This retrospective study consecutively included 242 patients with HCV genotype 1 or 4 infection who received at least one dose of EBR/GZR therapy between May 2017 and June 2018. Seven tertiary hospitals located in different regions of South Korea had participated. EBR/GZR was administered orally at a fixed dose of 50 mg of EBR and 100 mg of GZR once daily according to the label. This study was approved by the Institutional Review Boards of the seven participating hospitals (i.e., Seoul National University Bundang Hospital, B-1809/495-108), and the requirement for obtaining written informed consent was waived because this study was based on the retrospective review of existing medical records.

Patients who had been treated with at least one dose of interferon/peginterferon-based therapy or direct-acting antiviral agents other than EBR/GZR were considered as treatment-experienced group, whereas all other patients were considered as treatment-naïve.

The persistence of HCV RNA for more than 6 months was defined as chronic hepatitis C. The diagnosis of LC was made by histologic or clinical findings of portal hypertension [13], including cirrhotic appearance of the liver with splenomegaly, revealed by imaging (ultrasonography, computed tomography, or magnetic resonance imaging), thrombocytopenia, presence of varices on endoscopy, ascites, and/or hepatic encephalopathy. Patients with hepatocellular carcinoma were considered as a separate HCC group, regardless of their liver function.

Estimated glomerular filtration rate (eGFR) was calculated using the original Modification of Diet in Renal Disease Study equation [14] based on creatinine and patient characteristics. Chronic kidney disease (CKD) was categorized into five stages according to eGFR values.

HCV genotyping and RNA concentration measurement by real-time polymerase chain reaction were performed at the certified laboratories at each participating site. In several patents with HCV genotype 1b, the presence of NS5A resistance-associated substitutions (RAS) was tested by direct Sanger sequencing at a central laboratory (Seoul Clinical Laboratories, Yongin, Korea). The results were reported as negative, positive, or “undetermined,” based on the presence of L31 or Y93 RAS. The limit of HCV RNA concentration for the detection of RAS was 1,000 IU/mL.

SVR was defined as undetectable HCV RNA level at 12 weeks after completion of treatment according to the practice guideline for hepatitis C management [15]. Viral breakthrough referred to the reappearance of HCV RNA during the treatment, and relapse was defined as the reappearance of HCV RNA after initial viral elimination with undetectable HCV RNA level at the end of treatment. Because several patients did not visit the clinic for SVR evaluation at the exact weeks, the RNA data obtained in a window period of ± 4 weeks were accepted. Patients lost to follow-up after the completion of antiviral therapy and not evaluated for SVR were considered as “no SVR” in the intention-to-treat (ITT) analysis.

The adverse events were based on medical chart review by the attending physician. Owing to the limitation of the study’s retrospective design, the grade of adverse events could not be evaluated.

Analyses were conducted by descriptive statistics for virological outcomes, safety, and comorbid diseases using the chi-squared test. SVR in the ITT analysis was calculated for all enrolled patients (n = 242). In the per-protocol (PP) analysis, SVR was calculated for the subjects who completed the scheduled treatment and follow-up for ≥ 12 weeks after treatment completion (n = 213). All statistical analyses were performed using Stata version 14.0 (Stata, College Station, TX, USA).

As shown in Table 1, the mean age of the participants was 59.0 years (SD, 12.6), and 111 (47.5%) were male. Most patients had chronic hepatitis (69.8%), and 29.3% had compensated LC. A total of 213 patients (88.0%) were naïve for antiviral treatment, and 29 (12.0%) had experience of other antiviral therapy before the EBR/GZR therapy (Table 1). Only one patient was infected with HCV genotype 4, and most enrolled patients had HCV genotype 1b, which is the major genotype in Korea. HCV genotype 1a cases were not included in this study. Forty-one patients with HCV genotype 1b were screened in the RAS test, and 24 patients were found positive for NS5A RAS: one (for L31), 15 (for L31 + Y93), seven (for Y93), and one (for an undetermined RAS).

As shown in Fig. 1A, SVR was achieved by 86.4% and 98.1% Korean patients on EBR/GRZ therapy according to the ITT and PP analyses, respectively. Of the 29 patients who were excluded from the PP analysis, four had stopped antiviral therapy within 30 days of treatment for the reasons unrelated to an adverse event or inadequate response, and 25 had completed the scheduled therapy for 12 weeks but did not visit the clinic for SVR evaluation. According to subgroup analyses (Fig. 1B), 97.8% of treatment-naïve and 100% of treatment-experienced patients developed SVR in the PP analysis (p = 0.442). We looked for the effect of the underlying liver disease and found that 100% of compensated LC patients and 97.2% of chronic hepatitis patients showed SVR (p = 0.159). Two HCC patients who had been treated and not recurred for more than 6 months also achieved SVR. Although their number was small, fewer patients with HCV genotype 1 of unspecified subtype achieved SVR (81.2%) compared to the fraction of those with HCV genotype 1b (99%). Notably, two genotype 1b patients who failed to achieve SVR had Y93 substitution. Therefore, genotype and RAS were important predictive factors for SVR following EBR/GRZ therapy. Detailed clinical characteristics of the four patients who did not show SVR after EBR/GRZ therapy are described in Table 2.

In the 242 HCV-infected patients, the most common comorbid diseases were hypertension (29.8%) and diabetes mellitus (22.7%) (Table 3). Moderate or severe renal disease, i.e., CKD stage ≥ 3 (eGFR < 60 mL/min/1.73 m²) was found in 30 (12.4%) patients. Of them, 20 had stage 5 CKD (eGFR < 15 mL/min/1.73 m²). All CKD patients had completed 12 weeks of EBR/GZR therapy and achieved SVR according to the PP analysis. Fifteen patients had a history of hepatic or extrahepatic malignancy (6.2%), and cerebrovascular diseases were found in 5.0%. Of the six patients with depression, one failed to achieve SVR despite the completion of EBR/GZR therapy. Other comorbid diseases were not frequently found in our study cohort, and all individuals with those diseases achieved SVR.

Adverse events of any grade were reported in 24.4% (59/242) of patients during EBR/GZR therapy (Table 4). Itching was the most common symptom found in 12% of patients. Alanine aminotransferase (ALT) elevation greater than five times the upper limit of normal (ULN) was found in one (0.4%) patient at week 12, whereas ALT elevation greater than 2 × ULN was detected in 11 (4.5%) patients. In three of these patients (27.3%), ALT elevation was detected within 4 weeks after the start of antiviral treatment. In five patients (45.5%), it was found on week 8, and in another three patients (27.3%)—towards the end of the 12 weeks of treatment (Supplementary Table 1). All of these patients, except one lost to follow-up, achieved SVR successfully after 12 weeks of antiviral therapy, and 8 of 11 patients (72.7%) showed improved ALT level without any specific treatment.

Dyspepsia, fatigue, epigastric pain, nausea was found in 2–4% of the patients (Table 4). Nonetheless, no subject had considered to withdraw from EBZ/GZR therapy because of the symptoms. Of the four patients who stopped antiviral therapy within 30 days in our study, three did not report any symptoms and one (54-year-old woman) felt mild fatigue during antiviral treatment.