Date Published: January 26, 2017
Publisher: Public Library of Science
Author(s): Delphine Degré, Thomas Sersté, Luc Lasser, Jean Delwaide, Peter Starkel, Wim Laleman, Philippe Langlet, Hendrik Reynaert, Stefan Bourgeois, Thomas Vanwolleghem, Sergio Negrin Dastis, Thierry Gustot, Anja Geerts, Christophe Van Steenkiste, Chantal de Galocsy, Antonia Lepida, Hans Orlent, Christophe Moreno, Ravi Jhaveri.
Hepatitis C virus (HCV) is a major global health issue and successful treatment has been associated with a reduction of risk of all-cause mortality. Advancements have been made in HCV treatment through the use of interferon-free regimens. Most trials have been conducted in HCV genotype (GT) 1 and data for interferon-free regimens in GT4 patients are limited. The aim of this study was to evaluate the safety and efficacy of sofosbuvir plus simeprevir in a real-world cohort of HCV GT4 patients with advanced fibrosis.
Eighty-seven GT4 treatment-naïve or –Interferon (IFN) ribavirin (RBV) experienced patients treated with sofosbuvir and simeprevir +/- ribavirin (RBV) were enrolled in this cohort study (41% severe fibrosis, 59% cirrhosis).
Patients were 51.7% male, 78.2% IFN/RBV treatment-experienced, and 37.9% received RBV treatment. The overall sustained virologic response at least 12 weeks after treatment (SVR12) rate was 87.4% while patients treated with and without RBV had rates of 87.9% and 87% (p = 0.593), respectively, and patients with advanced fibrosis (F3) and patients with cirrhosis had SVR12 rates of 94.4% and 82.4% (p = 0.087), respectively. SVR12 rates in treatment-naïve patients and in IFN/RBV -experienced patients were 78.9% and 89.7% (p = 0.191), respectively. Treatment failure occurred most commonly in patients with cirrhosis and severe disease. The treatment was well tolerated and no patient died or discontinued treatment due to adverse events.
Sofosbuvir in combination with simeprevir +/- ribavirin in GT 4 HCV patients with advanced fibrosis achieved high SVR12 rates and was well tolerated. RBV did not appear to increase the rate of SVR12.
Hepatitis C virus (HCV) is a major global health issue affecting 170 million patients worldwide . Chronic infection leads to progressive liver fibrosis, end stage liver disease, or hepatocellular carcinoma [2,3] and successful treatment resulting in a sustained virologic response (SVR) has been associated with a reduction of risk of all-cause mortality in HCV patients [4,5]. Advancements have recently been made in HCV treatment through the use of interferon-free regimens that combine direct-acting antiviral agents (DAA), resulting in high efficacy rates and a better safety profile than those of interferon (IFN)-based regimens [6–10]. Most trials have been conducted in Western countries where HCV genotype (GT) 1 is prevalent. The phase 2 COSMOS study showed that combined simeprevir and sofosbuvir was efficacious and well tolerated in HCV GT1 infections . Based on the results of this study, this treatment was recommended for GT1 HCV patients by the European Association for the study of the Liver (EASL)  and the American Association for the Study of the Liver (AASLD) . The phase 3 OPTIMIST-1 study confirmed these results  and additional large, prospective cohort studies showed that combination of simeprevir plus sofosbuvir was associated with high rates of SVR and low rates of treatment discontinuation in real-world patients with HCV GT1 infection [15,16].
In this Belgian real-world cohort of HCV GT4 patients with advanced fibrosis, we showed that the combination of SOF + SMV achieved in ITT analysis an SVR12 rate of 87.4%, 87.9% for patients treated with RBV and 87% for patients treated without RBV. After exclusion of patients who did not achieve SVR12 for reasons other than virologic failure, we observed an SVR rate of 91.6%. These results showed that the combination of SOF+SMV is efficacious in HCV GT4 patients with advanced fibrosis and that the addition of RBV did not appear to increase the rate of SVR12 although patients treated with RBV seemed to have a faster decrease of their viral load with a higher rate of negative viral load at week 4 and at the EOT. Interestingly, some patients had detectable HCV RNA but below LLOQ at the EOT but achieved SVR12. We did not observe a significant difference in SVR12 between patients with severe fibrosis F3 and patients with cirrhosis. This may be due to the small size of the cohort. However, all but one patient who failed to achieve SVR12 were patients with cirrhosis and advanced disease. This observation is consistent with results observed previously in other studies . After exclusion of patients who did not achieve SVR12 for reasons other than virologic failure, we observed an SVR12 rate of 87.5% in patients with cirrhosis. This result is comparable to the result of the OPTIMIST-2 study in GT1 patients with cirrhosis treated with SOF + SMV, who achieved SVR12 of 83%  while decompensated patients were excluded in this study. One patient with positive viral load after the end of treatment was a patient without cirrhosis but this patient was lost to follow-up during the treatment and no compliance data was available. Finally, SVR12 rate in IFN/RBV experienced patients and treatment naïve patients was not significantly different. Treatment was well tolerated. No patient died or discontinued treatment due to adverse events. Among patients treated with RBV, 18% of patients modified ribavirin dosage. The median baseline hemoglobin levels and the median baseline RBV dosage did not differ between patients who modified ribavirin dosage compared with those patients who did not. However, RBV posology was decreased only in patients with cirrhosis.