Sofosbuvir in Combination with Simeprevir +/- Ribavirin in Genotype 4 Hepatitis C Patients with Advanced Fibrosis or Cirrhosis

Research Article
PLoS One. 2017 Jan 26;12(1):e0170933. doi: 10.1371/journal.pone.0170933. eCollection 2017.

Sofosbuvir in Combination with Simeprevir +/- Ribavirin in Genotype 4 Hepatitis C Patients with Advanced Fibrosis or Cirrhosis: A Real-World Experience from Belgium
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 Moreno

Published: January 26, 2017 http://dx.doi.org/10.1371/journal.pone.0170933

Abstract
INTRODUCTION:
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.

PATIENTS AND METHODS:
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).

RESULTS:
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.

CONCLUSIONS:
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.

Discussion Only
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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 [15]. 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% [31] 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.

Limited data are currently available to guide treatment in chronic HCV GT4 patients especially with advanced fibrosis. However it is important to develop optimal treatment strategies for HCV GT4 patients because this genotype is highly endemic in non-Western parts of the world and its prevalence has increased in several European countries [19–21] Moreover, in real life, patients with advanced fibrosis have an urgent need of treatment and robust data are lacking for this population. Several treatment regimens containing sofosbuvir or simeprevir have been evaluated previously for GT4 HCV patients. The combination of SOF and RBV for 24 weeks in a cohort of Egyptian patients showed an SVR rate of 90% but this cohort included few patients with cirrhosis and the SVR rate in patients with cirrhosis was lower (78%) [32]. Recently, a real life study including HCV GT4 patients with advanced fibrosis showed that SOF/SMV+/- RBV combination for 12 weeks was an effective regimen with an overall SVR rate of 92% [33].Other studies including a few patients with cirrhosis showed that sofosbuvir with ledipasvir [34] had also high SVR rates in GT4 patients. A recent study evaluated the efficacy of the SOF+ ledipasvir+ RBV combination in GT1 and GT4 patients with cirrhosis and seemed to be promising but the number of GT4 patients was low[35]. Other studies have evaluated the efficacy of newer direct-acting antiviral therapies for treatment of HCV GT4 patients including the combination of grazoprevir and elbasvir [36]. This treatment seemed to be efficacious but the results in patients with cirrhosis seemed to be worse [37]. The combination of sofosbuvir and velpatasvir provided high rates of SVR among patients infected with HCV genotypes 1,2,4,5, and 6, including those with compensated cirrhosis [38] and decompensated cirrhosis [39]. However, this study included few GT 4 patients. The AGATE-1 study evaluated the efficacy of the combination of ombitasvir and paritaprevir/ritonavir with ribavirin in HCV GT4 patients with cirrhosis. This study showed that this regimen is very efficacious for GT4 patients with cirrhosis [40]. However, conversely to the SOF-SMV combination, RBV use is obligatory. Moreover, this combination is not allowed in patients with decompensed cirrhosis. Indeed, post-marketing surveillance identified several cirrhotic patients who developed hepatic decompensation or liver failure while receiving this therapy [41].

Our study is subject to several limitations. First, ribavirin treatment was not given after randomization but only at the discretion of the treating clinician and the number of patients with cirrhosis receiving RBV is probably too small to show a potential benefit of RBV treatment in this population. It is thus difficult to make definitive conclusions concerning the role of ribavirin in the efficacy of treatment in our cohort of patients. Moreover, we had no data about resistance associated variants (RAV) which might influence the treatment response. Indeed, in the COSMOS study, the viral relapse rate was mainly correlated with mutations that have previously been associated with simeprevir resistance [11]. However, the Q80K mutation has not been reported in GT4.

In conclusion, we showed in this real-world cohort of GT4 patients with severe fibrosis and cirrhosis that the combination of SOF and SMV is efficacious and well tolerated and represents a good therapeutic option in HCV GT4 patients with advanced fibrosis and compensated cirrhosis. In patients with decompensated cirrhosis, second-generation IFN-free combinations would be better suited.

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