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Real-World Safety and Efficacy of Paritaprevir/Ritonavir/Ombitasvir Plus

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Real-World Safety and Efficacy of Paritaprevir/Ritonavir/Ombitasvir Plus www.nature.com/scientificreports OPEN Real-world safety and efcacy of paritaprevir/ritonavir/ombitasvir plus dasabuvir ± ribavirin in Received: 10 July 2018 Accepted: 27 April 2019 patients with hepatitis C virus Published: xx xx xxxx genotype 1 and advanced hepatic fbrosis or compensated cirrhosis: a multicenter pooled analysis Chun-Hsien Chen1, Chien-Hung Chen2, Chih-Lang Lin3, Chun-Yen Lin 4, Tsung-Hui Hu 2, Shui-Yi Tung1, Sen-Yung Hsieh4, Sheng-Nan Lu1,2, Rong-Nan Chien 4, Chao-Hung Hung1,2 & I-Shyan Sheen4 Paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin shows favorable results in hepatitis C virus genotype 1 (HCV-1) patients in terms of safety and efcacy, but real-world data remain limited for those with advanced hepatic fbrosis (fbrosis 3, F3) or compensated cirrhosis (F4). A total of 941 patients treated in four hospitals (the Keelung, the Linkuo, the Chiayi and the Kaohsiung Chang Gung Memorial Hospital) through a nationwide government-funded program in Taiwan were enrolled. Patients with HCV and advanced hepatic fbrosis or compensated cirrhosis received 12 weeks of PrOD in HCV-1b and 12 or 24 weeks of PrOD plus ribavirin therapy in HCV-1a without or with cirrhosis. Advanced hepatic fbrosis or compensated cirrhosis was confrmed by either ultrasonography, fbrosis index based on 4 factors (FIB-4) test, or transient elastography/acoustic radiation force impulse (ARFI). The safety and efcacy (sustained virologic response 12 weeks of therapy, SVR12) were evaluated. An SVR12 was achieved in 887 of 898 (98.8%) patients based on the per- protocol analysis (subjects receiving ≥1 dose of any study medication and HCV RNA data available at post-treatment week 12). Child-Pugh A6 (odds ratio: 0.168; 95% confdence interval (CI): 0.043–0.659, p = 0.011) was the only signifcant factor of poor SVR12. Fifty-four (5.7%) patients were withdrawn early from the treatment because of hepatic decompensation (n = 18, 1.9%) and other adverse reactions. Multivariate analyses identifed old age (odds ratio: 1.062; 95% CI: 1.008–1.119, p = 0.024) and Child- Pugh A6 (odds ratio: 4.957; 95% CI: 1.691–14.528, p = 0.004) were signifcantly associated with hepatic decompensation. In conclusion, this large real-world cohort proved PrOD with or without ribavirin to be highly efective in chronic hepatitis C patients with advanced hepatic fbrosis or compensated cirrhosis. However, Child-Pugh A6 should be an exclusion criterion for frst-line treatment in these patients. 1Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan. 2Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 3Liver Research Unit, Chang Gung Memorial Hospital, Keelung, Taiwan. 4Department of Hepatogastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan. Chun-Hsien Chen and Chien-Hung Chen contributed equally. Chao-Hung Hung and I-Shyan Sheen jointly supervised. Correspondence and requests for materials should be addressed to C.-H.H. (email: [email protected]) SCIENTIFIC REPORTS | (2019) 9:7086 | https://doi.org/10.1038/s41598-019-43554-3 1 www.nature.com/scientificreports/ www.nature.com/scientificreports Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, afecting approximately 150 million people worldwide1. Chronic infection with HCV leads to progressive hepatic fbrosis and cirrhosis in around 20% of patients, and 10–20% of cirrhotic patients will develop hepatocellular carcinoma (HCC) within 5 years1–3. Tis implies that HCV eradication is very important in preventing disease progression and associated morbidity and mortality. Tis is also essential in reducing the future health care burden in society. Combination of interferon (IFN) and ribavirin (RBV) was the previous standard treatment for chronic hep- atitis C. However, lower virologic response rate and lots of side efects with poor adherence limited the applica- tion of treatment, and resulted in low sustained virologic response (SVR) rate of 40–50% among patients with HCV genotype 1 (HCV-1) infection4,5. Te recent advent of direct-acting antiviral agent (DAA) therapy has been widely acknowledged as a revolution in the feld of HCV infection. In clinical trials, IFN-free regimens using second generation DAA combinations yield SVR rates above 90% in HCV-1 infected patients6–8. Due to high virologic response rates even in difcult-to-treat subgroups such as cirrhosis, non-responders to prior therapy, and transplant recipients, and less side efects with better tolerance, DAA has become the frst-line therapy of HCV in the latest guidelines. Paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD)-based regimens for HCV-1 infection have been approved by the Food and Drug Administration (FDA) in the United States (US) since 2016. In one meta-analysis, the SVR rate in PrOD-based regimens with or without RBV can reach up to 94–100% in HCV-1a or HCV-1b patients with and without cirrhosis7. However, warning of severe liver injury, hepatic decompensation and even mortality during this treatment were reported and informed by US FDA in 20159. As far, most of the published studies were performed in the US and in Europe; Asian data is still limited10,11. In Asia, HCV-1 is the most preva- lent form, accounting for 60–70% of HCV infection in Taiwan12. Since January 2017, PrOD-based therapies have been reimbursed in Taiwan for HCV-1 patients with advanced hepatic fbrosis (fbrosis 3, F3) or compensated cirrhosis (F4) through a nationwide government-funded program. Tus, we conducted this study to evaluate the safety and efcacy of PrOD-based therapies in a large real-world cohort of patient with advanced hepatic fbrosis or compensated cirrhosis. Methods Patients and treatments. Tis was a retrospective cohort study of PrOD-based therapies in patients with HCV-1a or HCV-1b and advanced hepatic fbrosis or compensated cirrhosis from four hospitals in Taiwan (the Keelung, the Linkou, the Chiayi, and the Kaohsiung Chang Gung Memorial Hospital). In Taiwan, patients with HCV and advanced hepatic fbrosis or compensated cirrhosis were treated with DAA via a nationwide govern- ment-funded program since 2017. Te patients should have positive HCV antibody or detectable HCV RNA in serum for more than 6 months before treatment. Patient who had any evidence of hepatic decompensation or previous exposure to DAA before PrOD-based therapies should be excluded. Te provided regimens were 12 weeks of PrOD in HCV-1b with or without cirrhosis, 12 weeks of PrOD plus RBV therapy (PrOD + RBV/12w) in HCV-1a without cirrhosis, and 24 weeks of PrOD plus RBV therapy (PrOD + RBV/24w) in HCV-1a with cirrhosis, respectively. Te severity of fbrosis was confrmed by either ultrasonography, fbrosis index based on 4 factors (FIB-4) test, FibroScan (Echosens, Paris, France), or acoustic radiation force impulse (ARFI) (Siemens AG, Erlangen, Germany). Advanced hepatic fbrosis or compensated cirrhosis (Metavir F3-F4) was defned as FIB-4 test ≧3.25, FibroScan ≧9.5 Kpa, or ARFI ≧1.81 m/s. Patients with BCLC advanced or terminal stage and/or limited life expectancy were excluded. Informed con- sent was obtained from all patients prior to registration into the program. Demographic data including patient characteristics, treatment information, laboratory studies, and adverse reactions were recorded. For patients with hepatitis B virus (HBV) coinfection, HBV reactivation was defned as either an increase in HBV DNA level of ≥1 log10 IU/mL in patients with baseline detectable HBV DNA level or the HBV DNA level became detectable in patients with undetectable baseline HBV DNA level. Clinically signifcant hepatitis was defned as an ALT level of ≥3 times upper limit of normal13. Tis study was approved by the Research Ethics Committee of Chang Gung Memorial Hospital and was conducted in accordance with the principles of Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice. Outcomes. Virologic response (VR) was defned as HCV RNA less than the lower limit of quantifcation (LLOQ) at week 2, week 4, week 8, and week 12. Te primary outcome was SVR12 rate, which was defned as the proportion of patients with HCV RNA < LLOQ at post-treatment week 12 in per-protocol population (subjects receiving ≥1 dose of any study medication and HCV RNA data available at post-treatment week 12). Te second- ary outcome was the early withdrawal rate, which was defned as the percentage of patients who failed to complete the course of PrOD-based therapies because of adverse events, comorbidity, or other reasons. Hepatic decompen- sation was defned as the presence of clinical events (variceal hemorrhage, and/or ascites, and/or hepatic enceph- alopathy) or biochemical evidence of worsening liver function (signifcantly increased total bilirubin >3 mg/dL and/or prolonged prothrombin time ≥3 seconds). Serum HCV RNA levels were determined by COBAS TaqMan HCV Test (TaqMan HCV; Roche Molecular Systems Inc., Branchburg, N.J., 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). Genotyping of HCV was performed by reverse hybridization assay (Inno-LiPATM HCV II; Innogenetics N.V., Gent, Belgium) using the HCV-Amplicor prod- ucts, or RealTime Genotyping II RUO assay (Abbott Molecular, Des Plaines, IL). Serum HBV DNA levels were measured
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