infection;  Recommended for use in HIV co-infected individuals although not concomitantly with several HIV antiretrovirals;  Recommended for use in patients with severe renal impairment;  Not recommended for use in patients with decompensated cirrhosis.

Additional requirements associated with treatment

Prior to administration of HCV treatment, active chronic HCV needs to be confirmed. In most settings, this is conducted through an initial assay to detect the hepatitis C antibody (HCVAb). If HCVAb are detected, HCV RNA should be determined by a sensitive molecular method. [5] In areas where HCV RNA assays are not available or not affordable, measurement of HCV core antigen levels provides an alternative measure to confirm infection and whether treatment has been successful. [6, 7]

If feasible, other pre-therapeutic assessments should be conducted, including genotyping, liver disease severity, and renal function. Contraindications to therapy should be thoroughly explored, particularly in patients co-infected with HIV on antiretroviral regimens.

Treatment should be initiated and monitored by a physician experienced in the management of patients with chronic HCV. The safety and effectiveness of task shifting of HCV treatment to non-specialised providers are currently being explored in various settings. [8, 9, 10] Specialised treatment facilities are not required for the initiation or monitoring of treatment.

Monitoring includes assessments of treatment efficacy, of safety and side-effects, and of drug-drug interactions. Monitoring of treatment efficacy can be simplified by measuring HCV RNA (or HCV core antigen levels) at baseline and 12 or 24 weeks after the end of therapy. In terms of safety, grazoprevir/elbasvir are generally well tolerated with low frequencies of adverse advents.

Information supporting the public health relevance

Most recent analyses of the global prevalence of HCV indicate that an estimated 115 million persons are HCVAb positive of which approximately 80 million are chronically infected. [11] The prevalence varies greatly by region and population, with the highest burden, in terms of numbers chronically infected, observed in sub-Saharan Africa and South and East Asia.

Data from the Global Burden of Disease study indicates that the number of deaths attributable to HCV has been steadily increasing over the past decades from around 330,000 in 1990 to over 700,000 deaths per year in 2013. [12] This reflects the lag time between infection and the development of complications, such as liver cirrhosis and hepatocellular carcinoma. The number of deaths is projected to increase through several more decades unless there is a rapid scale-up in accessibility to treatment. [13]

The availability of direct-acting antivirals (DAAs) for treatment against HCV provide a realistic opportunity to scale-up treatment, particularly in resource-limited settings, where public health programmes were previously unfeasible. Scale-up of screening and treatment using efficacious DAA regimens, inclusive of grazoprevir/elbasvir, has the potential to reduce the incidence of liver-related complications and mortality in individuals with HCV infection. [14, 15] In fact, data suggests that an increase in screening rates and treatment with highly efficacious regimens will be necessary to curb the increased mortality expected over the coming years. [14] Inclusion of grazoprevir/elbasvir on the WHO EML will help to ensure timely access to HCV treatment worldwide, alleviating the projected future health and economic burden. [13]

Further, while several new DAA combinations have shown excellent SVR12 rates, certain groups, including patients who have previously failed treatment or who have developed cirrhosis, renal failure, or HIV coinfection remain difficult-to-treat subgroups. Grazoprevir/elbasvir combination has high efficacy in the treatment of HCV in many of these subgroups, providing a potent option in the fight against the disease.

Review of benefits: summary of comparative effectiveness in a variety of clinical settings

Several Phase 2 and 3 clinical studies have been carried out evaluating the efficacy of grazoprevir/elbasvir for treatment of HCV genotypes 1, 2, 3, 4, 5, and 6. These trials include C-EDGE, C-EDGE CO-INFECTED, C-EDGE CO-STAR, C-EDGE H2H, C-SCAPE, C-SALVAGE, C- SURFER, C-WORTHY (Lawitz et al. 2015 & Sulkowski et al. 2015), C-SWIFT (Poordad et al. 2015) and C-SWIFT (Lawitz et al. 2016).

Overview of grazoprevir/elbasvir efficacy

Table 4 below shows a summary of the clinical trials conducted and an estimate of grazoprevir/elbasvir efficacy in each genotype (as measured by sustained virologic response 12 weeks after treatment, SVR12). This information in displayed graphically in Figure 1.

Table 4 Summary of grazoprevir/elbasvir trials by genotype

Geno- Patient SVR12/Total (%) Trials included Interventions type Characteristics (95% C.I.)

1 C-SURFER, C-EDGE H2H, C-EDGE TN & TE, includes GZR 100mg/EBR 50mg 1809/1894 (95.5%) TE, HIV/HCV co- or 20mg  RBV or  (95% C.I.: 94.5% - 96.4%) C-EDGE TN, C-EDGE CO- infected and SOF, 4-18 wks INFECTED, C-EDGE CO-STAR, C- patients with SALVAGE, C-WORTHY (Sulkowski severe kidney et al.), C-WORTHY (Lawitz et al.) disease & C-SWIFT (Lawitz et al.) 2 C-SCAPE TN, non-cirrhotic GZR 100mg/EBR 50mg 24/30 (80.0%) + RBV, 12 wks (95% C.I.: 61.4% - 92.3%) 3 C-SWIFT (Poordad, F. et al. 2015) TN, Non-cirrhotic GZR 100mg/EBR 50mg 38/40 (95.0%) & Cirrhotic + SOF, 8 & 12 wks (95% C.I.: 83.1% - 99.4%)

4 C-EDGE H2H, C-EDGE TE, C-EDGE TN & TE, includes GZR 100mg/EBR 50mg 118/126 (93.7%) TN, C-EDGE CO-INFECTED, C- HIV/HCV co-  RBV, 12-16 wks (95% C.I.: 87.9% - 97.2%) EDGE CO-STAR, C-SCAPE infected 5 C-SCAPE TN, non-cirrhotic GZR 100mg/EBR 50mg 5/8 (62.5%)  RBV 12 wks (95 C.I.: 24.5% - 91.5%) 6 C-SCAPE, C-EDGE TE, C-EDGE TN, TN & TE, includes GZR 100mg/EBR 50mg 26/35 (74.3%) C-EDCGE CO-INFECTED, C-EDGE HIV/HCV co-  RBV, 12 – 16 wks. (95 C.I.: 56.7% - 87.5%) CO-STAR infected TOTAL All trials above All above GZR 100mg/EBR 50mg 2,020/2,133 (94.7%) characteristics or 20mg  RBV or  (95% C.I.: 93.7 % - included SOF, 4-18 wks 95.6%)*

Abbreviations: TN, treatment-naïve; TE, treatment-experienced; RBV, ribavirin; GZR, grazoprevir; EBR, elbasvir; PR, pegylated interferon *Not meta-analysis performed, simple addition of trial results

Figure 1 Overall proportion of patients achieving SVR when combining trials for each genotype. Confidence intervals are represented by error bars at 95% confidence

Genotype 1

Phase 3 trials

Table 5 Completed Phase 3 clinical trials in HCV genotype 1 infected individuals (intent-to-treat analyses)

Study Study design Patient Intervention SVR12, n(%) VF, LTFU, WC, reference characteristics n(%) n(%) n(%)

C-SURFER, Multicentre (68 - Chronic kidney GZR 100mg/EBR 115/116 (99.1%) 1/116 0 0 (Roth et al. global) double- disease (stage 50mg, 12 weeks (<1%) 2015) blind, placebo- 4-5), TN or TE controlled, randomised safety study, observational study of efficacy C-EDGE Randomised, GT1a (18) GT1b GZR 100mg/EBR 18/18 (100.0%) 0 0 0 H2H, (Sperl multisite (EU and (105), TN or TE 50mg, 12 weeks et al. 2016) Turkey), open- label trial, fixed GZR 100mg/EBR 104/105 (99.0%) 0 1 0 dose 50mg, 12 weeks (<1%)

C-EDGE TE, Randomised GT1a & b, TE GZR 100mg/EBR GT1a: 55/61 (90.2%) 6 2 0 (Kwo et al. control trial, 50mg, 12 weeks GT1b: 34/34 (100%) GT1- (6%) (2%) 2015) multisite, open- other:1/1 (100%)

label with GZR 100mg/EBR GT1a: 56/60 (93.3%) 6 0 0 parallel group. 50mg + RBV, 12 GT1b: 28/29 (96.6%) (7%) weeks

GZR 100mg/EBR GT1a:45/48 (93.8%) 7(7%) 1 0 50mg, 16 weeks GT1b:46/48 (95.8%) (<1%)

GZR 100mg/EBR GT1a: 55/58 (94.8%) 0 3 0 50mg + RBV, 16 GT1b: 36/36 (100%) GT1- (3%) weeks other:2/2 (100%)

C-EDGE Randomized, TN GZR 100mg/EBR GT1a: 144/157 (91.7%) 10 3 0 TN, blinded, placebo- 50mg, 12 weeks (6%) (1%) (Zeuzem et controlled trial, al. 2015) multicentre GZR 100mg/EBR GT1b: 129/131 (98.5%) 1 1 0 50mg, 12 weeks (<1%) (<1%)

C-EDGE Open-label, non- TN, HIV/HCV GZR 100 mg/ GT1a: 135/139 (97.1%) 4 5 0 CO- randomised, co-infection EBR 50 mg, 12 (3%) (4%) INFECTED, single arm, global wks (Rockstroh multicentre trial, GZR 100 mg/ GT1b: 42/42 (100.0%) 0 2 0 et al 2015.) EBR 50 mg, 12 (5%) wks C-EDGE Randomised, TN. HIV/HCV Immediate GZR GT1a: 147/154 (95.5%) 4 1 0 CO-STAR, parallel-group, co-infection. On 100mg/EBR (3%) (<1%) (Dore et al. placebo- opioid agonist 50mg, 12 weeks 2016) controlled, therapy (OAT) 3 double-blind trial months or Immediate GZR GT1b: 28/30 (93.3%) 1 1 0

longer, 100mg/EBR (3%) (3%) 50mg, 12 weeks

Deferred GZR GT1a: 64/71 (90.1%) 1 6 0 100mg/EBR (1%) (8%) 50mg, 12 weeks

Deferred GZR GT1b: 13/14 (92.9%) 0 1 0 100mg/EBR (7%) 50mg, 12 weeks

TOTAL: All - All above GZR 100mg/EBV 1,294/1,351 (95.8%) 41 28 1 Phase 3 characteristics 50mg  RBV, 12 - (95% C.I.: 94.6% -96.8%) (3%) (2%) (<1%) trials included 16 wks

Abbreviations: TN, treatment-naïve; TE, treatment-experienced; GT, genotype; RBV, ribavirin; GZR, grazoprevir; EBR, elbasvir; PR, pegylated interferon; VF, virological failure; LTFU, lost to follow up; WC, withdrawn consent

Phase 2 trials

Table 6 Completed Phase 2 clinical trials in HCV genotype 1 infected individuals (intent-to-treat analyses)

Patient VF LTFU W/C Study Reference Study Design Intervention SVR12, n(%) Characteristics n(%) n(%) n(%)

C-WORTHY, International Cohort 1: TN, GZR 100mg/EBR 50mg 28/31 3 0 0 (Lawitz et al. 2015) randomised compensated + RBV, 12 wks (90.3%) (10%) control trial, cirrhosis GZR 100mg/EBR 50mg, 28/29 1 (3%) 0 0 open-label, 12 wks (96.6%) multi-centre, with parallel GZR 100mg/EBR 50mg 31/32 0 0 group + RBV, 18 wks (96.9%) GZR 100mg/EBR 50mg, 29/31 2 (6%) 0 0 18 wks (93.5%) Cohort 2: TE, GZR 100mg/EBR 50mg 30/32 0 2 0 non-cirrhotic + RBV, 12 wks (93.8%) (6%) & GZR 100mg/EBR 50mg, 30/33 3 0 0 compensated 12 wks (90.9%) (10%) cirrhosis, GZR 100mg/EBR 50mg 33/33 0 0 0 + RBV, 18 wks (100.0%) GZR 100mg/EBR 50mg, 31/32 1 (3%) 0 0 18 wks (96.9%) C-WORTHY, Randomised, TN, HIV/HCV GZR 100mg/EBR 50mg+ 24/30 5 (2%) 1 0 (Sulkowski et al. parallel- co-infection RBV, 8 wks (80.0%) (3%) 2015) group, multi- GZR 100mg/EBR 50mg 79/85 3 (4%) 3 0 centre, open- or 20mg + RBV, 12 wks (92.9%) (4%) label, GZR 100mg/EBR 50mg, 43/44 1 (2%) 0 0 international 12 wks (97.7%) trial. GZR 100mg/EBR 50mg 28/29 1 (2%) 0 0 + RBV, 12 wks (96.6%) GZR 100mg/EBR 50mg, 26/30 2 (6%) 2 0 12 wks (86.7%) (6%) C-SALVAGE, (Forns International, TE GZR 100mg/EBR 50mg 76/79 3 (4%) 0 0 et al. 2015) prospective + RBV, 12 wks (96.2%) open-label trial C-SWIFT (Poordad, Open-label, TN, Non- GZR 100mg/EBR 50mg 10/30 20 0 0 F. et al. 2015) cirrhotic + SOF, 4 wks (33.3%) (67%)

GZR 100mg/EBR 50mg 26/30 4 0 0 + SOF, 6 wks (86.7%) (13%)

TN, Cirrhotic GZR 100mg/EBR 50mg 16/20 4 0 0 + SOF, 6 wks (80.0%) (20%)

GZR 100mg/EBR 50mg 17/18 1 (6%) 0 0 + SOF, 8 wks (94.4%)

C-SWIFT- FINAL, Patients Cirrhotic, TE GZR 100mg/EBR 50mg 5/5 0 0 0 (Lawitz, E.J. et al. failing 4, 6 or + SOF 400mg + RBV, 12 (100.0%) 2016 8 weeks of weeks

GZR/EBR + Non-cirrhotic, GZR 100mg/EBR 50mg 18/18 0 0 0 SOF are TE + SOF 400mg + RBV, 12 (100.0%) retreated weeks

TOTAL: All Phase 2 - All above GZR 100mg/EBR 50mg 608/671 25 9 0 trials characteristics or 20mg  RBV and (90.6%) (5%) (2%) included SOF, 4-18 wks (95% C.I.: 88.2% - 92.7%)

Genotype 1 summary

A total of 1894 individuals infected with HCV genotype 1 were treated in eleven trials (6 Phase 3 and 5 Phase 2) with grazoprevir (100 mg) and elbasvir (50 mg) ± ribavirin and sofosbuvir. The total cohort includes both treatment-naïve and experienced patients and those with HIV/HCV co-infection. The C-SURFER trial included patients with chronic kidney disease. For treatment regimens of 12 weeks or longer the overall SVR12 rate was 95% (95%CI 94.4-96.4). The results of these trials have led to grazoprevir/elbasvir approval and recommendation for use in individuals with genotype 1 HCV infection, regardless of treatment experience or HIV co-infection; treatment is also recommended in individuals with genotype 1 infection and renal impairment.

Genotype 2

Phase 3 trials

No Phase 3 trials of grazoprevir/elbasvir in HCV genotype 2 have been conducted.

Phase 2 trials

Table 7 Completed Phase 2 clinical trials in HCV genotype 2 infected individuals (intent-to-treat analyses)

Study Patient VF LTFU W/C Study Design Intervention SVR12, n(%) Reference Characteristics n(%) n(%) n(%)

C-SCAPE, Open-label, TN, non-cirrhotic GZR 100mg/EBR 50mg + 24/30 (80.0%) 4 2 (7%) 0 (Brown et Randomised RBV, 12 wks (13%) al. 2015) control trial

TOTAL: All - TN, non-cirrhotic GZR 100mg/EBR 50mg + 24/30 (80.0%) 4 2 (7%) 0 Phase 2 RBV, 12 wks (95% C.I.: 61.4% - (13%) trials 92.3%)

Genotype 2 summary

A total of 30 genotype 2 HCV-infected patients were treated in one Phase 2 trial with grazoprevir (100 mg) and elbasvir (50 mg) with ribavirin. Patient were treatment-naïve, non- cirrhotic and mono-infected with HCV. The overall SVR12 rate was 80% (95%CI 61.4-92.3). Given this low efficacy compared with other treatments, grazoprevir/elbasvir is currently not approved for use in individuals with genotype 2 HCV infection.

Genotype 3

Phase 3 trials

No Phase 3 trials of grazoprevir/elbasvir have been conducted in patients with genotype 3 infection.

Phase 2 trials

Table 8 Completed Phase 2 clinical trials in HCV genotype 3 infected individuals (intent-to-treat analyses)

Study Patient VF LTFU W/C Study Design Intervention SVR12, n(%) Reference Characteristics n(%) n(%) n(%)

C-SWIFT Open-label, TN, Non-cirrhotic GZR 100mg/EBR 50mg + 14/15 (93.3%) 1 0 0 (Poordad, SOF, 8 wks (7%) F. et al. 2015) GZR 100mg/EBR 50mg + 14/14 (100.0%) 0 0 0 SOF, 12 wks

TN, Cirrhotic GZR 100mg/EBR 50mg + 10/11 (90.9%) 1 0 0 SOF, 12 wks (9%)

TOTAL: All - TN, Cirrhotic and GZR 100mg/EBR 50mg + 38/40 (95.0%) 2 0 0 Phase 2 Non-cirrhotic SOF, 8 & 12 wks (95% C.I.: 83.1% - (5%) trials 99.4%)

Genotype 3 summary

A total of 40 individuals with HCV genotype 3 were treated in one Phase 2 trial with grazoprevir (100 mg), elbasvir (50 mg) and sofosbuvir (400 mg). Patients were treatment- naïve, cirrhotic and non-cirrhotic, and mono-infected with HCV. For treatment regimens 12 weeks or longer the overall SVR12 rate was 96.0% (95%CI 79.7-99.9). Grazoprevir/elbasvir is currently not recommended for use in individuals with genotype 3 infection, however the in combination with sofosbuvir, the regimen has demonstrated promising results.

Genotype 4

Phase 3 trials

Table 9 Completed Phase 3 clinical trials in HCV genotype 4 infected individuals (intent-to-treat analyses)

Study Patient LTFU W/C Study Design Intervention SVR12, n(%) VF n(%) Reference Characteristics n(%) n(%)

C-EDGE H2H, Randomised, multi-site TN or TE, GZR 100mg/EBR 6/6 (100.0%) 0 0 0 (Sperl et al. (EU and Turkey), open- 50mg, 12 weeks 2016) label trial, fixed dose, (vs SOF/PR)

C-EDGE TE, Randomised control TE, includes GZR 100mg/EBR 7/9 (77.8%) Failure - - (Kwo et al. trial, multisite, open- HCV/HIV co- 50mg, 12 weeks data 2015) label with parallel infected included in group. GT1

GZR 100mg/EBR 14/15 (93.3%) - - - 50mg + RBV, 12 weeks

GZR 100mg/EBR 3/5 (60.0%) - - - 50mg, 16 weeks

GZR 100mg/EBR 8/8 (100.0%) - - - 50mg + RBV, 16 weeks

C-EDGE TN, Randomized, blinded, TN GZR 100mg/EBR 18/18 0 0 0 (Zeuzem et placebo-controlled 50mg, 12 weeks (100.0%) al. 2015) trial, multicentre

C-EDGE CO- Open-label, non TN, HCV/HIV GZR 100 mg/ 26/27 (96.3%) 1 (4%) 1(4% 0 INFECTED, randomised, single co-infected EBR 50 mg, 12 ) (Rockstroh arm, global multicentre wks et al 2015.) trial

C-EDGE CO- Randomised, parallel- TN, HIV/HCV Immediate GZR 11/12 (91.7%) 0 1 0 STAR, (Dore group, placebo- co-infection 100mg/EBR (8%) et al. 2016) controlled, double- On Opioid 50mg, 12 weeks blind trial agonist

therapy (OAT) Deferred GZR 6/6 (100.0%) 0 0 0

3 months or 100mg/EBR longer 50mg, 12 weeks

TOTAL: All - All above GZR 100mg/EBR 99/106 - - - Phase 3 characteristics 50mg  RBV, 12- (93.4%) trials included 16 wks (95% CI: 86.9 - 97.3%)

Phase 2 trials

Table 10 Completed Phase 2 clinical trials in HCV genotype 4 infected individuals (intent-to-treat analyses)

Study Patient VF LTFU W/C Study Design Intervention SVR12, n(%) Reference Characteristics n(%) n(%) n(%)

C-SCAPE, Open-label, TN, non-cirrhotic GZR 100mg/EBR 50mg + 10/10 (100.0%) 0 0 0 (Brown et Randomised RBV, 12 wks al. 2015) control trial GZR 100mg/EBR 50mg, 9/10 (90.0%) 0 1 (10%) 0 12 wks

TOTAL: All - TN, non-cirrhotic GZR 100mg/EBR 50mg  19/20 (95.0%) 0 1 (5%) 0 Phase 2 RBV, 12 wks (95% C.I.: 75.1% trials - 99.9%)

Genotype 4 summary

A total of 125 individuals with HCV genotype 4 were treated in 6 trials (5 Phase 3 and 1 Phase 2) with grazoprevir (100 mg) and elbasvir (50 mg) with and without ribavirin. Patients were both treatment-naïve and experience, mono- and co-infected with HIV; 126 patients were on antiretroviral therapy (ART) and 18 were on opioid agonist therapy (OAT). For treatment regimens 12 weeks or longer, the overall SVR12 rate was 93.7% (95%CI 87.9- 97.2). These results have led to the approval and recommendation of grazoprevir/elbasvir for individuals with genotype 4 infection, regardless of treatment experience; individuals with previous treatment failure require the addition of ribavirin and 16 weeks of treatment.

Genotype 5

Phase 3 trials

No phase 3 trials of grazoprevir/elbasvir have been conducted in patients with genotype 5 infection.

Phase 2 trials

Table 11 Completed Phase 2 clinical trials in HCV genotype 5 infected individuals (intent-to-treat analyses)

Study Patient LTFU W/C Study Design Intervention SVR12, n(%) VF n(%) Reference Characteristics n(%) n(%)

C-SCAPE, Open-label, TN, non-cirrhotic GZR 100mg/EBR 50mg + 4/4 (100.0%) 0 0 0 (Brown et Randomised RBV, 12 wks al. 2015) control trial GZR 100mg/EBR 50mg, 1/4 (25.0%) 3 (75%) 0 0 12 wks

TOTAL: All - TN, non-cirrhotic GZR 100mg/EBR 50mg  5/8 (62.5%) 3 (38%) 0 0 Phase 2 RBV, 12 wks (95% C.I.: 24.5% - trials 91.5%)

Genotype 5 summary

A total of eight genotype 5 HCV infected patients were treated in one Phase 2 trial with grazoprevir (100 mg) and elbasvir (50 mg) with and without ribavirin. Patients were treatment-naïve, mono-infected with HCV, and non-cirrhotic. For treatment regimens 12 weeks or longer the overall SVR12 rate was 62.5% (95%CI 24.5-91.5). Treatment of genotype 5 infection with grazoprevir/elbasvir is not recommended under treatment guidelines.

Genotype 6

Phase 3 trials

Table 12 Completed Phase 3 clinical trials in HCV genotype 6 infected individuals (intent-to-treat analyses)

Study Patient VF LTFU W/C Study Design Intervention SVR12, n(%) Reference Characteristics n(%) n(%) n(%)

C-EDGE TE, Randomised control HIV co- GZR 100mg/EBR 3/4 (75.0%) Failure included in (Kwo et al. trial, multisite, open- infection and 50mg, 16 weeks GT1 2015) label with parallel mono- group. infection GZR 100mg/EBR 2/2 (100.0%) 50mg + RBV, 16 weeks

C-EDGE TN, Randomized, blinded, TN GZR 100mg/EBR 8/10 (80.0%) 2 0 0 (Zeuzem et al. placebo-controlled 50mg, 12 weeks 2015) trial, multicentre

C-EDGE CO- Open-label, non- TN, HCV/HIV GZR 100 mg/ 2/2 (100.0%) 0 0 0 INFECTED, randomised, single co-infection EBR 50 mg, 12 (Rockstroh et al arm, global wks 2015.) multicentre trial,

C-EDGE CO- Randomised, parallel- On Opioid Immediate GZR 3/5 (60.0%) 2 0 0 STAR, (Dore et group, placebo- agonist 100mg/EBR al. 2016) controlled, double- therapy (OAT) 50mg, 12 wks blind trial 3 months or longer, some Deferred GZR 2/4 (50.0%) 2 0 0 HIV/HCV co- 100mg/EBR infection, TN 50mg, 12 wks

TOTAL: All - All above GZR 100mg/EBR 20/27 (74.1%) - - - phase 3 trials characteristics 50mg  RBV, 12 (95% C.I.: included – 16 wks 53.7% - 88.9%)

Phase 2 trials

Table 13 Completed Phase 2 clinical trials in HCV genotype 6 infected individuals (intent-to-treat analyses)

Study Patient VF LTFU W/C Study Design Intervention SVR12, n(%) Reference Characteristics n(%) n(%) n(%)

C-SCAPE, Open-label, TN, Non-cirrhotic GZR 100mg/EBR 3/4 (75.0%) 1 0 0 (Brown et Randomised 50mg + RBV, 12 wks al. 2015) control trial GZR 100mg/EBR 3/4 (75.0%) 1 0 0 50mg, 12 wks

TOTAL: All - TN, Non-cirrhotic GZR 100mg/EBR 6/8 (75.0%) 2/8 0 0 Phase 2 50mg  RBV, 12 wks (95% C.I.: 34.9% - 96.8%) (25%) trials

Genotype 6 summary

A total of 35 genotype 6 HCV infected patients were treated in five trials (4 Phase 3 and 1 Phase 2) with grazoprevir (100 mg) and elbasvir (50 mg) with and without ribavirin. This included treatment-naïve and experienced, HIV/HCV co-infected patients, and both cirrhotic and non-cirrhotic patients. Two individuals were on ART and nine were on OAT. For treatment regimens 12 weeks or longer the overall SVR12 rate was 74.3% (95%CI 56.7- 87.5%). Grazoprevir/elbasvir treatment of genotype 6 infection is not approved.

Special populations

HCV-HIV coinfection

HCV-HIV coinfection is a significant concern, with over 4 million people worldwide coinfected with HIV and HCV. [16] Detectable HIV infection accelerates the progression of HCV and has been associated with higher rates of all-cause, liver-related, and AIDS-related deaths. [17] Thus, concurrent treatment of HIV and HCV is necessary.

Elbasvir/grazoprevir was tested in coinfected patients in two key trials: C-WORTHY and C- EDGE coinfection; the results of these studies have been incorporated above. In summary, over the two trials, 277 patients with HIV and HCV coinfection were treated. Individuals were treatment-naïve chronic HCV (genotype 1, 4, or 6), both with and without cirrhosis. Patients received grazoprevir/elbasvir with or without ribavirin for 12 weeks. A total of 264/277 (95.3%) individuals achieved SVR12.

Drug-drug interactions

Grazoprevir/elbasvir is not recommended for use in HIV patients whose ART regimens contain an HIV-protease inhibitor. Atazanavir, darunavir, lopinavir, saquinavir, and tipranavir are protease inhibitors whose use is contraindicated with grazoprevir/elbasvir because elevated concentrations of grazoprevir/elbasvir have been observed, leading to elevated ALT levels. [17] Conversely, efavirenz is contraindicated due to reductions in the concentration of grazoprevir/elbasvir. Cobicistat and ritonavir should be used with caution.

Severe renal impairment

Grazoprevir/elbasvir has been evaluated in one study Phase 3 study focusing on patients with stage 4 or 5 chronic kidney disease, including patients receiving haemodialysis. In the C-SURFER study, safety and efficacy of grazoprevir/elbasvir (100mg/50mg) for 12 weeks was evaluated in individuals with HCV genotype 1 infection, treatment-naïve or experienced, and with or without cirrhosis. In the intent-to-treat analysis, 115/122 (94.3%) individuals achieved SVR12.

Intravenous drug users receiving Opioid Agonist Therapy

Injection drug use is a major risk factor for infection with HCV, accounting for most new HCV infections. [18] The C-EDGE CO-STAR trial evaluated grazoprevir/elbasvir for 12 weeks in individuals who inject intravenous drugs currently receiving OAT. Individuals were genotype 1, 4, or 6, with or without HIV coinfection, and with or without cirrhosis. Of the 201 individuals enrolled, 184 (91.5%) achieved SVR12. Several individuals not achieving SVR12 were because of HCV reinfection (5 individuals). Where reinfection was counted as success, 189/201 (94.0%) individuals achieved SVR12 with grazoprevir/elbasvir therapy.

Efficacy conclusion

Grazoprevir/elbasvir is approved in HCV guidelines as a first-line option for the treatment of treatment-naïve and treatment-experienced individuals with HCV genotype 1a, 1b, or 4, with or without cirrhosis. Grazoprevir/elbasvir may be used in patients with HIV coinfection however the regimen has more drug-drug interactions than other treatments. Grazoprevir/elbasvir may also be used in individuals with severe renal impairment.

Review of harms and toxicity: summary of evidence on safety

Safety data from Phase 2 and 3 trials of grazoprevir/elbasvir have shown that the regimen is well tolerated and safe. A total of 2317 individuals have been treated with the regimen in Phase 2 and 3 trials; an unknown number of individuals have been treated in real-world situations since the approval of the regimen.

Data from the Phase 2/3 studies shows few discontinuations because of adverse events (<1%) and a rate of serious adverse events comparable to other regimens. No deaths have been observed in clinical trials that were deemed related to grazoprevir/elbasvir treatment.

The most frequently reported adverse effects were headache, nausea, fatigue, decreased appetite, anaemia, pyrexia, and elevations of ALT. These adverse events are similar to those observed with other DAA combinations.

Phase 3 trials

Table 14 Safety data from Phase 3 trials of grazoprevir/elbasvir

Deaths, n Total No. D/C due to AE, Serious AE n Study Reference Genotypes (%) of Patients n (%) (%) (causes) C-SURFER, (Roth et al. 2015) 1 122 0 16 (14%) 1 (<1%)

C-EDGE H2H, (Sperl et al. 1 & 4 129 0 1 (<1%) 0 2016)

C-EDGE CO-STAR, (Dore et al. 1, 4 & 6 296 1 (<1%) 10 (3%) (1 drug 1 (<1%) 2016) related) (placebo group)

C-EDGE TE, (Kwo et al. 2015) 1, 4 & 6 420 7 (2%) 14 (3%) 0

C-EDGE TN, (Zeuzem et al. 1, 4 & 6 316 3 (<1%) 9 (3%) 2 (<1%) 2015) unrelated unrelated

C-EDGE CO-INFECTED, 1, 4 & 6 218 0 8 (3%) 0 (Rockstroh et al 2015.) unrelated

Total 1, 4 & 6 1,501 11 (<1%) 58 (4%) 4 (<1%)

Abbreviations: GT, genotype; AE, adverse event; D/C, discontinuation

There were four deaths observed from a total of 1,501 patients treated in Phase 3 trials (<1%). In each case the investigators deemed the death to be unrelated to the study drug.

Phase 2 trials

Table 15 Safety data from Phase 2 trials of grazoprevir/elbasvir

Total No. D/C due to Deaths, n (%) Study Reference Genotypes Serious AE n (%) of Patients AE, n (%) (causes) C-SCAPE, (Brown et al. 2,4,5 & 6 98 1 (1%) 3 (3%) 1 drug related 0 2015)

C-WORTHY, (Lawitz et 1 253 2 (<1%) 7 (3%) 1 abdominal pain 1 (<1%) al. 2015) related to drug.

C-WORTHY, 1 218 0 3 (1%) 2 related to drug 0 (Sulkowski et al. 2015)

C-SALVAGE, (Forns et 1 79 1 (1%) 5 (6.3%) 0 al. 2015)

C-SWIFT- FINAL, 1 25 0 1(4%) 0 (Lawitz, E.J. et al. 2016

C-SWIFT (Poordad, F. 1 & 3 143 1 (<1%) 2 (1%) B cell 0 et al. 2015) lymphoma/Pyelonephritis

Total All GT’s 816 5 (<1%) 21 (2.6%) 1 (<1%)

Abbreviations: GT, genotype; AE, adverse event; D/C, discontinuation

Of a total of 816 patients enrolled in Phase 2 trials of grazoprevir/elbasvir, one individual died. Investigators deemed the death unrelated to study drugs.

Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group

United States pricing

The wholesale acquisition cost (WAC) for a 12-week course of therapy with grazoprevir/elbasvir is estimated at US$54,600 in the US. While this is higher than the cost of previous, interferon-based treatments, the original US market prices of other new alternative therapies are significantly higher. [17] This data is shown in Table 16.

Table 16 Original US market prices of interferon-free regimens (adapted from Bell et al. 2016)

Simeprevir Daclatasvir Elbasvir- Ledipasvir- (Olysio)- (Daklinza)- grazoprevir sofosbuvir sofosbuvir sofosbuvir (Zepatier) (Harvoni) (Sovaldi) (Sovaldi) 12 weeks $54,600 $150,000 $94,500 $147,000 16 weeks $72,800 NA NA NA 24 weeks NA NA $189,000 NA

Non-United States pricing

The cost of pharmaceuticals in the US is disproportionately high, even in comparison to other high income nations. [19] The total cost of a 12-week treatment course of grazoprevir/elbasvir in the UK is £36,500. [20] Merck have agreed a nationally available price reduction with the Commercial Medicines Unit; the contract prices agreed through the framework are in confidence.

Pharmaceutical companies have several strategies for access in low and middle-income countries to facilitate access without losing control of the product. No known strategies for the grazoprevir/elbasvir combination are currently in place.

Cost-effectiveness analyses

Using the US WAC costs, the cost of cure using grazoprevir/elbasvir is lower than that of interferon-based therapy and other DAA regimens.1 This is shown in Table 17 below. [19]

1 Calculations do not include the costs of diagnostics or other costs related to receiving treatment

Table 17 Standard of care regimens for non-cirrhosis, treatment-naive patients with HCV genotype 1, and cost per SVR (adapted from Rosenthal et al. 2016)

Regimena SVR ratea WAC price Cost per SVR Pegasys + ribavirin x48 weeks 41% $41,758 $101,849 Sofosbuvir + ledipasvir x12 weeks 99% $94,500 $95,454 Grazoprevir + elbasvir x12 weeks 94% $54,600 $58,085

aStandard of care regimen and efficacy data taken from package inserts

Grazoprevir/elbasvir treatment has been shown to be cost-effective in a range of different scenarios, including in the recent appraisal by the National Institute for Health and Care Excellence (NICE) for the NHS in England. [19, 20, 21, 17]

Regulatory information

Summary of regulatory status of the medicine

Grazoprevir/elbasvir (as Zepatier, Merck Sharp & Dohme Corp.) received US-FDA regulatory approval in January 2016. The product has also received approval from several other SRA boards including EMA, Australia, and Health Canada. This data is shown in Table 18.

Table 18 Regulatory status according to stringent regulatory authorities

Product SRA board Approval status US-FDA Approved (28/01/16) Zepatier (100 mg EMA Approved (22/07/16) grazoprevir + 50 mg Australia Approved (29/08/16) elbasvir) Japan Not listed Health Canada Approved (19/01/16)

Availability of pharmacopoeial standards

None of the drugs included in this application are included in the British, International, US, or European Pharmacopeia’s.

References

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Clinical trial references

Brown, A. et al. (2015). C-SCAPE: EFFICACY AND SAFETY OF 12 WEEKS OF GRAZOPREVIR ± ELBASVIR ± RIBAVIRIN IN PATIENTS WITH HCV GT2, 4, 5, OR 6 INFECTION. Retrieved October 12, 2016, from http://www.natap.org/2015/EASL/EASL_06.htm

Dore, G. J. et al. (2016). Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med. http://doi.org/10.7326/m16-0816 [Date accessed 21/10/2016] (C-EDGE CO-STAR)

Forns, X. et al. (2015). Grazoprevir and Elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. Journal of Hepatology. 63(3), 564-572. [Date accessed 12/10/2016] (C-SALVAGE)

Kwo, P. et al. (2015). C-EDGE TE: EFFICACY AND SAFETY OF GRAZOPREVIR/ELBASVIR +/- RBV FOR 12 OR 16 WEEKS IN PATIENTS WITH HCV G1, G4 OR G6 INFECTION WHO PREVIOUSLY FAILED PEGINTERFERON/RBV: C- EDGE TREATMENT-EXPERIENCED. Retrieved from http://www.natap.org/2015/EASL/EASL_04.htm [Accessed 25/10/2016]

Lawitz, E. et al. (2014). Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK- 5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous . The Lancet, 385(9973), 1075–1086. http://doi.org/10.1016/S0140-6736(14)61795-5 (C-WORTHY) [Accessed 26/10/2016]

Lawitz, E. J. et al. (2016). C-SWIFT - RETREATMENT FINAL RESULTS: HIGHLY SUCCESSFUL RETREATMENT OF GT1-INFECTED PATIENTS WITH 12 WEEKS OF ELBASVIR/GRAZOPREVIR PLUS SOFOSBUVIR AND RIBAVIRIN AFTER FAILURE OF SHORT-DURATION ALL-ORAL THERAPY. Retrieved November 2, 2016, from http://www.natap.org/2016/EASL/EASL_110.htm

Poordad, F. et al. (2015). C-SWIFT: GRAZOPREVIR/ELBASVIR + SOFOSBUVIR IN CIRRHOTIC AND NONCIRRHOTIC, TREATMENT-NAIVE PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 1 INFECTION, FOR DURATIONS OF 4, 6 OR 8 WEEKS AND GENOTYPE 3 INFECTION FOR DURATIONS OF 8 OR 12 WEEKS. Retrieved October 2, 2016, from http://www.natap.org/2015/EASL/EASL_11.htm

Rockstroh, J.K. et al. (2015). C-EDGE Co-Infected: final results from Phase 3 Study of elbasvir / grazoprevir in Patients with HCV/HIV. Retrieved October 24, 2016 from http://www.natap.org/2015/AASLD/AASLD_61.htm

Roth, D. et al. (2015). Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. The Lancet. 386(10003), 1537-1545. [Date accessed 12/10/2016]

Sperl, J. et al. (2016) C-EDGE H2H Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial. Journal of Hepatology. http://doi.org/10.1016/j.jhep.2016.07.050 [Date accessed 12/10/2016]

Sulkowski, M. et al. (2015). Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK- 5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono- infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. The Lancet. 385(9973) 1087-1097. http://dx.doi.org/10.1016/S0140-6736(14)61793-1 [Date accessed 13/10/2016]

Zeuzem, A. et al. (2015). Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection. Annals of Internal Medicine, 163(1), 1–13. http://doi.org/10.7326/M15-0785 [Accessed 14/10/2016] (C-EDGE TN)