The efficacy and safety of elbasvir/grazoprevir treatment in HCV genotype 1 patients in Taiwan

Abstract Background Elbasvir/grazoprevir (EBR/GZR) is a new generation, fixed‐dose, combination antiviral drug used in chronic hepatitis C virus (HCV) genotype (GT) 1 or 4 infection. Our study evaluates the clinical efficacy and safety of EBR/GZR after its launch in Taiwan. Methods This is a retrospective observational study. Patients who had received EBR/GZR for chronic HCV GT 1 between June 2017 and April 2018 were recruited. Patients’ age, sex, HCV GT, changes in HCV RNA level before and after treatment, sustained virologic response 12 weeks (SVR12) after the cessation of drug administration, side effects, and interaction effects were used to evaluate the clinical efficacy and safety. Results A total of 149 patients were recruited. Of them, 145 (97.3%) had HCV GT 1b, and the rest had HCV GT 1a; most of the EBR/GZR‐related side effects in this study were mild. Three participants were discontinued because their alanine transaminase levels were elevated to over 10 times the upper limit of normal. The therapeutic effect analyses revealed a rapid virologic response rate of 95.3% and an SVR12 rate of 98%. Subgroup analyses performed using SVR12 as the outcome variable revealed three demographic factors HCV GT 1, hepatocellular carcinoma medical history, and noncirrhosis plus HCV RNA level. Conclusions This study confirmed that EBR/GZR is safe and effective for treating patients with HCV GT 1 and exhibited excellent overall clinical efficacy in Taiwan. The therapeutic effects are unrelated to factors such as sex, HCV RNA level before treatment, and history of liver cirrhosis.

Since 2011, various direct-acting antiviral (DAA) drugs have been successively launched in the the United States, Europe, and Japan markets. DAA inhibits the NS3/4A protease, the NS5A protein, or the RNA polymerase, which are crucial in the life cycle of HCV. Two of the most notable DAAs are boceprevir and telaprevir. The sustained virologic response (SVR) can be as high as 90%. Nevertheless, the DAA is considerably expensive. Furthermore, they must be used with interferon and ribavirin (RBV), and they are poorly tolerated and often elicit severe side effects. [3][4][5] However, since interferon-free DAAs were developed and launched in 2014, they have superseded other treatments for chronic hepatitis C patients. Nowadays, we have several DAAs to treat HCV infection, such as sofosbuvir base, glecaprevir/pibrentasvir, elbasvir/grazoprevir (EBR/GZR), and others.
Some DAAs have limitations due to renal insufficiency or protease inhibitor-related hyperbilirubinemia. Thus, we decided to study ERB/ GZB because of its simple use and did not concern for renal function issue; in addition, patient compliance might be adequate. 6,7 EBR/GZR is a fixed-dose combination DAA composed of 50 mg of EBR and 100 mg of GZR. EBR is an NS5A inhibitor and GZR is an NS3/4A protease inhibitor and was approved by the US Food and Drug Administration in 2016 for chronic HCV GT 1 or GT 4 infection regardless of whether they have received pegylated interferon alfa (PEG-IFN) plus RBV treatment previously. 1,5,[8][9][10][11] The results of phase 3 random assignment clinical trials such as C-EDGE TN, C-EDGE TX, and C-SURFER have revealed that EBR/GZR has excellent therapeutic effects in chronic hepatitis C patients. The SVR12 (HCV RNA is undetectable at week 12) rates for these three groups were 95%, 92%, and 94%, respectively. 1,[9][10][11] Subsequently, it has been listed as a novel DAA covered by National Health Insurance (NHI) in Taiwan since August 2017. This policy has benefited numerous patients with hepatitis C and has encouraged patients to actively seek treatment.
The aim of this study is to evaluate the clinical efficacy and safety of EBR/GZR based on clinical data collected after the introduction of EBR/GZR to the study site hospital in 2017 in Taiwan. In addition, it is verified if these results in Taiwan match those reported in clinical trials such as C-EDGE TN and C-EDGE TX.

| Design
This study is a retrospective observational study and was approved

| Sample
Inclusion criteria: Outpatients with chronic HCV GT 1 who fit the inclusion criteria were identified using ICD-10-CM codes, laboratory examination codes, and NHI data. The applicable diagnostic codes were B18.2 (chronic viral hepatitis C) and Z22.52 (carrier of viral hepatitis C).

| Data collection
The medical research database of the Lin-Kou Chang Gung Medical Center was used to perform data clustering and analysis. Approval was granted to use the following data sets for research purposes basic demographic information files, outpatient diagnostic files, outpatient expense quotation files, laboratory examination result files, medical and medication order files, and drug-related files.
Monitored items: Patient age and sex, measured anti-HCV, HCV RNA level, aspartate aminotransferase or alanine aminotransferase (ALT) level, bilirubin level, blood urea nitrogen, creatinine, albumin, HCV GT, resistance-associated substitution, and complete blood count, which includes laboratory examination results related to white blood cell counts, hemoglobin level, and platelet count, before EBR/ GZR administration, 4, 12, or 16 weeks after drug administration and 12 weeks after the treatment course ended.
Evaluations of clinical efficacy and safety: SVR12 analysis, measured 12 weeks after the cessation of drug intake; analysis of inappropriate prescriptions; analysis of drug interaction effects; types and severity of side effects. In addition, data were collected on drugs that could cause interaction effects when used concomitantly with EBR/GZR, such as carbamazepine, phenytoin, rifampicin, rifater, and cyclosporine. Finally, this study also collected data on the side effects and the corresponding treatment measures. The severity and the corresponding treatment measures were mild (no medication is given), moderate (medication administered), and severe (cessation of EBR/ GZR treatment or hospitalization).

| Analysis methods
Analyses in this study were mainly conducted using descriptive statistics. If the dependent or outcome variable was continuous, the data were represented as mean ± standard error and analyzed using Student t test; if the dependent or outcome variable was categorical, the data were represented as a numerical value and percentage and analyzed using the χ 2 method. Significance was set at P < .05.

| RESULTS
The participant recruitment process is illustrated in the flowchart in unexamined: n = 1). In terms of medical history, 79 participants (53%) reported a history of liver cirrhosis, whereas 27 participants reported switching to EBR/GZR treatment after failure to respond to PEG-IFN plus RBV treatment previously. Finally, 88 participants (59.1%) had an HCV RNA viral load higher than 800 000 IU/mL. The average HCV RNA viral load among participants was 2 523 970 IU/mL (Table 1).
Regarding the analysis of coinfections related to HCV, 9 participants (6.0%) had a coinfection of hepatitis B, none had a coinfection of HIV, and 27 (18.1%) had comorbidity with HCC.
Between-group comparisons using liver cirrhosis medical history as the between-group factor revealed the following: (a) the average age of those in the cirrhosis group (71.6 ± 9.3 years) was significantly higher than that of those in the noncirrhosis group (66.1 ± 11.4 years; P = .0014), and (b) the proportion of patients with a history of HCC was significantly higher in the cirrhosis group than in the noncirrhosis group (27.8% vs 7.1%; P = .0011). No significant differences were observed for the between-group differences of the cirrhosis and noncirrhosis group on other outcome variables such as sex, HCV GT, HCV RNA viral load, and hepatitis C treatment history (Table 1).
In terms of the interaction effects between concomitant medications and EBR/GZR, most prescriptions were reasonable, and the medications showed no obvious interaction effects with each other.
Only four cases of established drug interaction effects of EBR/GZR with statin drugs (n = 3 for atorvastatin; n = 1 for simvastatin) were noted. The average dosage for atorvastatin was <10 mg/day and the average length of concomitant use was 51.3 days; the average dosage for simvastatin was <10 mg/day and the average length of concomitant use was 77 days.
The proportion of patients who experienced the side effect of elevated bilirubin level was significantly higher in the cirrhosis group than in the noncirrhosis group (12.7% vs 1.4%; P = .0089) ( Table 2).   Subsequently, subgroup analyses were performed using SVR12 as the outcome variable. The results of the univariate analyses revealed that three demographic factors exhibited significant differences in terms of SVR12 rates, namely HCV GT 1 subtype (GT 1a vs GT 1b; P = .001), medical history of HCC (HCC vs non-HCC; P = .028), and noncirrhosis plus HCV RNA viral load (≧800 000 vs <800 000 IU/mL; P = .011). No significant between-group differences in terms of SVR12 rate were noted for any of the other demographic factors analyzed (ie, sex, age, cirrhosis history, and HCV RNA viral load level before treatment; Figure 3). using a history of liver cirrhosis revealed that those in the cirrhosis group were significantly older than those in the noncirrhosis group and the percentage of patients with a medical history of HCC was significantly higher in the cirrhosis group than in the noncirrhosis group. No significant between-group differences between the cirrhosis and noncirrhosis groups were observed for sex, HCV RNA viral load level, and hepatitis C treatment history.

| DISCUSSION
EBR/GZR is metabolized by the liver, both are transformed into substrates for the cytochrome P450 3A (CYP3A) protein. Therefore, using EBR/GZR concomitantly with strong inducers and inhibitors of the CYP3A protein is prohibited. This is to prevent the concentration of EBR/GZR from being lowered or raised, which subsequently leads to the attenuation or enhancement of therapeutic effects. 1,11 According to related studies, when EBR/GZR is used concomitantly with drugs such as carbamazepine, phenytoin, rifampicin, rifater, and cyclosporine, prominent interaction effects occur. 12  be administered. This is to prevent EBR/GZR from enhancing the concentration of statin drugs. In addition to administering these drugs, the patients' conditions should be closely monitored to timely detect any statin-related side effects. 12 In the current study, four patients concomitantly used statin drugs and EBR/GZR. Although the average length of concomitant use was more than 50 days, the average daily dosage was ≦10 mg/day. No significant drug interaction effects were observed, and the relevant lipid profile values were within a reasonable range.
According to the results of large-scale clinical trial studies, such   as C-EDGE TN, C-EDGE, TEC-CORAL, and CO-INFECTION, 2 be stopped when a patient's ALT level is more than 10 × ULN according to the instruction of medicine or physician concern the safety issue. In our study, only three patients' discontinuous EBR/ GZR may be related to protease inhibitors. Therefore, patients' liver function should be monitored both before and during the treatment course. 4,10,11 Related studies have posited that the risk of ALT elevation is related to the concentration of grazoprevir; the higher the concentration of grazoprevir is, the higher the elevation risk is.
ALT elevation is relatively unrelated to the presence of cirrhosis and the length of EBR/GZR treatment. 11 Elevation of bilirubin caused by EBR/GZR usually occurs 2 weeks after the drug is taken and usually decreases gradually along the treatment course. 11 Bilirubin elevation is not necessarily related to the presence of liver cirrhosis and changes in liver function. 2 In this study, side effects were reported in 45 patients. Among the reports, elevated bilirubin level was the most common, followed by fatigue, insomnia, dizziness, and increased ALT level.
In most patients, the side effects were mild; only nine patients (6.0%) needed medication to relieve these side effects. EBR/GZRrelated elevation of the bilirubin level was reported in 11 patients. impairment was 99%, and the SVR12 rate of patients in the noncirrhosis group was higher than that for the cirrhosis group (100% vs 96%). 13 The aforementioned Italian study on the efficacy and safety of EBR/GZR had a considerably smaller sample size than this study (29 patients with HCV). In terms of clinical efficacy, an SVR12 rate of 100% was reported. The clinical safety evaluation revealed that common side effects such as fatigue or headache were not observed. However, four participants experienced asymptomatic elevation of ALT levels at week 8, but their ALT levels subsequently returned to the normal range at weeks 10 to 12. 14 In our study, 12 of the recruited participants had comorbid chronic kidney failure, and 8 of them were required to undergo hemodialysis regularly. There was no significant statistical difference between cirrhosis and noncirrhosis during the course of treatment or follow-up period ( Figure 2).
This finding was comparable with recent publication in Japan, 15 and an SVR12 rate of 100% was established in this subgroup.
This study analyzed the clinical efficacy and safety of EBR/GZR after its launch in Taiwan

| CONCLUSIONS
This study confirmed that EBR/GZR is safe and effective for treating patients with HCV GT 1. An overall SVR rate as high as 98% was achieved. The medication-related side effects reported in most patients were mild. For patients with ALT levels >10 × ULN after the administration of EBR/GZR, the physicians stopped the EBR/GZR, as recommended.
The therapeutic effects are unrelated to factors such as sex, HCV RNA viral load before treatment, and medical history of liver cirrhosis. TSAI ET AL.