Elsevier

Journal of Hepatology

Volume 66, Issue 1, January 2017, Pages 39-47
Journal of Hepatology

Research Article
Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients

https://doi.org/10.1016/j.jhep.2016.08.021Get rights and content

Background & Aims

We report the first real-life results of the sofosbuvir + daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients.

Methods

The France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER “Therapeutic options for hepatitis B and C: A French cohort” is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n = 768) with a HCV genotype 1 who initiated sofosbuvir (400 mg/day) and daclatasvir (60 mg/day) before October 1st 2014, with or without ribavirin (1–1.2 g/day) for a duration of 12 weeks or 24 weeks. The main endpoint criterion was sustained virological response at 12 weeks (SVR12), defined by the absence of detectable HCV-RNA 12 weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n = 45), otherwise considered as virological failure (n = 18).

Results

A SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir + daclatasvir) to 99% (24-week sofosbuvir + daclatasvir + ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p = 0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p = 0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p = 0.0054).

Conclusion

The sofosbuvir + daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12 weeks in non-cirrhotic and 24 weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact.

Lay summary

The sofosbuvir + daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir + daclatasvir combination seems to be 12 weeks in non-cirrhotic patients and 24 weeks for those with cirrhosis.

Clinical trial number: NCT01953458.

Introduction

The very rapidly evolving field of hepatitis C virus (HCV) therapy indicates the need for an extensive screening of HCV-infected patients and their access to antiviral treatment, due to the high rate of sustained virological response (SVR). Antiviral therapy may be considered for the treatment of any patient with chronic HCV infection, as recently recommended by the European Association for the Study of the Liver (EASL) guidelines.

Since 2011, the treatment of chronic hepatitis C has dramatically improved with the development of direct-acting antiviral (DAA) agents.

A better understanding of the viral lifecycle, and the characterization of viral enzymes, which are potential targets, has resulted in the development of new molecules, DAAs against HCV. These are either specific for genotype 1 (NS3/NS4A protease inhibitors) or cover a wider spectrum (NS5A and NS5B polymerase inhibitors or entry inhibitors), as well as non-specific antivirals [1], [2], [3], [4], [5]. The available drugs in 2016 are from a second generation of NS5B polymerase inhibitors (sofosbuvir, dasabuvir), protease inhibitors (simeprevir, paritaprevir, grazoprevir) and NS5A replication complex inhibitors (daclatasvir, then ledipasvir, ombitasvir and elbasvir) [6], [7]. They have been approved, evaluated [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], and their combination is now recommended for treating HCV chronic infection [17], [18]. Given the timelines for approval and usage beyond the results of the clinical trials, real-life results of the sofosbuvir + ribavirin [25] or sofosbuvir + simeprevir combination have been extensively reported [26], [27], [28]. However, there is little data regarding the sofosbuvir + daclatasvir combination in genotype 1-infected patients.

We report the first real-life results of the France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER cohort (Therapeutic options for hepatitis B and C: A French cohort) for the sofosbuvir + daclatasvir combination in genotype 1-infected patients.

Section snippets

Study design and participants

The ANRS CO22 HEPATHER cohort “Therapeutic options for hepatitis B and C: a French cohort” is a national multicentre prospective observational cohort study of patients with viral hepatitis B or C (this study is registered with ClinicalTrials.gov, number: NCT01953458). The cohort was set up in August 2012 with the main objectives to quantify the clinical efficacy and safety of new hepatitis treatments in real-life, and to identify, at the patient level, who were most likely improve in overall

Results

By October 1st 2014, 768 cohort participants with a HCV genotype 1 infection had started a sofosbuvir + daclatasvir combination, of which 599 (78%) did not receive and 169 (22%) received ribavirin, according to the physician (Fig. 1). One hundred and ninety-four (25%) patients were treated for 12 weeks, and 574 (75%) were treated for 24 weeks. There was no difference according to whether the regimen contained ribavirin (p = 0.0886). The patient characteristics are described in Table 1. Patients who

Discussion

This is the first report of the real-life results of the sofosbuvir + daclatasvir combination in genotype 1-infected patients. We showed that the sofosbuvir + daclatasvir combination was associated with a high SVR12 rate and we explored the impact of treatment duration and ribavirin combination in patients infected with HCV genotype 1. Cirrhosis was strongly associated with treatment failure. Almost all non-cirrhotic patients achieved a SVR irrespective of the treatment schedule and a 12-week

Financial support

INSERM-ANRS (France REcherche Nord&sud Sida-vih Hépatites), France, ANR (Agence Nationale de la Recherche), France, DGS (Direction Générale de la Santé), France and MSD, United States, Janssen, United States, Gilead, United States, Abbvie, United States, BMS, United States, Roche, Switzerland.

Conflict of interest

Dr. Hezode reports personal fees from Abbvie, personal fees from BMS, personal fees from Gilead, personal fees from Janssen, personal fees from MSD, personal fees from Roche, outside the submitted work. Dr. Guyader reports grants and personal fees from JANSSEN, personal fees from GILEAD, personal fees from MSD, personal fees from INTERCEPT, personal fees from ABBVIE, personal fees from BMS, outside the submitted work. Dr. Samuel reports other from Astellas, other from BMS, other from Gilead,

Authors’ contributions

Dr Carrat had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Pol, Fontaine, Carrat. Acquisition of data: Pol, Bourlière, Hezode, Larrey, Bronowicki, De Ledinghen, Zoulim, Tran, Metivier, Zarski, Samuel, Guyader, Marcellin, Minello, Alric, Thabut, Chazouillères, Riachi, Bourcier, Mathurin, Loustaud-Ratti, D’Alteroche, Hubert, Habersetzer, Causse, Geist, Rosa, Gournay, Saillard,

Acknowledgements

We thank the study participants and the participating clinicians at each site.

We thank the Inserm-ANRS for sponsoring, funding and conducting the ANRS CO22 HEPATHER cohort in collaboration with Association Française pour l’Etude du Foie (AFEF). The cohort received supports from ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé) and MSD, Janssen, Gilead, Abbvie, BMS, Roche. Please find details of the ANRS-AFEF HEPATHER study group in the Supplementary material.

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