Expert Review of Clinical Pharmacology

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Elbasvir and grazoprevir for chronic genotypes 1 and 4

Mohamed El Kassas, Tamer Elbaz, Yasmeen Abd El Latif & Gamal Esmat

To cite this article: Mohamed El Kassas, Tamer Elbaz, Yasmeen Abd El Latif & Gamal Esmat (2016): Elbasvir and grazoprevir for chronic hepatitis C genotypes 1 and 4, Expert Review of Clinical Pharmacology, DOI: 10.1080/17512433.2016.1233813

To link to this article: http://dx.doi.org/10.1080/17512433.2016.1233813

Accepted author version posted online: 07 Sep 2016. Published online: 26 Sep 2016.

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Download by: [T&F Internal Users], [Priti Nagda] Date: 18 October 2016, At: 05:00 EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2016 http://dx.doi.org/10.1080/17512433.2016.1233813

DRUG PROFILE Elbasvir and grazoprevir for chronic hepatitis C genotypes 1 and 4 Mohamed El Kassasa, Tamer Elbazb, Yasmeen Abd El Latifc and Gamal Esmatb aEndemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt; bEndemic Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt; cTropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

ABSTRACT ARTICLE HISTORY Introduction: During the last few years, treatment of hepatitis C virus (HCV) revolutionized with the Received 16 June 2016 appearance of direct antiviral agents especially for patients with HCV genotypes 1 and 4 infections. Accepted 5 September 2016 Elbasvir (NS5A inhibitor) and grazoprevir (NS3/4A protease inhibitor) are newly developed drugs that Published online 26 are presented in fixed dose combination tablets. September 2016 Areas covered: This review covers the mechanism of action, pharmacokinetic and pharmacodynamics KEYWORDS properties, clinical uses, safety and efficacy of elbasvir/grazoprevir in managing a wide variety of easy HCV; genotype 1; genotype and difficult to treat populations (such as presence of , treatment experienced, co-infection 4; elbasvir and grazoprevir with HIV and patients with inherited blood disorders). Expert commentary: Elbasvir/grazoprevir combination showed great efficacy with high rates of sus- tained virological response rates in genotypes 1 and 4 HCV infection. In addition, it retained a good safety profile and is generally well tolerated.

1. Introduction in selected genotypes including genotype 1. However, the approval of the NS5B drug, , changed the map of Chronic hepatitis C virus (HCV) infection represents a world- HCV management. USA and/or Europe approvals included wide health problem due to its major drastic sequelae that different drug combinations as sofosbuvir/ fixed-

result from end-stage liver disease which may end up with dose combination, sofosbuvir/daclatasvir, sofosbuvir/simepre- liver transplantation. It carries a possibility of malignancy vir, and ritonavir-boosted paritaprevir//dasabuvir development () certainly on top of [9,10]. One of the recently approved combinations was that liver cirrhosis [1]. Six major genotypes (1–6) and more than 50 produced by Merck Company marketed under the name of subtypes of HCV have been described with clear geographical Zepatier™. This combination includes elbasvir (EBR, NS5A inhi- distribution [2]. This variation in genotypes represents an bitor) and grazoprevir (GZR, NS3/4A inhibitor) [11]. It has been obstacle in developing a standard pan-genotypic treatment, US FDA approved for treatment of adult patients chronically and hence, the global trends in HCV genotype prevalence are infected with HCV genotypes 1 or 4 [12]. EBR and GZR have a to be considered in treatment options and guidelines. high barrier to resistance as well as a good spectrum of Genotype 1 is the most prevalent genotype worldwide with activity against many common resistant-associated variants more than half of the global HCV cases and shows a particular (RAVs). Even more, different clinical trials conducted for this higher prevalence in western developed countries [3]. HCV combination hit difficult frontiers such as patients coinfected genotype 4 is predominant in Africa and the Middle East with HIV, patients with hepatic or renal impairment, and region where it represents more than 90% of detected HCV patients with inherited blood disorders (IBLD). genotypes in a country with a very high seroprevalence of HCV like Egypt [4]. In the past and till recent years, pegylated interferon-based 2. Pharmacokinetic and pharmacodynamic therapy represented the mainstay treatment for chronic HCV. properties However, it was associated with suboptimal cure rates and a Both EBR and GZR are delivered as a fixed-dose combination poorly tolerated safety profile [5]. Cirrhotic patients were tablet that is taken once daily regardless to food intake. Peak always considered to be difficult to treat due to low sustained plasma concentration reaches 3 h for EBR and 2 h for GZR. virologic response (SVR) rates and higher incidence of serious Both bind to plasma proteins at a rate of 99.9% for EBR and adverse events (SAEs) [6,7]. 98.8% for GZR [13]. They are partially eliminated by oxidative During the pegylated interferon-based treatment era, both metabolism and they have no circulating metabolites that HCV genotypes 1 and 4 were considered to be the most hard- could be detected in human plasma. Both are primarily to-treat genotypes [8]. The emergence of new directly acting excreted by feces and just less than 1% is excreted in urine [1]. antiviral agents (DAAs) from the protease group (telaprevir As regards antimutant potency and antiviral pressure, GZR and boceprevir) has markedly improved the treatment results showed potency against many protease-resistant mutants

CONTACT Mohamed El Kassas [email protected] Endemic Medicine Department, Faculty of Medicine, Helwan University, Helwan, Egypt © 2016 Informa UK Limited, trading as Taylor & Francis Group 2 M. EL KASSAS ET AL. observed in previous studies. GZR maintains its potency with Table 1. The main drug–drug interactions for elbasvir/grazoprevir combination. continued dosing while retaining high plasma and hepatic con- Drug Class Reasons for interactions centrations without cellular toxicities [14,15]. Studies showed a Phenytoin Antiepileptic agents CYP3A inducers mean maximum viral load reduction equivalent to 5.38 and Carbamazepine Rifampin Antibiotic 5.22 log10 in genotypes 1 and 3 infections, respectively [16]. Efavirenz Antiretrovirals In patients with hepatic decompensation, EBR area under Atazanavir OATP inhibitors the curve (AUC) showed unaltered plasma concentration– Lopinavir Darunavir time in non-HCV patients who had mild-to-severe liver Tipranavir impairment. This differed with GZR. Different degrees of Cuclosporins Immunosupressants hepatic impairment in non-HCV-infected patients were asso- ciated with progressively higher AUC in direct relation to Table 2. degree of hepatic severity and as compared to persons with Safety of elbasvir/grazoprevir in clinical trials. normal hepatic function [13]. In advanced liver disease, Occurrence of serious adverse CYP3A4 that is responsible for drug metabolism (including Trial Study population events (%) metabolism of GZR) is usually affected and so leads to C-WORTHY [29,30] HIV confection, genotype 1 3 increased exposure to the drug. Also, efflux and uptake C-SALVAGE [27,28] Previous DAA failure; non- 5.1 transporters may show upregulation and downregulation, cirrhotic and compensated cirrhosis, genotype 1 respectively. Downregulation of organic anion transporting C-SALT [31] Cirrhosis with decompensation, 13.3 polypeptide (OATP) uptake transporters in advanced liver genotype 1 disease will decrease the uptake of GZR from the circulation C-SURFER [33] Advanced kidney disease 15.6 C-EDGE [34] Non-cirrhotic and compensated 3 to the hepatocytes with subsequent increase of its plasma cirrhosis, genotypes 1, 4, 6 concentration. Other related factors include decreased pre- DAA: Directly acting antiviral agent. systemic metabolism due to portal shunting (therefore bypassing the liver) and the decreased production of pro- teins (including the binding proteins) with a subsequent The main drug–drug interactions for EBR/GZR combination are increase of free unbound drugs leading to toxicity [17–20]. outlined in Table 1. For these safety reasons, it is not generally recommended to treat HCV-infected patients who are Child–Pugh class B or

higher with EBR/GZR regimen. As compared to AUC in patients without severe renal 3. Safety issues impairment, AUC is 10% and 25% higher in dialysis-dependent Many phase II and III clinical trials discussed the safety profile subjects for GZR and EBR, respectively. Also, AUC is 40% and of EBR/GZR combination in a large group of various patient 46% higher in non-dialysis-dependent patients for GZR and populations [26–36]. Generally, this combination was found to EBR, respectively [1]. In patients with severe renal impairment be safe and tolerable with varying prevalence of adverse or patients on dialysis, no clinically important changes or need events according to the study population (Table 2). The most to dose adjustment was recorded while treating chronic HCV common adverse events were headache, fatigability, nausea, by using EBR/GZR regimen [21]. and diarrhea. Most of these events were mild with no obvious drug discontinuation because of side effects. The detailed adverse events within each study will be discussed. 2.1. Drug–drug interactions Concerning drug–drug interactions, both EBR and GZR are sub- strates of CYP3A4, p-glycoprotein, and OATP. In addition, GZR is 4. Recommended dosing regimens an inhibitor of CYP2C8, UGT, and BRCP [22,23]. Therefore, strong EBR/GZR combination dosing regimens differ according to the inducers of CYP3A4 are contraindicated. This group includes treated genotype in terms of duration and ribavirin addition carbamazepine, phenytoin, rifampicin, and efavirenz. Moderate (Table 3). inducers (such as nafcillin, etravirine, and modafinil) are not recommended. Also, CYP3A4 inhibitors are not recommended [13]. Inhibitors of OATP include cyclosporine, atazanavir, lopina- Table 3. Recommended dosing regimens for elbasvir/grazoprevir combination vir, darunavir, and tipranavir. They are contraindicated with EBR/ according to genotype. GZR regimen. Otherwise, maximum allowed daily dose intake of Duration statins that could be coadministered is 20 mg for atorvastatin Genotype Subpopulation Ribavirin (weeks) and 10 mg for rosuvastatin [24]. As HCV patients may perform 1a Naïve or experienced, without NS5A − 12 RAVs liver transplantation, it is important to monitor tacrolimus if 1a Naïve or experienced (Peg-IFN/RBV), +16 taken as immunosuppression as its plasma concentration may with NS5A RAVs increase more than 40% usual levels when taken while patient on 1b Naïve or experienced (Peg-IFN/RBV) − 12 1a or 1b Experienced (Peg-IFN/RBV/PI) + 12 EBR/GZR treatment. No drug interactions were recorded 4 Naïve − 12 between EBR/GZR and mycophenolate mofetil and prednisone. 4 Experienced (Peg-IFN/RBV) + 16 No known interactions were with proton pump inhibitors [25]. RAV: Resistant-associated variant. EXPERT REVIEW OF CLINICAL PHARMACOLOGY 3

Table 4. SVR in patients with baseline NS3/4A or NS5A RAVs in different trials treatment-experienced patients who took treatment for evaluating elbasvir/grazoprevir. 18 weeks with ribavirin. From the total number of patients, SVR with pretreatment SVR with pretreatment only two patients discontinued treatment due to SAEs (one Trial NS3–4A RAVs NS5A RAVs patient had atrial fibrillation and the second case had uterine C-WORTHY [29,30] 91% (68/75) 68% (17/25) C-SALVAGE [27,28] 91.2% (31/34) 75% (6/8) bleeding). One patient stopped due to noncompliance with C-SALT [31] 100% (17/17) 87.5% (7/8) study drugs. Regarding virological failure, eight patients C-SURFER [33] 100% showed virologic relapse while two patients experienced C-EDGE TE [35] 94.2% (115/122) 67% (38/50) viral breakthrough. Interestingly, 18 patients (out of 25 SVR: Sustained virologic response; RAV: resistant-associated variant. patients) who had low baseline platelet count less than 90,000/μL achieved SVR12, 5 of them had also low baseline albumin. 5. Virologic analysis and RAVs Common adverse events (more than 10% incidence) included fatigue, headache, and asthenia. Drugs are generally Both EBR and GZR are thoroughly studied and showed to be well tolerated. No grade 4 alanine aminotransferase elevations potent inhibitors of HCV RNA synthesis (due to action of two occurred. No patients developed hepatic decompensation. different DAAs as NS5A and NS3/4A inhibitors). They repre- Incidence of bilirubin elevation or hemoglobin drop was sented high genetic barriers to resistance. No cross-resistance higher in cohort of patients who took ribavirin. was detected when most clinically relevant NS5A- and NS3/ Another part of C-WORTHY trial was performed by 4A-resistant variants were studied and profiled versus GZR and Sulkowski et al. [30]. They focused on reducing treatment EBR, respectively [26]. duration to 8 versus 12 weeks in patients who are either In many studies of EBR/GZR treatment efficacy, the pre- HCV mono-infected of HIV coinfected. This study included sence of pretreatment RAVs was well studied (Table 4). The 218 patients who were treatment naïve and non-cirrhotic. prevalence of RAVs before treatment in patients recruited for Overall, SVR12 was 93–98% in mono-infected patients, irre- the C-EDGE, C-WORTHY, C-SURFER, and C-SALVAGE studies spective of ribavirin intake. For HIV coinfected patients, SVR12 was 32–43.6% for NS3 RAVs (genotype 1a is triple folds geno- ranged 87–97%. In mono-infected patients who were treated type 1b) and 10–14.8% for NS5A RAVs [27,30,33,34]. The pre- for 8 weeks, SVR12 was 80%. Totally, 12 patients experienced sence of pretreatment RAVs seems to have a little effect on virological failure (3 viral breakthrough and 9 relapses). the SVR to EBR/GZR. While baseline NS3 RAVs in both C-EDGE, Common adverse events were fatigue, headache, nausea, C-SURFER, and C-WORTHY studies didn’t have an impact on

and diarrhea. EBR/GZR combination could offer a solution to the response to treatment, a mild decrease in SVR was present patients with HIV coinfected patients. Some issues like possi- in patients with pretreatment NS3 RAVs in C-SALVAGE study. ble drug–drug interactions with HIV treatments should be The known Q80K polymorphism, which was proved to impact considered. SVR to , appears to have no significant effect on response to EBR/GZR [27]. NS5A RAVs have more important clinical impact especially in genotype 1a patients where a marked reduction in SVR was encountered with the occur- 6.2. C-SALVAGE study rence of these types of RAVs. This wasn’t the situation with In this prospective randomized phase II study, Forns et al. genotype 1b. In C-EDGE trial, 75.7% of patients with pretreat- tested for the efficacy of 12 weeks treatment using EBR and ment NS5A RAVs achieved SVR versus 99.2% of patients with GZR in managing chronic HCV genotype 1 patients who wild-type NS5A [34]. The same reduction in virological experienced previous treatment of pegylated interferon and responses was also reported in the C-WORTHY study (68% ribavirin plus either boceprevir, telaprevir, or simeprevir [27]. vs. 95%) [30] and the C-SALVAGE study (75% vs. 98.6%) [27]. Overall, SVR rates were achieved in 96.2% of patients. SVR12 was well appreciated in subgroup analysis such as genotype 6. Efficacy and safety of EBR/GZR according to 1a infection (93.3% SVR12), previous virological failure (95.5% phase II and III studies SVR12), and presence of underlying cirrhosis (94.1% SVR12). Three patients relapsed (3.8%). 6.1. C-WORTHY study Concerning safety analysis, one patient prematurely discon- Lawitz et al. enrolled a randomized phase II trial to assess the tinued treatment due to drug intolerance. Five SAEs were efficacy of combined EBR/GZR in managing chronic HCV gen- recorded and all were considered nondrug related (bacterial otype 1 different populations including those who are difficult pharyngitis, laryngeal squamous cell carcinoma, appendicitis, to treat such as cirrhotic patients and previous null responders urinary tract infection, and chronic obstructive pulmonary dis- to pegylated interferon therapy (Table 5)[29]. They assessed ease). Otherwise, 57% reported drug-related adverse events. treatment with/without ribavirin for 12/18 weeks duration in The most frequent events were fatigue, headache, asthenia, 253 patients (67% were cirrhotic). Presence or absence of and nausea. Less frequent events included insomnia, anemia, ribavirin did not influence SVR12. Similarly, both treatment altered bowel habits, abdominal pain, and vomiting. Anemia durations (12 and 18 weeks) had no effect on SVR12 rates. that necessitated ribavirin dose reduction did not affect SVR Totally, SVR12 rates ranged between 90% and 100%, being and all of them achieved SVR12. lowest (90%) in treatment-naïve cirrhotic patients who took Finally, Buti et al. published final SVR24 results. All patients 12 weeks treatment with ribavirin and highest (100%) in who had SVR12 succeeded to achieve SVR24 [28].

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Table 5. Efficacy of elbasvir/grazoprevir combination in clinical trials. .E ASSE AL. ET KASSAS EL M. Name of the study Design of the study Studied GT Study details Population Duration of the ttt SVR C-SALVAGE Single-arm open-label trial GT1 Total patient no. = 79 ±Cirrhosis TEc Elbasvir/Grazoprevir + RBV Overall SVR = 96.6% (76/79) 66 patients previously failed treatment 12/13 adverse 12 weeks GT1A SVR = 93.3% effect TE SVR = 95.5% Baseline no RAVS SVR = 100% Baseline NS3RAVS SVR = 91.2% Cirrhotic patient SVR = 94.1% C-EDGE TN Double blind placebo GT 1, 4, 6 Total patient no. = 421 patients TN ± cirrhosis Elbasvir/Grazoprevir GT1A SVR = 92% controlled 316 Immediate gp. Ttt. 12 weeks GT1B SVR = 99% GT1A = 50% (157) GT4 = 100% GT1B = 42% (131) GT6 = 80% GT4 = 6% (18) SVR in ¢ patients = 97% GT6 = 3% (10) SVR in non ¢ = 94% ¢ Patient = 22% C-EDGE CO- Open label single arm GT 1, 4, 6 Total patient no. = 218 patients TN ± cirrhosis Elbasvir/Grazoprevir GT1A SVR = 94.4% INFXN GT1A = 66.1% (144) + HIV-1 coinfection 12 weeks GT1B SVR = 95.5% GT1B = 20.2% (44) GT4 = 96.4% GT1other = 0.5% (1) SVR in ¢ patients = 100% GT4 = 12.8% (22) SVR in non ¢ = 94% GT6 = 0.5% (1) ¢ Patient = 16.1% (35) C-SURFER Double blind placebo GT1 Total patient no. = 224 patients TN/TEa ± cirrhosis + Elbasvir/Grazoprevir SVR TN = 100% controlled 111 Immediate gp. Ttt. severe RI 12 weeks SVR TEa = 95% 76% (176 patients on hemodialysis) SVR patients on dialysis = 98.9% GT1A = 52% (122) SVR patients with no dialysis = 100% 80% TN (189) SVR in ¢ patients = 100% 6% ¢ (14) SVR in non ¢ = 99.1% SVR GT1A = 100% SVR GT1B = 98.2% SVR stage 4 RI = 100% SVR stage 5 RI = 98.9% C-EDGE TEb Open label comparative GT 1, 4, 6 Four-arm study TEb ± cirrhosis ± HIV-1 Elbasvir/Grazoprevir + RBV GT1A SVR = 95% coinfection 16 weeks GT1B SVR = 100% GT4 = 100% GT6 = 100% C-EDGE Head Randomized multisite open- GT 1, 4 Total no. = 255 patients TN/TE ± cirrhosis Elbasvir/Grazoprevir vs. Overall SVR for Zepatier patients = 99.2% to Head label study 129 Patients for Zepatier 12 weeks (100 TN + 29 TE) Elbasvir/Grazoprevir vs. SOF/ SOF/PR Overall SVR for SOF/PR = 90.5% 126 Patients for SOF/PR (91 TN + 35 TE) PR treatment 12 weeks SVR according to GT: 25% of the patients are ¢ GT1A Zepatier patients = 100% GT1B Zepatier patients = 99% GT4 Zepatier patients = 100% GT1A SOF/PR patients = 100% GT1B SOF/PR patients = 90.4% GT4 SOF/PR patients = 60% SVR according ¢: Zepatier patient no ¢ = 99% (106/107) Zepatier patients with ¢ = 100% (22/22) SOF/PR patients no ¢ = 93% (98/105) SOF/PR patients with ¢ = 76.1% (16/21) (Continued)

Table 5. (Continued). Name of the study Design of the study Studied GT Study details Population Duration of the ttt SVR C-SWIFT Seven arm study GT 1, 3 Total no. = 102 patients TN ± cirrhosis Zepatier + SOF for 4, 6, 8, SVR (Zepatier + Sofosbuvier in ¢ Divided into 4-arm GT1 and 3-arm GT3 ¢ and non ¢ and 12 weeks GT1 non ¢ patients 4 weeks = 33% and non ¢ TN GT1 non ¢ patients 6 weeks = 87% GT1 ¢ patients 6 weeks = 80% GT1 ¢ patients 8 weeks = 94% GT3 non ¢ patients 8 weeks = 93% GT3 non ¢ patients 12 weeks = 100% GT3 ¢ patients 12 weeks = 91% C-WORTHY Open-labeled phase 2 study GT1 Total no. = 253 patients TN/TE ± ¢ ± HIV infection Zepatier for 12–18 weeks SVR according to GT: 130 Patients TE and 123 patients TN +/− RBV GT1A = 93% GT1B = 99% SVR according to ¢: ¢ Patients = 95% No ¢ patients = 95% SVR according to TE/TN: TE + RBV 12 weeks = 94% TE − RBV 12 weeks = 91% TE + RBV 18 weeks = 100% TE − RBV 18 weeks = 97% TN + RBV 12 weeks = 90% TN − RBV 12 weeks = 97% TN + RBV 18 weeks = 97%

TN − RBV 18 weeks = 94% PHARMACOLOGY CLINICAL OF REVIEW EXPERT C-SALT Open-labeled phase 2 study GT1 Total no. = 40 patients Decompensated liver Zepatier 12 weeks SVR according to GT: 30 Patients child B and 10 patients non ¢ GT1A = 89% 70% B7 and 23% B8 and 7% B9 and 90% GT1A and 2/ GT1B = 100% 3 of the patients are TN SVR according to ¢: Mean MELD 9.9% ¢ Patients = 90% No ¢ patients = 100% aFailed prior IFN or PegIFN ± RBV. bFailed prior PegIFN + RBV. cFailed prior PegIFN + RBV + HCV NS3/4A protease inhibitor. SVR: Sustained virologic response; RI: renal impairment; ttt: treatment. 5 6 M. EL KASSAS ET AL.

6.3. C-SALT study from viral breakthrough. All SAEs were considered nondrug related. Drug-related adverse events occurred in 36.1% and This phase II trial studied decompensated patients who were 39% of immediate and deferred patient groups, respectively. Child–Pugh class B and who were treated using EBR/GZR. Frequent adverse events were headache and fatigue. Thirty patients with genotype 1 infection were compared to 10 non-cirrhotic patients. GZR was used in half dosage (50 mg) for cirrhotic patients. The cirrhotic decompensated group 6.7. C-EDGE TE study ended up with 90% SVR12 achievement (compared to 100% in non-cirrhotic group) while two patients relapsed. Nondrug- This is another trial that recruited 420 treatment-experienced related SAEs were recorded in 13.3% of cases [31]. patients. They were treated for 12 versus 16 weeks [35]. Longer treatment duration led to 97% SVR12 compared to 92% in patients treated for 12 weeks. Presence of ribavirin 6.4. C-SWIFT study led to 94% SVR12 compared to 92% if without ribavirin. Another phase II trial used EBR and GZR with sofosbuvir and reduced treatment duration to 4, 6, and 8 weeks for chronic HCV genotype 1 (102 patients) while genotype 3 (41 patients) 6.8. C-EDGE CO-INFECTION study patients were treated for 8 or 12 weeks. In genotype 1 It treated a cohort of patients (218 patients) who were coin- patients, SVR12 was achieved in 33%, 87%, and 94% of fected with HIV and HCV genotypes 1, 4, and 6. All were patients treated for 4, 6, and 8 weeks, respectively. In geno- treatment naïve. SVR12 was 96%. Seven patients had virologic type 3 patients, SVR12 was 93% (8 weeks arm) and 100% failure [36]. (12 weeks arm) if they were non-cirrhotic. For cirrhotic patients, SVR12 was 91% after 12 weeks of treatment. Relapsed patients (of groups of short duration 4, 6, and 8 weeks) were retreated again with same drugs for 12 weeks 6.9. C-EDGE HEAD TO HEAD study and with adding ribavirin. All such patients achieved Sperl et al. recently published a clinical trial of EBR/GZR in SVR12 [32]. managing 129 patients with chronic HCV genotype 1, 4, or 6 treatment naïve or experienced. They were compared to another arm of patients (126 patients) who were treated by 6.5. C-SURFER study sofosbuvir, peginterferon, and ribavirin. SVR4 was 99.2% and

This phase III trial was concerned with management of chronic 89.7% in patients treated by EBR/GZR and sofosbuvir/ HCV genotype 1 patients (either treatment naïve or previous Peginterferon/ribavirin, respectively. No virologic failure experienced) and additionally had stage 4–5 chronic renal occurred in EBR/GZR group versus eight patients in second disease (with or without hemodialysis). EBR and GZR were group. Also, EBR/GZR was better tolerated and showed fewer used for 12 weeks. Hemodialysis-dependent patients repre- overall adverse events [37]. sented 76% of total patients. Eleven patients discontinued treatment (five due to side effects, two were lost to follow- up, one died, one did renal transplantation, one noncompli- 6.10. C-EDGE IBLD study ant, and one withdrawn by patient). Among patients who It is a clinical study that looked for efficacy of EBR/GZR in continued treatment, SVR12 was achieved in 99% of patients patients who are chronic HCV infected and had IBLD. Both and just one case relapsed 12 weeks after end of treatment. treatment-naïve and -experienced genotype 1, 4, and 6 Headache, nausea, and asthenia represented the most fre- patients were recruited. Randomization was performed quent adverse events. Cardiac SAEs were reported in five according to cirrhotic status and IBLD group that included patients (cardiac arrest, myocardial infarction, and cardiomyo- patients with hemophilia or Von Willbrand disease, beta tha- pathy). SAEs were reported in 31% of patients, mostly were lassemia, and sickle cell anemia. No patients prematurely nondrug related due to the nature of underlying morbidities stopped treatment due to worsening of underlying IBLD. in this set of patients [33]. Generally, treatment is well tolerated. SVR4 ranged between 96% and 100% [38]. 6.6. C-EDGE TN study Zeuzem et al. enrolled a phase III trial (C-EDGE TN) using GZR/ 6.11. C-EDGE CO-STAR study EBR combination therapy to treat different HCV genotypes (1, 4, 6) for 12 weeks [34]. Recruited patients were treatment- This study searched for the impact of using EBR/GZR on naïve cirrhotic and non-cirrhotic cases. Studied patients (421 health-related quality of life (HR-QOL) in treating naïve patients) were randomly assigned 3:1 to immediate (316 patients infected with HCV and who inject drugs receiving patients) or deferred (105 patients) therapy. In the immediate opioid agonist treatment. Treated patients had better changes group, 95% achieved SVR12. According to genotypes, SVR12 in HR-QOL compared to placebo group. This included scores was 92% (genotype 1a), 99% (genotype 1b), 100% (genotype related to Physical Functioning, Bodily Pain, Vitality, General 4), and 80% (genotype 6). Cirrhotic patients showed high Health, Mental Health, Physical Component Summary (PCS), SVR12 rates (97%). Also, 12 patients relapsed while 1 suffered and Mental Component Summary (MCS) [39]. EXPERT REVIEW OF CLINICAL PHARMACOLOGY 7

6.12. EBR/GZR in patients with cirrhosis With the growing access to newer HCV drugs, more and more patients will be treated and the number of patients who fail Patients with cirrhosis were thoroughly challenged with EBR/ treatment will accordingly increase. This will highlight the issue GZR combination in many clinical trials. In C-EDGE study, one of of drug resistance in those who fail therapy and necessitate the study arms was dedicated for naïve patients with compen- further studies for those patients. The availability of many treat- sated cirrhosis. For testing the safety of this regimen in this ment options for HCV and the continuous reduction in treat- patient population, an initial placebo control arm was designed. ment prices will eventually maximize the access for treatment for The SVR results of a 12-week treatment course were 92%, 99%, a wide sector of patients and this will offer a great opportunity 100%, and 80% in genotypes 1a (50% of patients), 1b (41% of to hit a major health problem like HCV in the coming few years. patients), 4 (6% of patients), and 6 (3% of patients), respectively. There were no significant statistical differences in rates of SVR between patients with compensated cirrhosis (97.1%) and Key issues those with no cirrhosis (93.3%). Also, there were no differences in the safety profile between treatment (overall adverse events ● HCV treatment had a great revolution with the appearance 36.1% and 3% was serious) and placebo (overall adverse events of DAAs especially for patients with genotypes 1 and 4 39% and 3% was serious) groups. This study concluded that the infections. presence of cirrhosis didn’t have a significant impact on the ● Elbasvir/grazoprevir (ZepatierTM) is an oral fixed dose com- safety and efficacy of this regimen [34]. bination of an NS5A inhibitor (elbasvir), and an NS3/4A protease inhibitor (grazoprevir). ● This combination was issued the US FDA approval for treat- 7. Expert commentary ment of adult patients chronically infected with genotypes EBR/GZR combination is a safe, very effective, well-tolerated, all 1 and 4. oral, single once-daily tablet that was approved for both treat- ● Elbasvir/grazoprevir combination have a high barrier to ment-naïve and treatment-experienced patients with genotype 1 resistance as well as a good spectrum of activity against or 4 HCV infection. This regimengainednewfieldsthrough many common known RAVs. hitting difficult frontiers such HIV coinfection cases. The main ● The available data for this combination coming from different concern in managing this group of patients is the possible drug– clinical trials covers many special patient populations such as drug interactions of HCV drugs with the used antiretroviral patients co-infected with HIV, patients with hepatic or renal agents. This should be considered always before planning for impairment and patients with inherited blood disorders. managing those patients. Another important HCV population ● Delivered as a fixed dose combination -once daily- tablet that was challenged in clinical trials with this combination was regardless to food intake. They are partially eliminated by patients with inherited blood diseases. EBR/GZR combination oxidative metabolism and excreted primarily through was proved to be safe and effective for such patients. This feces. combination could also offer a good and safe option for patients ● This combination is not generally recommended to treat with end-stage renal disease including patients under dialysis. HCV infected patients with Child Pugh class B and C. This is one of the main advantages of this combination over ● Both EBR and GZR are substrates of CYP3A4, p-glycoprtein (p- other currently available DAAs. Overall, the availability of an gp) and OATP. In addition, GZR is an inhibitor of CYP2C8, UGT effective and safe antiviral combination in these specific patient and BRCP. Therefore, the list of DDI includes inducers and populations represents a great step in HCV management. inhibitors of CYP3A4, and inhibitors of OATP.

Funding 8. Five-year view The paper was not funded. The landscape for HCV treatment doesn’t appear to exhibit marked changes in the near future. The currently available treatment options with the proved high efficacy in genotypes 1 and 4 could stand for the next few years. The fixed-dose Declaration of interest combination therapies like EBR/GZR may represent the opti- G Esmat has acted as an advisory committee board member for MSD, mum solutions for HCV management with its obvious better Gilead Sc. and BMS, and a speaker for BMS, Roche, MSD and GSK, and had compliance and the availability of a cumulative evidence of grants and research Supports from Gilead Sc., Roche, MSD, GSK, BMS, Abbvie and Janssen. The authors have no other relevant affiliations or efficacy in various patient population groups. With the high financial involvement with any organization or entity with a financial efficacy of the available treatment options and the reasonable interest in or financial conflict with the subject matter or materials dis- safety profile of the used agents, the future challenges may be cussed in the manuscript apart from those disclosed. limited to the shortening of treatment duration and addres- sing some treatment-related issues like drug–drug interac- tions. More detailed and comprehensive studies are still References required for some unique patient populations. This includes Papers of special note have been highlighted as of interest (•) to readers cases with advanced and decompensated cirrhosis, patients 1. Alric L, Bonnet D. Grazoprevir + elbasvir for the treatment of with renal failure, combined infection with HIV, and posttrans- hepatitis C virus infection. Expert Opin Pharmacother. 2016;17 plantation settings. (5):735–742. 8 M. EL KASSAS ET AL.

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