Sofosbuvir/velpatasvir for patients with chronic hepatitis C virus infection and compensated liver disease: real-world data in Taiwan

Data regarding the real-world effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) for East Asian patients with chronic hepatitis C virus (HCV) infection and compensated liver disease are limited. We evaluated the performance of SOF/VEL for 12 weeks for HCV-infected patients with compensated liver disease in a large real-world cohort in Taiwan. Between July 2019 and March 2020, 1880 HCV-infected patients with compensated liver disease who received SOF/VEL 400/100 mg once daily for 12 weeks were included at 15 academic centers in Taiwan. The sustained virologic response at off-treatment week 12 (SVR12) was assessed for evaluable (EP) and per-protocol populations (PP). The tolerance was also reported. The SVR12 rates by EP and PP analyses were 95.6% [1798 of 1880 patients; 95% confidence interval (CI) 94.6–96.5%] and 99.3% (1798 of 1811 patients; 95% CI 98.8–99.6%), respectively. Among 82 patients who failed to achieve SVR12, 13 (15.9%) were attributed to virologic failures. The SVR12 rates were comparable regardless of baseline characteristics. A total of 1859 (98.9%) patients completed 12-week SOF/VEL treatment. Four (0.2%) patients discontinued treatment due to adverse events (AEs). All patients with serious AEs or deaths were judged not related to SOF/VEL. The AEs occurring in ≥ 10% included headache (16.8%), fatigue (16.2%), nausea (11.8%), and insomnia (11.1%). Nine (0.5%) and 2 (0.1%) patients had grade 3 total bilirubin and alanine aminotransferase elevations. SOF/VEL for 12 weeks is efficacious and well-tolerated by chronic HCV-infected patients with compensated liver disease in Taiwan.


Introduction
Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), hepatic decompensation, and liver transplantation. The estimated global prevalence of HCV infection is 1.0% and about 71 million people are living with HCV [1]. Patients with persistent HCV viremia are associated with an increased risk of various hepatic and extrahepatic manifestations, which compromise the overall morbidity and mortality [2,3]. In contrast, the health-related outcomes are substantially improved following effective antiviral therapies for HCV [4]. Based on the high sustained virologic response (SVR) rate, low treatment-emergent adverse events (AEs) rate, and all-oral regimen with short-treatment duration, the advent of interferon (IFN)-free direct acting antivirals (DAAs) has become the standard of care for managing HCV. Currently, DAAs with pangenotypic potency and fixed-dose combination (FDC) are recommended to be the first-line therapies, because these regimens can simplify the care by obviating the needs for HCV genotype (GT) testing and intensive ontreatment monitoring [5][6][7]. Moreover, the World Health Organization (WHO) recommends the pangenotypic DAAs for HCV to move toward the viral elimination by 2030.
Sofosbuvir/velpatasvir (SOF/VEL) is formulated in the form of FDC by HCV non-structural protein 5B (NS5B) and NS5A inhibitors [8]. Clinically, SOF/VEL is administered once daily orally with pangenotypic and panfibrotic potency. In addition, this regimen has a high genetic barrier to viral resistance and has a lower potential for drug-drug interactions (DDIs) than protease inhibitor (PI)-based regimens [9,10].
The phase 3 global trials evaluating the performance of SOF/VEL for 12 weeks in patients with HCV GT 1-6 and compensated liver disease demonstrated that the SVR 12 rates were 99% for HCV GT 1, 2, 4, 5, and 6 and 95% for HCV GT 3 infections [11,12]. The phase 3 Asian trial indicated that the SVR 12 rate was 97% for patients with HCV GT 1, 2, 3, and 6 infection, and compensated liver disease receiving SOF/VEL for 12 weeks [13]. Furthermore, most patients tolerated treatment well. Recently, a meta-analysis recruiting 5,552 HCV-infected patients receiving SOF/VEL for 12 weeks from 12 real-world cohort studies in the USA, Canada, and Europe revealed that the SVR 12 rates were 92.6% and 99.0% for those who received at least one dose of treatment and for those who had available data for offtreatment effectiveness analysis [14]. Based on the excellent safety and efficacy, most Western countries have approved the use of SOF/VEL for HCV-infected patients with compensated liver disease. In East Asia, China and Taiwan have approved the use of SOF/VEL for 12 weeks for patients with compensated liver disease, whereas Japan has approved this regimen only for patients with decompensated liver disease. Till now, data regarding the real-world effectiveness and safety of SOF/VEL for 12 weeks in East Asian chronic HCV-infected patients remain limited. Only 4 small-scale studies from China and Taiwan reported the effectiveness of brand-name and generic SOF/VEL for 12 weeks, showing that the SVR 12 rates ranged from 97.7 to 100% [15][16][17][18]. We thus conducted a large-scale multicenter study to assess the performance of brand-name SOF/VEL for 12 weeks in chronic HCV-infected patients with compensated liver disease in Taiwan.

Patients
Between July 2019 and March 2020, we retrospectively recruited patients with chronic HCV infection and compensated liver disease who were aged ≥ 20 years and received SOF/VEL for 12 weeks at 15 academic centers in Taiwan. Chronic HCV infection was defined as the presence of detectable HCV antibody (anti-HCV; Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park, Illinois, USA) and quantifiable serum HCV RNA [Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, lower limit of quantification (LLOQ): 15 IU/mL] for ≥ 6 months. Patients with compensated liver disease were defined as those without cirrhosis or with compensated cirrhosis (Child-Pugh A).
Patients received SOF/VEL (Epclusa®, FDC 400/100 mg per tablet, Gilead Sciences, Carrigtohill, Co. Cork, Ireland) 1 tablet once daily for 12 weeks. After the initiation of treatment, patients underwent monitoring at on-treatment weeks 4, 8, and 12 and at off-treatment week 12. Hemogram, total bilirubin, direct bilirubin, AST, and ALT were assessed at on-treatment weeks 4 and 12. Hemogram, INR, albumin, total bilirubin, direct bilirubin, AST, ALT, eGFR, and hepatic imaging studies were assessed at off-treatment week 12. Serum HCV RNA levels were assessed at on-treatment week 12 and at off-treatment week 12.

Drug adherence
The adherence was presented as the percentage of the total pills consumed during treatment divided by the 84 dispended pills for SOF/VEL.

Effectiveness
We assessed the end-of-treatment virologic response and sustained virologic response at on-treatment week 12 and off-treatment week 12, respectively. All patients were judged not to achieve SVR 12 if the HCV RNA level was > LLOQ at off-treatment week 12 (virologic failure) or if patients had missing SVR 12 data (non-virologic failure). The SVR 12 endpoints included evaluable population (EP) for patients who received at least one dose of SOF/VEL, and per-protocol population (PP) for patients who had available SVR 12 data.

Safety
In patients who prematurely discontinued treatment, or who had serious adverse events (AEs) including death, lifethreatening condition, in-patient hospitalization, persistent disability, or important medical events requiring emergent intervention, the investigators reviewed the medical records and judged the causal relationship between the events and SOF/VEL. We also reported common AEs with rates of ≥ 10% and the proportion of patients with ≥ grade 2 total bilirubin or ALT elevation according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The eGFR changes between baseline and SVR 12 were compared for all patients.

Statistical analysis
All analyses were performed by Statistical Program for Social Sciences (SPSS Statistics Version 23.0, IBM Corp., Armonk, New York, USA). Baseline characteristics were shown in median (interquartile range, IQR) and numbers (percentages) when appropriate. The virologic response rates at on-treatment and off-treatment weeks 12 were shown in numbers (percentages) with 95% confidence interval (CI). We demonstrated the subgroup analyses of SVR 12 in number (percentage) with 95% CI according to PP analysis. The common AEs and laboratory abnormalities were shown in numbers (percentages) when appropriate. The eGFR at baseline and SVR 12 was shown in mean (standard deviation), and the changes of the eGFR were compared by paired t test according to baseline CKD stage.

Effectiveness
At on-treatment week 12, 1853 of 1859 patients with available data (99.7%; 95% CI 99.3-99.9%) had serum HCV RNA level < LLOQ. By EP and PP analyses, the SVR 12 rates were 95.6% (1798 of 1880 patients; 95% CI 94.6-96.5%) and 99.3% (1798 of 1811 patients; 95% CI 98.8-99.6%). Among the 82 patients who failed to achieve SVR 12 , 13 (15.9%) were attributed to virologic failures and the remaining 69 (84.1%) were attributed to non-virologic failures ( Table 2). The baseline characteristics of patients with virologic failures are summarized in Table 3. Among the 6 patients who had serum HCV RNA ≥ LLOQ at on-treatment week 12, 2 with on-treatment week 12 HCV RNA levels of 28 IU/mL and 51 IU/m achieved SVR 12 , 3 with on-treatment week 12 HCV RNA levels of 1600 IU/mL, 1,500,000 IU/mL, and 3,710,000 IU/mL remained viremic at off-treatment week 12, and one with on-treatment week 12 HCV RNA level of 838,000 IU/mL did not have available SVR 12 data due to loss to follow up after stopping SOF/VEL. The SVR 12 rates of subgroups by PP analysis are shown in Fig. 2.

Discussion
In addition to the pangenotypic, panfibrotic, PI-free, and ribavirin (RBV)-free advantages for chronic HCV-infected patients with compensated liver disease, the high efficacy, and tolerability of SOF/VEL demonstrated in global and regional clinical trials confirm the excellent performance of SOF/VEL against HCV which may facilitate the HCV elimination [11][12][13]. To our knowledge, this study is the first large-scale real-world study in East Asia to evaluate the effectiveness and safety of SOF/VEL for 12 weeks in chronic HCV-infected patients with compensated liver disease. In line with a recently published meta-analysis which showed that the overall SVR 12 rate was 92.6%, we demonstrated that the SVR 12 rate was 95.6% by EP analysis [14]. By excluding patients who failed to achieve SVR 12 due to non-virologic failures, the proportion of virologic failures in our study was only 0.7%, which was similar to the phase 3 trials and the real-world pooled meta-analysis [11][12][13][14]. Furthermore, the subgroup analyses demonstrated that the SVR 12 rates were comparably high regardless of age, sex, prior treatment experience, prior HCC history, HBV or HIV coinfection, renal function, HCV viral load, HCV genotype, and stage of hepatic fibrosis. Compared to the SVR 12 rate of 95% for HCV GT 3a or other GT 3 unconfirmed subgenotypes, the Asian phase 3 trial indicated that the SVR 12 rate was only 76% for HCV GT 3b by SOF/VEL for 12 weeks [13]. Because most HCV GT 3 patients in Taiwan were infected with HCV GT 3a, the SVR 12 rate in our HCV GT 3 patients was 97.2%, which was similar to the SVR 12 rate of 97.5% in HCV GT 3a patients in a pooled analysis of phase 3 SOF/VEL trials [20,23]. While we did not find any clinical parameter to predict 13 patients with virologic failures, HCV GT3 patients with NS5A resistance-associated substitution (RAS) at locus Y93H significantly compromised the SVR 12 rate by SOF/VEL which was not tested in our patients [23]. Furthermore, we also showed that the SVR 12 rate in patients with Child-Pugh A6 cirrhosis remained excellent, compared to patients without cirrhosis or with Child-Pugh A5 cirrhosis (100% versus 97.9-99.3%). It is clinically relevant to practitioners because of the safety concerns for Child-Pugh A6 cirrhotic patients receiving PIbased DAAs [24].
Interestingly, 2 patients who had low levels of serum HCV RNA (28 IU/mL and 51 IU/mL) at on-treatment week 12 achieved SVR 12 after stopping SOF/VEL, whereas 3 who had relatively high levels of serum HCV RNA (1600 IU/mL, 1,500,000 IU/mL and 3,710,000 IU/mL) failed to achieve SVR 12 . The presence of low-level HCV viremia at the end of treatment in our patients with SVR 12 could be reasoned by the persistent augmentation of host immune system which might clear low-level viremia after stopping DAAs, and by the detection of noninfectious or fragmented viral particles [25]. Therefore, the patients and practitioners should not worry too much about the presence of low-level viremia at the end of DAA treatment, because it may not necessarily suggest treatment failure.
Our real-world study included 20 patients with BCLC stage B or C active HCC and 5 with virologic failures to prior NS5A-containing DAAs, who were conventionally excluded from the clinical trials. Seven of our 20 patients with active HCC died during the study period, although all the remaining 13 patients who completed follow-up achieved SVR 12 . The physicians should judiciously optimize DAA treatment, because the benefit of achieving SVR 12 would be minimal in patients with limited life expectancy [5][6][7]. All 5 patients with HCV GT1 or GT2 infection who relapsed from prior course of GLE/PIB, SOF/LDV, or SOF plus DCV in our study achieved SVR 12 . Currently, SOF/VEL has not been labeled for retreating patients who fail prior NS5Acontaining DAAs, although a recent study revealed that the SVR 12 rate of SOF/VEL plus RBV for 24 weeks can reach 97% for retreating HCV GT1 or GT2 patients [26]. Therefore, the physicians should be cautious about the routine use of SOF/VEL alone for 12 weeks to retreat patients not responsive to prior NS5A-containing DAAs to avoid treatment failures. This is of particular importance, because the SVR 12 rates would be even lower in the presence of NS5A L31 or Y93 RAS [26].
Regarding drug adherence, 98.9% of our patients consumed > 95% of the dispended pills. Because that SOF/VEL has the advantages of easy dosing without food effects, low pill burden, short-treatment duration, low risk of treatmentemergent AEs, the excellent drug adherence may contribute to the high SVR 12 rate in our patients [27].
Although 56.6% of our patients were reported to have at least one AE, only 4 (0.2%) patients discontinued treatment due to treatment-emergent AE. Moreover, all serious AEs and deaths were considered not related to the use of SOF/VEL. The proportions of patients with common AEs in our study were also in line with those reported in clinical trials [11][12][13]. With regard to laboratory abnormalities, only a limited number of patients had ≥ grade 2 total bilirubin or ALT elevation, implying that treatment with SOF/ VEL has a high degree of liver safety. The proportions of HCC occurrence and recurrence in our study were 1.7% and 5.1%, respectively, during a 24-week study interval, which were comparable to the annual HCC risks of occurrence and recurrence of 3.0% and 12.2% in a meta-analysis study [28]. In addition to achieving comparably high SVR 12 rates, the eGFR tended to improve in patients with baseline CKD stages 3a-5, implying that the HCV-related renal damages tended to be mitigated following successful viral eradication. Taken together, the tolerance of SOF/VEL for 12 weeks was excellent in our HCV-infected patients with compensated liver disease. In addition to the distinguishing performance of SOF/VEL in terms of efficacy and safety, SOF/VEL for HCV has also been shown to improve patients' quality of life and to be cost-effective which warrants consideration in implementing programs for HCV elimination [29].
Our study had several limitations. First, the numbers of patients with HCV GT4 and GT5 infection were limited, making the effectiveness and safety of SOF/VEL for patients with HCV GT4 and GT5 infection in Taiwan uncertain. Second, we did not have stored blood samples to assess the profiles of RASs in patients with virologic failures due to the retrospective nature of our study. Third, information regarding the HCV GT3 subtypes was not available, because we used commercially based HCV genotyping in this study. Fourth, all patients were included at academic centers, and the effectiveness and safety of SOF/VEL at community hospitals or local clinics need to be validated. Fifth, our study was retrospective in nature which lacked the standardized report forms for AEs, and therefore, the reporting biases might exist. Finally, the proportion of HBV reactivation following SOF/VEL was unknown. However, none developed HBV-associated  Table 4 Safety summary AE adverse event; DAA direct acting antiviral; ULN upper limit of normal; ALT alanine aminotransferase a Twenty deaths, including lung cancer (n = 2), pneumonia (n = 2), traumatic subdural hemorrhage (n = 1), urinary tract infection with septic shock (n = 2), pancreatic cancer (n = 1), intra-abdominal infection with septic shock (n = 1), unknown reason (n = 4), cardiac arrest (n = 1) and hepatocellular carcinoma (n = 6). Twenty-four events with in-patient hospitalization, including recurrence of hepatocellular carcinoma (n = 4), occurrence of hepatocellular carcinoma (n = 2), active hepatocellular carcinoma (n = 3), pneumonia (n = 1), urinary tract infection (n = 1), colorectal cancer (n = 2), lung cancer (n = 1), schizophrenia (n = 1), ischemic stroke (n = 1), peptic ulcer bleeding (n = 2), traffic accident (n = 1), chronic obstructive pulmonary disease (n = 1), esophageal variceal bleeding (n = 1), near syncope (n = 1), thalassemia with symptomatic anemia (n = 1), and rheumatoid arthritis (n = 1) b Four patients had unconjugated hyperbilirubinemia. Three of them had on-treatment ALT levels of < ULN, and one had on-treatment ALT levels of 1.0-2.0 × ULN. No patients developed hepatic decompensation. The other 5 patients, all of whom had active hepatocellular carcinoma, had conjugated hyperbilirubinemia. Two of the 5 patients had on-treatment ALT levels of 3.0-5.0 × ULN c One patient had HBV coinfection, and the serum HBV DNA level was undetectable at the time of ALT elevation. No patients developed grade 3 total bilirubin elevation or hepatic decompensation. Two patients had active hepatocellular carcinoma and developed grade 3 total bilirubin elevation. Both patients died of hepatocellular carcinoma at on-treatment weeks 6 and 10, respectively. All except the two patients with active hepatocellular carcinoma had undetectable HCV RNA level at on-treatment week 12 and off-treatment weeks 12 d One patient had persistently ALT levels of 5.3 × ULN and 6.8 × ULN at on-treatment weeks 4 and 12, and the ALT level was 3.8 × ULN at off-treatment week 12. The other one patient had ALT levels of 5.9 × ULN and 2.7 × ULN at on-treatment weeks 4 and 12, and the ALT levels was 1.5 × ULN at off-treatment week 12. Both patients did not have total bilirubin elevation or hepatic decompensation. Both patients had undetectable HCV RNA levels at on-treatment week 12 and off-treatment weeks 12  hepatitis, defined as the presence of ≥ grade 2 ALT elevation and ≥ 1 log 10 increase of serum HBV DNA level, which led to hepatic decompensation in our HBV-coinfected patients [30]. In summary, our large-scale real-world study shows that SOF/VEL for 12 weeks is efficacious and well tolerated for chronic HCV-infected patients without cirrhosis and with compensated cirrhosis in Taiwan.