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Effectiveness of Ravidasvir Plus Sofosbuvir in Interferon-Naïve and Treated Patients with Chronic Hepatitis C Genotype-4

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Effectiveness of Ravidasvir Plus Sofosbuvir in Interferon-Naïve and Treated Patients with Chronic Hepatitis C Genotype-4 Research Article Viral Hepatitis Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis C genotype-4 Graphical abstract Authors Gamal Esmat, Tamer Elbaz, Maissa El 425 patients screened Raziky, ...,Eric Ruby, Pamela Vig, Imam 300 patients Waked randomized 150 80 70 treatment naïve treatment treatment Correspondence with and experienced experienced Safety population 300 without cirrhosis without cirrhosis with cirrhosis [email protected] 1 excluded 1 excluded RNA <10,000 IU/ml TLC <3,500/ml before first dose before first dose (T. Elbaz) [email protected] ITT population 149 79 70 (I. Waked) 298 started started started treatment treatment treatment 90 without 59 with cirrhosis cirrhosis Lay summary This study evaluated efficacy and safety of 45 patients 30 patients 29 patients 40 patients 39 patients 35 patients 35 patients Safety 45 patients population RDV + SOF RDV + SOF + RBV RDV + SOF RDV + SOF + RBV RDV + SOF RDV + SOF + RBV RDV + SOF + RBV RDV + SOF + RBV the new oral hepatitis C drug ravidasvir in 300 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 16 weeks 1 discontinued 1 withdrew 1 died for SAE consent combination with the approved oral drug 1 withdrew consent sofosbuvir in 298 patients infected with End of treatment 45 patients 44 patients 30 patients 29 patients 38 patients 39 patients 34 patients 35 patients 294 hepatitis C type 4. Our results showed 2 relapse 1 relapse 3 relapse 1 relapse that treatment with ravidasvir plus sofos- 1 died 1 lost to FU buvir, with or without ribavirin, was well 1 withdrew consent tolerated and associated with high SVR12 284* 45 patients 44 patients* 28 patients 26 patients 38 patients 39 patients 31 patients 33 patients* response rate in patients with and 100% 97.8% 93.3% 89.7% 95% 100% 88.6% 94.3% without cirrhosis. 1 lost to FU 1 lost to FU SVR24 282 45 patients 43 patients 28 patients 26 patients 38 patients 39 patients 31 patients 32 patients 100% 95.6% 93.3% 89.7% 95% 100% 88.6% 91.4% * Including one patient in each group who missed this visit but had SVR4 and SVR24 response Highlights Ravidasvir is a new NS5A inhibitor for HCV. Sofosbuvir + Ravidasvir with or without RBV has achieved very high SVR rates. Results are comparable for both patients with and without cirrhosis. Serious adverse events were noticed in very few treated patients. http://dx.doi.org/10.1016/j.jhep.2017.09.006 Ó 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. J. Hepatol. 2017, xxx, xxx–xxx Research Article Viral Hepatitis Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis C genotype-4 ⇑ Gamal Esmat1, Tamer Elbaz1, , Maissa El Raziky1,2, Asmaa Gomaa3, Mahmoud Abouelkhair1,2, Hadeel Gamal El Deen1, Aliaa Sabry3, Mohamed Ashour1,2, Naglaa Allam3, Mohamed Abdel-Hamid4, Ola Nada5, Sherine Helmy6, Hanaa Abdel-Maguid6, Richard Colonno7, Nathaniel Brown7, Eric Ruby7, ⇑ Pamela Vig7, Imam Waked3, 1Endemic Medicine Department, Faculty of Medicine, Cairo University, Egypt; 2Cairo Fatemic Hospital, Ministry of Health, Egypt; 3National Liver Institute, Menoufiya University, Shebeen EL Kom, Egypt; 4Department of Microbiology, Faculty of Medicine, Minia University, El Minia, Egypt; 5Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 6Pharco Pharmaceuticals, Amriya, Alexandria, Egypt; 7Presidio Pharmaceuticals, Inc., San Francisco, California, USA Background & Aims: Although treatment of hepatitis C virus Trial Registration number: ClinicalTrials.gov Identifier: (HCV) and HCV-genotype-4 (GT4) has become very effective, it NCT02371408. remains very expensive, and affordable options are needed, Lay summary: This study evaluated efficacy and safety of the especially in limited resource countries. The aim of this study new oral hepatitis C drug ravidasvir in combination with the was to assess the efficacy and safety of the combination of ravi- approved oral drug sofosbuvir in 298 patients infected with dasvir (an NS5A inhibitor) and sofosbuvir to treat patients with hepatitis C type 4. Our results showed that treatment with ravi- chronic HCV-GT4 infection. dasvir plus sofosbuvir, with or without ribavirin, was well toler- Methods: A total of 300 patients with HCV-GT4 infection were ated and associated with high response rate in patients with and recruited in three groups: treatment-naïve patients with or without cirrhosis. without compensated Child-A cirrhosis (Group 1); interferon- Ó 2017 European Association for the Study of the Liver. Published by experienced patients without cirrhosis (Group 2); and Elsevier B.V. All rights reserved. interferon-experienced patients with cirrhosis (Group 3). Groups 1 and 2 received ravidasvir 200 mg QD plus sofosbuvir 400 mg QD for 12 weeks and were randomized 1:1 to treatment Introduction with or without weight-based ribavirin. Group 3 patients Hepatitis C virus (HCV) infection is a major global health prob- 1 received ravidasvir plus sofosbuvir with ribavirin and were ran- lem, affecting 70 million to 100 million people worldwide, and domized 1:1 to a treatment duration of 12 weeks or 16 weeks. accounting for around 360,000 deaths annually, owing to 2 The primary endpoint was sustained virologic response at 12 decompensated cirrhosis and hepatocellular carcinoma. HCV- weeks post-treatment (SVR12). genotype-4 (GT4) accounts for 10%–15% of chronic HCV infec- Results: A total of 298 patients were enrolled: 149 in Group 1, tion worldwide, affecting 12 to 15 million patients, mostly in 79 in Group 2 and 70 in Group 3. SVR12 was achieved in limited resource countries in Africa and the Middle East. Egypt 95.3% of all patients who started the study, including 98% of has the highest prevalence of chronic HCV worldwide; with patients without cirrhosis and 91% of patients with cirrhosis, genotype-4 the predominant genotype, present in more than 3 whether treatment-naïve or interferon-experienced. Ribavirin 90% of affected patients. intake and history of previous interferon therapy did not affect Treatment of HCV-GT4 with pegylated interferon (PEG-IFN) SVR12 rates. No virologic breakthroughs were observed and the and ribavirin (RBV) resulted in sustained virologic response 4 study treatment was well tolerated. (SVR) rates of less than 50%. Introduction of direct acting antivi- Conclusions: Treatment with ravidasvir plus sofosbuvir, with or ral (DAA) therapies proved much more effective with better 5–11 without ribavirin, was well tolerated and associated with high safety profiles. Ravidasvir (RDV, formerly PPI-668) is a pan- sustained virologic response rate for HCV-GT4 infected patients genotypic NS5A inhibitor, with potent inhibitory activity against with and without cirrhosis, regardless of previous interferon- HCV-GT4, and was effective in phase I and II trials, where it based treatments. inhibited replication of HCV variants that encoded known NS5A resistance mutations.12–14 Sofosbuvir (SOF) is a pan- genotypic NS5B polymerase inhibitor. It serves as the backbone of many combination regimens, owing to its high efficacy, good 6 Keywords: HCV; Ravidasvir; PPI-668; Sofosbuvir; Genotype-4; Sustained virologic safety profile and high barrier to resistance. response (SVR). There is still a need to develop effective interferon free direct Received 5 June 2017; received in revised form 20 August 2017; accepted 4 September acting oral antiviral therapies for HCV that are affordable in lim- 2017 ⇑ Corresponding authors. Addresses: Endemic Medicine Department, Faculty of ited resource settings, where HCV-GT4 is one of the predomi- Medicine, Cairo University, Cairo, Egypt (T. Elbaz) or National Liver Institute, nant genotypes. RDV has not been studied in the treatment of Menoufiya University, Shebeen EL Kom, Egypt (I. Waked). E-mail addresses: [email protected] (T. Elbaz), [email protected] (I. Waked). Journal of Hepatology 2017 vol. xxx j xxx–xxx Please cite this article in press as: Esmat G et al. Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis C genotype-4. J Hepatol (2017), https://doi.org/10.1016/j.jhep.2017.09.006 Research Article Viral Hepatitis HCV-GT4 patients, and was not previously studied in combina- Exclusion criteria tion with SOF. Exclusion criteria included coinfection with HBV or HIV, mixed Herein, we present the results of a multicenter phase III trial HCV genotypes, elevated alpha fetoprotein more than 100 ng/ that was designed to study the safety and efficacy of RDV in ml, uncontrolled diabetes (HbA1C higher than 8.5%), clinical or combination with SOF, with or without RBV in Egyptian patients laboratory evidence or history of hepatic decompensation, or with HCV-GT4. history of malignancy within the preceding 5 years. We also excluded patients with creatinine clearance less than 50 ml/ minute or serum creatinine ≥1.5 times the upper limit of normal Patients and methods (ULN), serum albumin ≤3.2 g/dl for patients without cirrhosis or  This was a randomized, open-label, multicenter, phase III study <3 g/dl for patients with cirrhosis, total bilirubin >2 times ULN, to assess the efficacy and safety of RDV plus SOF, with or with- aspartate aminotransferase or alanine aminotransferase ele- out RBV, in patients with chronic HCV-GT4 enrolled at three vated more than 10 times ULN, international normalized ratio clinical sites in Egypt. (INR) >1.5 for patients without cirrhosis or >2.0 for patients with cirrhosis, hemoglobin <11 g/dl for females and <12 g/dl 3 Patients for males, leukocyte count < 3,500/mm or absolute neutrophil 3 3 We included male or female patients, 18 to 65 years of age, with count <1,500/mm or platelet count <75,000/mm for patients 3 chronic HCV-GT4 infection, with or without compensated Child- without cirrhosis, and leukocyte count <3,000/mm or absolute 3 A cirrhosis, with serum HCV-RNA levels ≥10,000 IU/ml.
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