Real-world experience of elbasvir/grazoprevir in Taiwan: This
study was focused on liver and renal adverse effects
Yi-Chung Hsieh1 | Chih-Lang Lin2 | Chao-Hung Hung3,4 | Chien-Hung Chen4,5 |
Shui-Yi Tung3,4 | Chun-Yen Lin1,4 | Tsung-Hui Hu4,5 | Sheng-Nan Lu3,4 |
Rong-Nan Chien2,4 | I-Shyan Sheen1,4
Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; CHC, chronic hepatitis C; CI, confidence interval; CKD, chronic kidney disease; DAA, direct-acting antiviral; DM,
diabetes mellitus; eGFR, Estimated glomerular filtration rate; EOT, end of treatment; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; INR, international
normalized ratio; MDRD, Modification of Diet in Renal Disease; NS, nonstructural protein; RASs, resistance-associated substitutions; RNA, ribonucleic acid; RVR, rapid virologic
response; VRs, virologic responses.
Division of Hepatogastroenterology, Linkou
Chang Gung Memorial Hospital, Taoyuan,
Taiwan
Division of Hepatogastroenterology,
Keelung Chang Gung Memorial Hospital,
Keelung, Taiwan
Division of Hepatogastroenterology, Chiayi
Chang Gung Memorial Hospital, Chiayi,
Taiwan
College of Medicine, Chang Gung
University, Taoyuan, Taiwan
Division of Hepatogastroenterology,
Kaohsiung Chang Gung Memorial Hospital,
Kaohsiung, Taiwan
Correspondence
Chien-Hung Chen, Division of
Hepatogastroenterology, Department of
Internal Medicine, Kaohsiung Chang Gung
Memorial Hospital, No. 123, Dapi Rd.,
Niaosong Dist., Kaohsiung City 83301,
Taiwan (R.O.C.).
Email: [email protected]
Shui-Yi Tung, Division of
Hepatogastroenterology, Department
of Internal Medicine, Chiayi Chang Gung
Memorial Hospital, No. 6, Sec. W., Jiapu
Rd., Puzi City, Chiayi County 61363, Taiwan
(R.O.C.).
Email: [email protected]
Abstract
Elbasvir/grazoprevir with or without ribavirin has excellent efficacy and safety for
the treatment of hepatitis C virus (HCV) genotype 1 and 4 patients. The real-world
experience has been reported but the detailed analysis of liver and renal adverse
effects is lacking. This study evaluated the real-world experience relating to the ef￾fectiveness and liver/renal safety of elbasvir/grazoprevir in HCV genotype 1 patients
with compensated liver disease. In the four medical centres of Chang Gung Medical
System, 350 HCV genotype 1 patients with compensated liver disease who were
treated with elbasvir/grazoprevir were enrolled. Clinical characteristics and labora￾tory data were collected. The effectiveness (sustained virologic response 12 weeks
after end of treatment, SVR12) and safety were assessed. A consecutive series of
350 patients with a mean age of 68.8 ± 10.0 years old were enrolled. The majority
were treatment-naïve (72.3%), genotype 1b (97.7%) and advanced fibrosis/cirrhosis
(94.3%). Seventy-nine (22.6%) had hepatocellular carcinoma and 23 (6.6%) had co￾infection with hepatitis B. The effectiveness of SVR12 was 94.6% (95% CI: 92.2%-
97.0%) in the full analysis set and 99.1% (95% CI: 98.1%-100.1%) in the per-protocol
set. There were two relapses and one nonresponder. Seven (2.0%) patients had ad￾verse events resulting in premature discontinuation of treatment. Five of them were
considered drug-related. One was due to autoimmune hepatitis. Contrary to previ￾ous reports, around 49% of ALT elevation was observed after 8 weeks, and in two
patients was due to hepatitis B flares. As to the renal function during the course of
therapy, a minor deterioration of eGFR was observed in patients with baseline eGFR
≥60 mL/min/1.73 m2
, but not in those with baseline eGFR <60, <60-30 or <30 mL/
min/1.73 m2
. In this real-world data, elbasvir/grazoprevir was effective with few
liver/renal adverse effects. One patient developed autoimmune hepatitis.
KEYWORDS
adverse effect, elbasvir/grazoprevir, hepatitis C, real-world experience
2  |    HSIEH et al.
1 | INTRODUCTION
Hepatitis C virus (HCV) can cause chronic infection, which fol￾lows a progressive hepatitis over years, and chronic hepatitis C
(CHC) can lead to cirrhosis, hepatocellular carcinoma (HCC) and
the need of liver transplantation. In addition to hepatic outcomes,
chronic HCV infection might cause increased mortality related
to higher risks of cardiovascular disease, chronic kidney disease,
diabetes mellitus (DM) and neurologic stroke. Fortunately, the
elimination of virus can induce reduction of liver-related compli￾cations and all-cause mortality, improve quality of life and prevent
transmission.1-3
The antiviral treatment of CHC developed revolutionarily since
2011, and various interferon-free direct-acting antiviral (DAA)-
containing regimens are currently available. Owing to excellent ef￾fectiveness, safety and benefits of viral clearance, treatment for all
HCV-infected persons is now strongly recommended except those
with limited life expectancy. For the past few years, some DAA reg￾imens have been downgraded to alternative or not recommended
status due to adverse events, pill burden, longer duration or/and
ribavirin use. Elbasvir/grazoprevir has been remaining the recom￾mended list of the updated guidelines.2-4
Elbasvir/grazoprevir is not only one of the highly potent DAA
combination regimens consisting of inhibitors of the nonstructural
protein (NS) 3/4A (grazoprevir) and the NS5A protein (elbasvir)
for the treatment of chronic HCV genotype 1 and 4 infection, but
also can treat patients with renal dysfunction and haemodialysis.
National Health Insurance Administration of Taiwan has reimbursed
this drug for patients with genotype 1 and 4 since August 1, 2017.
Because there were few real-world studies focused on the liver and
renal safety of elbasvir/grazoprevir, we performed this multicenter
pooled analysis to explore this issue.
2 | MATERIALS AND METHODS
2.1 | Patients
This retrospective study cohort included subjects from four medical
centres of Chang Gung Memorial Hospitals (Keelung, Linkou, Chiayi,
Kaohsiung) in Taiwan. These patients received elbasvir/grazoprevir￾based treatment between June 28, 2017 and March 6, 2018 and had
a determination of sustained virologic response at post-treatment
week 12 (SVR12) if possible. The inclusion criteria included HCV
genotype 1, compensated liver disease (Child-Turcotte-Pugh class
A) at the entry, and treatment with elbasvir/grazoprevir with ± rib￾avirin. Patients with easy genotyping errors (such as genotype 4)
and coinfection with human immunodeficiency virus were excluded.
The study protocol was approved by the Ethics Committee of Chang
Gung Memorial Hospital.
The oral DAA regimen consisted of fixed-dose combination of el￾basvir (50 mg)/grazoprevir (100 mg) and was administered once daily
with or without weight-based ribavirin (daily dose 1000 mg for those
<75 kg and 1200 mg for those ≥75 kg). Patients with genotype 1a
infection were tested for NS5A resistance-associated substitutions
(RASs) prior to treatment; the regimen was given for 16 weeks with
weight-based ribavirin to those with RASs but for 12 weeks to those
without RASs. For genotype 1b-infected patients, the regimen was
given for 12 weeks.
Baseline demographic and laboratory variables included age,
gender, experience of HCV treatment, hemogram, international nor￾malized ratio (INR), HCV ribonucleic acid (RNA) and genotype, NS5A
RAS testing for subtype 1a and biochemical profiles. The stage of he￾patic fibrosis used the METAVIR scoring system and was defined by
transient elastography (FibroScan). The cut-off values for FibroScan
(kPa) were F0: <6.5, F1: ≥6.5, F2: ≥8, F3: ≥9.5 and F4: ≥12. Estimated
glomerular filtration rate (eGFR), calculated by the Modification of
Diet in Renal Disease (MDRD) study equation, was used to stage
chronic kidney disease (CKD). RASs at NS5A gene amino acid posi￾tions 28, 30, 31, 58 and 93 were determined with a method of deep
sequencing.
The HCV antibody was tested by a commercial kit (Abbott
Laboratories). The HCV RNA level was determined by a commercial
quantitative PCR assay: COBAS TaqMan HCV Test (TaqMan HCV;
Roche Molecular Systems Inc, lower limit of detection: 15 IU/mL) or
Abbott RealTime HCV assay (ART; Abbott Molecular, Des Plaines, IL,
lower limit of detection: 12 IU/mL). The HCV genotype was identified
using cobas® HCV GT assay (Roche Molecular System) or the Abbott
RealTime HCV Genotyping II assay (Abbott Molecular).
2.2 | Outcomes
The endpoint of effectiveness was SVR12, defined by the absence of
HCV RNA at least 12 weeks after stopping treatment. On-treatment
virologic responses (VRs) were the secondary endpoint of effective￾ness and defined by undetectable HCV RNA at weeks 2, 4 and 12 of
therapy. The definition of rapid virologic response (RVR) was unde￾tectable HCV RNA at week 4 of therapy. Undetectable HCV RNA
at the end of treatment (EOT) was called virologic response at EOT
(EOTVR). Nonresponse was regarded as persistent seropositive for
HCV RNA throughout the treatment course. Relapse meant reap￾pearance of serum HCV RNA after completion of therapy in patients
achieving EOTVR.
Safety included evaluation of adverse events and monitoring
of laboratory parameters. Adverse events were recorded during
the course of treatment and lab abnormality was graded based on
definitions of Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0.
2.3 | Statistical analysis
The statistical software, IBM SPSS Statistics Version 20, was used for all
data analyses. Continuous variables were expressed as mean ± stand￾ard deviation or median [quartile 1, quartile 3], and categorical variables
   | HSIEH et al.  3
were expressed as number (percentage). Chi-square test or Fisher's
exact test and repeated measures analysis of variance (ANOVA) were
used to compare differences. Univariate and multivariate logistic re￾gression analyses were done to find out factors of the group with
on-treatment renal function deterioration. P values < .05 by the two￾tailed test were considered statistically significant.
3 | RESULTS
A total of 350 patients were enrolled into this study and served as
the full analysis population. Of those ten patients prematurely dis￾continued the treatment, seven were due to adverse events, and
three due to personal reasons (one lost follow-up, one had no fam￾ily bringing him to the outpatient department, and one had poor
adherence). Remaining 340 patients had completed the full course
of treatment, but 6 did not have a 12-week follow-up (one died of
liver failure and another mortality with the unknown cause, and four
lost follow-up). The per-protocol population contained 334 patients
(Figure 1).
3.1 | Baseline characteristics
The baseline clinical characteristics of 350 participants were shown
in Table 1. The mean age was 68.6 ± 10.0 years old, and 165 (47.1%)
were male. Mean body mass index (BMI) was 24.7 ± 4.0 kg/m2
. The
majority of patients were treatment-naïve (N = 253, 72.3%). All the
treatment-experienced ones (N = 97, 27.7%) were failures of pe￾gylated interferon/ribavirin. Twenty-three (6.6%) had coinfection
with hepatitis B virus (HBV). The majority of patients had advanced
fibrosis/cirrhosis, 108 (30.9%) of F3 and 222 (63.4%) of F4. Seventy￾nine (22.6%) had a history of HCC, 50 (14.3%) patients had nonviable
HCC and 29 (8.3%) were viable at the time of elbasvir/grazoprevir
treatment. Seventy-two (20.6%) patients had DM. Eight (2.3%) pa￾tients were infected with genotype 1a, and no one had RASs. Median
HCV RNA level was 1.0 [0.3, 2.6] MIU/mL, in which 190 (54.3%)
were ≥800 000 IU/mL and 107 (30.6%) were ≥2 000 000 IU/mL.
There were 70 (21.8%) patients of CKD stage 3-5.
3.2 | Effectiveness
On- and post-treatment VRs were presented in Figure 2. Rates of
undetectable HCV RNA at week 2 and 4 of treatment, EOT and
week 12 after EOT were 78.9% (30/38), 88.3% (303/343), 99.7%
(339/340) and 99.1% (331/334). SVR12 rates were 94.6% [331/350,
95% confidence interval (CI): 92.2%-97.0%] in the full analysis set
and 99.1% (331/334, 95% CI: 98.1%-100%) in the per-protocol set.
No variable had an impact on SVR12 (Figure 3).
The baseline characteristics of the 3 non-SVR12 patients were
shown in Table 2. The case 1 had no RVR at week 4 of therapy (HCV
RNA 67 IU/mL) and finally suffered from nonresponse. Both case 2
and case 3 had RVR and EOTVR, but got relapses. Of them, two were
older than 70 years old, and one was 51.5 years old. All three persons
were female and treatment-naïve and did not have HBV coinfection or
HCC at entry. One had genotype 1a infection and nonresponse, and
two genotype 1b ones both met relapses. The case 1 had lower base￾line viral load (541 466 IU/mL), and in contrast, other two had higher
viral load (3 270 771 and 5 010 790 IU/mL).
Besides, we retrospectively repeated genotyping and RAS test￾ing if subtype 1a for these three people: In the case 1, HCV genotype
changed from 1a at baseline to genotype 2 after EOT. However, during
treatment period (week 1), the detectable HCV RNA showed a mixed
genotype of 1a and 2. As for NS5A RAS, the wild type at baseline was
confirmed after rechecking by the deep sequencing, but the NS5A
L31M was noted after treatment. The serum of the case 2 was unavail￾able and she was lost follow-up. The case 3 was confirmed as subtype
FIGURE 1 Flowchart of selection of
patients in the study. D, day; EOT, end
of treatment; HCV GT, hepatitis C virus
genotype; HE, hepatic encephalopathy;
SVR12, sustained virologic response
12 wk after treatment; UTI, urinary tract
infection; W, week
2017/06/28-2018/03/06
Patients of HCV GT1
treated with elbasvir/grazoprevir Ʋ ribavarin
(N = 350)
Completed treatment
(N = 340)
6 patients had insufficient follow-up time after EOT
Death (N = 2, liver failure, unknown cause)
Loss of follow-up (N = 4)
Finished post-treatment 12-W follow-up
(N = 334)
10 patients discontinued treatment
1. D3 due to skin rashes
2. W1 due to UTI-induced HE
3. W2 due to diarrhea
4. W2 due to loss of follow-up
5. W3 due to hepatitis
6. W4 due to no family
7. W4 due to discomfort
8. W6 due to delirium
9. W10 due to asthma-induced death
10. W11 due to poor adherence
4  |    HSIEH et al.
1b again via sera at baseline and at the time of relapse by using the
different genotyping method from the original one.
3.3 | Safety
The overall incidence of adverse events was 2% (7/350) and that of
drug-related adverse events was 0.9% (3/350) (Table 3). Totally, 7
(2%) adverse events were reported and resulted in treatment dis￾continuation. Of them, only two (asthma and urinary tract infection)
were considered to be nondrug-related (Table 3). The one withdraw￾ing treatment due to a hepatitis flare was a 62-year-old woman. She
had alanine aminotransferase (ALT) 88 U/L at baseline, then ALT of
155 U/L at week 2. The treatment was discontinued at week 3 be￾cause of rapidly increasing ALT of 341 U/L. Her HCV RNA was unde￾tectable at EOT (3 weeks), and 12 and 24 weeks after EOT. However,
her ALT level continued elevation after stopping elbasvir/grazoprevir
(up to 781 U/L two weeks later). Liver biopsy disclosed features of
autoimmune hepatitis. Her ALT level decreased to the normal value
after 1-week azathioprine plus prednisolone. Death happened in
three persons after EOT, from asthma, liver failure after HCC treat￾ment and the unknown cause.
The most common laboratory abnormality was ALT elevation
(28%), 80 (22.9%), nine (2.6%) and nine (2.6%) patients had CTCAE
grade 1, grade 2 and grade 3, respectively (Table 3). The timing of
occurrence of elevation of ALT was 21 (21.4%) patients within the
first 4 weeks, 29 (29.6%) in 4-8 weeks and 48 (49%) after 8 weeks.
Patients with on-treatment ALT elevation were 68.8 ± 9.1 years old
and 55.1% were female. There were no significant results in age
and gender between patients with ALT elevation or not. Further,
two (0.57%) patients had late grade 3 ALT increases (after treat￾ment week 8), and both resulted from flares of hepatitis B (Table 4,
Table S1). The case 1 encountered ALT 519 U/L at on-treatment
week 10 (83 U/L at week 8), and entecavir was prescribed pro￾phylactically under the diagnosis of a flare of hepatitis B. Later,
FIGURE 2 Virologic responses during and after elbasvir/
grazoprevir treatment. EOT, the end of treatment; F12, week 12
after EOT; HCV RNA, hepatitis C virus ribonucleic acid
Week 2 Week 4 EOT F12
Undetectable HCV RNA rate (%)
TABLE 1 Baseline clinical characteristics
Variables
Patients
(N = 350)
Age (years) 68.6 ± 10.0
Male 165 (47.1%)
BMI (kg/m2
) 24.7 ± 4.0
Treatment-naïve 253 (72.3%)
HBV coinfection 23 (6.6%)
METAVIR hepatic fibrosis stage
F0 1 (0.3%)
F1 10 (2.9%)
F2 9 (2.6%)
F3 108 (30.9%)
F4 222 (63.4%)
HCC at entry 79 (22.6%)
Nonviable 50 (14.3%)
Viable 29 (8.3%)
DM 72 (20.6%)
HCV genotype
1a 8 (2.3%)
1b 342 (97.7%)
HCV RNA level (MIU/mL) 1.0 [0.3, 2.6]
≥800 000 (IU/mL) 190 (54.3%)
≥2 000 000 (IU/mL) 107 (30.6%)
INR 1.1 [1.0, 1.1]
Haemoglobin (g/dL) 13.0 ± 1.8
WBC (103
/µL) 5.3 [4.2, 6.4]
Platelet (103
/µL) 139.8 ± 55.3
Albumin (g/dL) 4.1 ± 0.4
ALT (U/L) 57 [38, 103]
AST (U/L) 59.5 [40, 90]
Bilirubin (mg/dL)
Total form 0.9 [0.6, 1.2]
Direct form 0.2 [0.2, 0.3]
Creatinine (mg/dL) 0.8 [0.7, 1.1]
eGFR (mL/min/1.73 m2
) 77.6 ± 34.0
CKD stage (nondialysis)
1 124 (38.6%)
2 127 (39.6%)
3 60 (18.7%)
4 7 (2.2%)
5 3 (0.9%)
Haemodialysis 29 (8.3%)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase; BMI, body mass index; CKD, chronic kidney disease;
DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HBV,
hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus;
INR, international normalized ratio; RNA, ribonucleic acid; WBC, white
blood cell.
   | HSIEH et al.  5
HCV RNA < 12 IU/mL and HBV DNA 42 381 423 IU/mL (553 IU/
mL before treatment) were checked. His ALT improved and finally
became normal 12 weeks after EOT. The case 2 had ALT 280 U/L
at EOT, and then ALT abnormality aggravated up to 1165 U/L.
Undetectable HCV RNA but HBV DNA 11 710 807 IU/mL was
noted. No anti-HBV agent was used due to no clinical symptoms,
and ALT recovered gradually. HBV DNA declined to 568 IU/mL
10 weeks after EOT. The rate of on-treatment hepatitis B flares
was 8.7% (2/23). Fifty-four (15.4%) and 17 (4.9%) patients had
grade 1 and 2 elevations in serum total bilirubin levels.
There was no significant difference among eGFR of base￾line, EOT and 12 weeks after EOT after excluding haemodialysis
(Figure 4). We further stratified participants into four subgroups:
eGFR ≥60, <60, <60-30 and <30 mL/min/1.73 m2
. Only persons
with eGFR ≥60 mL/min/1.73 m2
had significantly longitudinal
changes of eGFR during and after elbasvir/grazoprevir treatment.
Post hoc tests revealed that eGFR at baseline was significantly
higher than that at EOT but not 12 weeks after EOT (P = .008
and P = .77, respectively). Overall, 223 patients had baseline
eGFR ≥ 60 mL/min/1.73 m2
(Table S2). They were younger and
had lower BMI and higher levels of haemoglobin, ALT and aspar￾tate aminotransferase (AST) as compared to the group with eGFR
<60 mL/min/1.73 m2
. As shown in Table S3, the univariate anal￾ysis indicated that younger age, lower BMI, higher haemoglobin
and higher ALT were predictive factors of patients with eGFR
≥60 mL/min/1.73 m2
. After multivariate adjustment, younger age
[odds ratio (OR): 0.92, 95% CI: 0.88-0.96, P ≤ .001], female gender
(OR: 3.18, 95% CI: 1.44-7.04, P = .004), lower BMI (OR: 0.83, 95%
CI: 0.75-0.91, P < .001) and higher haemoglobin level (OR: 1.65,
95% CI: 1.31-2.08, P < .001) were independently associated with
people of eGFR ≥60 mL/min/1.73 m2
. Patients with renal impair￾ment did not have significant concerns about the renal safe issues
during the treatment.
4 | DISCUSSION
High rates of SVR12 were reported in clinical trials and two inte￾grated analysis of elbasvir/grazoprevir-based therapies for HCV gen￾otype 1 and 4 infected patients with compensated liver disease.5-17
However, the efficacy and safety in clinical trials might not be exactly
equal to that in the real-life circumstance. The HCV genotype and
races also vary by region.18 Our study is one of the few real-world
cohort studies of elbasvir/grazoprevir-based therapy and demon￾strated the fixed-dose combination of elbasvir (50 mg)/grazoprevir
(100 mg) is highly effective and well tolerated for HCV genotype
1 patients in the Asia-Pacific region. In this study, the SVR12 rates
of per-protocol were 83.3% in subtype 1a, and 99.4% in subtype 1b
with the adverse event rate of 2%.
With great consistency, real-world studies also showed el￾basvir/grazoprevir-based regimens achieved marvellous SVR12
rates of 96.7%-99% in genotype 1, 88.5%-99% in genotype 1a and
FIGURE 3 Subgroup analyses of SVR12 (per-protocol set). BMI, body mass index; CKD, chronic kidney disease; DM, diabetes mellitus; F,
female; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; M, male; RNA, ribonucleic acid; SVR12, sustained virologic response 12 wk
after treatment
227/230 104/104 155/155 176/179 239/242 92/92
248/249 83/85 160/161 117/119 5/6 326/328 149/150 182/184 229/230 102/104 114/116 123/124 57/57 7/7 2/2
309/312 22/22 1/1 9/9 9/9 102/103 210/212 305/308 26/26
P = 0.555 P = 0.252 P = 0.565 P = 1.000 P = 0.996 P = 1.000
P = 0.126 P = 0.577 P = 0.053 P = 1.000 P = 0.230 P = 0.852
6  |    HSIEH et al.
98%-100% genotype 1b.19-25 Based on these real-life data, it seemed
that SVR12 rates were lower and variable in genotype 1a-infected
patients. However, only 8 genotype 1a patients could not draw any
conclusion.
In this cohort, no significant differences in SVR12 rates had
been observed in all subgroups, regardless of patient age, gender,
prior treatment, HBV coinfection, hepatic fibrosis stage, HCC sta￾tus, DM, BMI, genotype, baseline HCV RNA and CKD stages. As
compared with other real-world studies, our patient group was
elder (68.5 ± 10 years old) and had more advanced liver disease
[advanced fibrosis (F3) 30.9% and cirrhosis (F4) 63.4%].19-25 Even
so, excellent SVR12 rates were still noted across all ages and fi￾brosis stages. Former studies had reported HCV-related HCC
patients with or without cirrhosis might have higher risk of DAA
treatment failure, but this seems not a problem to the regimen
of elbasvir/grazoprevir according to our results.26-28 Although
several real-world data observed that lower SVR12 rates (89.1%-
93.3%) in those with baseline HCV RNA >800 000 or >2 million
IU/mL, our investigation revealed high SVR12 rates between both
high and low viral load at baseline.19,21,22,24 It is worth noting that
two Japanese studies both presented a history of failure to all oral
IFN-free DAA regimens may have a negative impact on elbasvir/
grazoprevir outcome, but this need further research in the future
to verify due to a smaller sample size.23,25 Finally, the RVR rate
seemed no longer a good predictor of SVR12 in this study (RVR
rate 88.3%, and SVR12 rate 99.1%). It was interesting that the shift
of genotype before and after DAA treatment happened in one pa￾tient without SVR12. The reason of treatment failure might result
from the occult mixed HCV genotype.
The rate of adverse events in our study was 2%, and the rate
of drug-related adverse events was 1.5%. Most adverse events
were not severe, and 3 patients all had a rapid recovery from the
drug-related adverse event after withdrawing treatment with el￾basvir/grazoprevir. Causes of mortality were all unrelated to el￾basvir/grazoprevir. This rate was quite low as compared to other
real-world reports (ranging from 3.4% to 51.2%).19,21-23 Our data
cannot demonstrate Asian (no control group), elderly (≥65 years
old but no statistical significance) or female patients suffer higher
event rates suggested by previous population pharmacokinetic
TABLE 2 Baseline characteristics of 3 patients without SVR12
Variables Case 1 Case 2 Case 3
Type of SVR12 failure Nonresponse Relapse Relapse
Age (years) 70.8 74.7 51.5
Gender Female Female Female
BMI (kg/m2
) 21.5 28.3 25.2
Prior treatment Naïve Naïve Naïve
HBV coinfection No No No
METAVIR hepatic
fibrosis stage
F4 F4 F3
HCC at entry No No No
DM Yes Yes No
HCV genotype 1a 1b 1b
Baseline HCV RNA
(IU/mL)
541 466 3 270 771 5 010 790
INR 1.17 1.08 0.98
Haemoglobin (g/dL) 13.7 13.2 12.9
WBC (103
/µL) 3600 7200 7300
Platelet (103
/µL) 65 222 186
Albumin (g/dL) 3.7 4.5 4.52
ALT (U/L) 378 32 71
AST (U/L) 371 27 47
Bilirubin (mg/dL)
Total form 1.6 1.6 0.5
Direct form 0.4 0.4 0.1
Creatinine (mg/dL) 0.48 0.83 0.67
eGFR (mL/
min/1.73 m2
127.6 67 93
Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase; BMI, body mass index; DM, diabetes mellitus; eGFR,
estimated glomerular filtration rate; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; INR, international
normalized ratio; RNA, ribonucleic acid; SVR12, sustained virologic
response 12 wk after treatment; WBC, white blood cell.
TABLE 3 Safety and adverse events
Variables
Patients
(N = 350)
Adverse events 7 (2.0%)
Asthma 1 (0.3%)
Deliriuma 1 (0.3%)
Diarrhoeaa 1 (0.3%)
Hepatitisa 1 (0.3%)
Skin rashes and pruritusa 1 (0.3%)
Irritabilitya 1 (0.3%)
Urinary tract infection 1 (0.3%)
Discontinuation due to adverse event 7 (2.0%)
ALT elevationb
Grade 1 (1-3X ULN) 80
(22.9%)
Grade 2 (3-5X ULN) 9 (2.6%)
Grade 3 (5-20X ULN) 9 (2.6%)
Total bilirubin elevationb
Grade 1 (1.0-1.5X ULN) 54
(15.4%)
Grade 2 (1.5-3.0X ULN) 17 (4.9%)
Drug-unrelated death 3 (0.9%)
Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of
normal.
Drug-related adverse events.
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
was for grading.
   | HSIEH et al.  7
analyses.1,2,29 ALT elevation was the most common lab change in
this study. Nine (2.6%) patients encountered ALT levels more than
5-fold the upper limit of normal, and one female had an attack
of autoimmune hepatitis. Case reports of autoimmune hepatitis
during DAA therapy were published recently, and this disease
should be put into the differential diagnosis when meeting liver
injury during DAA.30 Besides, two (22.2%) had late elevation of
ALT level after treatment week 8, and both had flares of hepati￾tis B. The rate of hepatitis B flares was 8.7% in our study, similar
to that reported by a systemic review and meta-analysis (9%).31
Reactivation of hepatitis B during DAA treatment should be kept
alert in the HBV endemic area. Different from American and
European guidelines, close monitor may be a good strategy for an
on-treatment HBV flare without hepatic decompensation based
on our experience.1,2
Elbasvir/grazoprevir had been proved by the C-SURFER trial for
the use in patients with severe renal impairment or end-stage renal
disease, and CKD and haemodialysis status also did not affect the ef￾fectiveness and adverse events in the real-life populations.10,19,23-25
Although the primary route of elimination of elbasvir/grazoprevir is
<1% in the urine, an increase of the exposure in non-HCV-infected
people with eGFR <30 mL/min/1.73 m2
was reported.2,29 In our group
of renal impairment (eGFR <60 mL/min/1.73 m2
), elbasvir/grazoprevir
cannot cause adverse events. Nevertheless, rare studies discussed dy￾namic changes in renal function before and after the treatment. Ogawa
et al exhibited no significant changes during treatment or the follow-up
time in two groups of eGFR ≥60 and 15-<60 mL/min/1.73 m2
25 On
the other hand, our study showed a sight but significant decrease of
eGFR from the baseline to EOT if eGFR ≥60 mL/min/1.73 m2
, but no
significant results among other CKD stages (Figure 4). This phenom￾enon was common for other DAAs as described in the recent publi￾cation.32 In addition, a slight decrease in eGFR at EOT with recovery
at the time of week 12 after treatment implies it is a phenomenon
without clinical significance, especially it was only observed in patients
with eGFR ≥ 60 mL/min/1.73 m2
Our study had several strengths. First, the majority of our par￾ticipants had genotype 1b (97.7%), so effectiveness and safety of
elbasvir/grazoprevir in our study can reflect the real-world condition
in areas of predominant genotype 1b. Second, dosage and duration
variation, regimen modification and missing data are rare in our co￾hort. Our government made strict regulations for HCV treatment,
so dosage, duration and regimen of DAA was closely followed as
guidelines suggested. Also, we all prescribed the uniform formula of
12-week elbasvir/grazoprevir without ribavirin for all patients. Third,
our enrolled patients came from northern and southern Taiwan
where different prevalence existed, and this heterogeneous popu￾lation may reduce a geographical variation.33 Fourth, the details of
patients with on-treatment ALT elevations and without SVR12 were
described, and this was difficult to be done by using delinked bid
data. There were several limitations in our study. Firstly, this was a
retrospective study and no control group was compared. The deci￾sion to cease treatment due to adverse events by a physician might
have a bias, and some adverse events might be underestimated.
Secondly, analysis of factors of SVR12 may be inadequate because
of very small proportion of all samples failing to achieve SVR12.
Thirdly, findings from this study were obtained from elder patients
with more advanced liver disease, and this represents only a part of
the general population.
In conclusion, our cohort suggests that high SVR12 rates (99.1%)
in genotype 1b patients across all subgroups and low incidence of
adverse events (2%) in an Asia real-world clinical setting. One pa￾tient developed autoimmune hepatitis and two had hepatitis B
flares. Renal function could change during the treatment but without
clinical significance.
TABLE 4 Characteristics of 2 patients with CTCAE grade 3 and
late onset ALT elevation (after treatment week 8)
Variables Case 1 Case 2
ALT elevation
Peak value (U/L) 519 280
Onset time (week) 10 12
Outcome
SVR12 Yes Yes
HBV coinfection Yes Yes
Age (years) 60.9 61.0
Gender Male Male
BMI (kg/m2
) - 21.3
Prior treatment Experienced Naïve
METAVIR hepatic fibrosis stage F4 F4
HCC at entry No No
DM Yes Yes
HCV genotype 1b 1b
Baseline HCV RNA (IU/mL) 1 137 855 4 426 670
INR 1.1 1.1
Haemoglobin (g/dL) 13.1 16.4
WBC (103
/µL) 6300 6000
Platelet (103
/µL) 224 174
Albumin (g/dL) 4.6 4.1
ALT (U/L) 25 174
AST (U/L) 24 176
Bilirubin (mg/dL)
Total form 0.5 1.0
Direct form 0.2 0.3
Creatinine (mg/dL) 1.16 0.6
eGFR (mL/min/1.73 m2
) 64.0 129.5
Abbreviations: ALT, alanine aminotransferase; AST, aspartate
aminotransferase; BMI, body mass index; CTCAE, Common
Terminology Criteria for Adverse Events; DM, diabetes mellitus; eGFR,
estimated glomerular filtration rate; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; INR, international
normalized ratio; RNA, ribonucleic acid; SVR12, sustained virologic
response 12 wk after treatment; WBC, white blood cell.
8  |    HSIEH et al.
ACKNOWLEDGEMENTS
This study was supported by the Chang Gung Memory Research
Grant. We thank all patients, their medical providers, and collectors
of clinical data enrolled in this study, and all authors for their contri￾butions to the manuscript.
CONFLICT OF INTEREST
The authors had no potential conflicts of interest.
ORCID
Yi-Chung Hsieh https://orcid.org/0000-0002-1191-4399
Chun-Yen Lin https://orcid.org/0000-0003-3007-3190
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FIGURE 4 Renal function changes during and after elbasvir/grazoprevir treatment. A, All patients; B, eGFR <60 mL/min/1.73 m2
; C,
eGFR <60 mL/min/1.73 m2
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   | HSIEH et al.  9
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Hsieh Y-C, Lin C-L, Hung C-H, et al.
Real-world experience of elbasvir/grazoprevir in Taiwan: This
study was focused on liver and renal adverse effects. J Viral
Hepat. 2020;00:1–9. https://doi.org/10.1111/jvh.13262