Liver, Pancreas and Biliary Tract
Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: Potent antiviral activity but no clinical benefit if treatment is given late

https://doi.org/10.1016/j.dld.2014.06.004Get rights and content

Abstract

Background

We evaluated efficacy and safety of sofosbuvir and daclatasvir ± ribavirin in liver transplant recipients with severe recurrent hepatitis C.

Methods

Patients included in an international compassionate use programme for treatment with sofosbuvir and daclatasvir ± ribavirin for 24 weeks were prospectively studied. Serum hepatitis C virus RNA was measured at treatment weeks 4, 12, and 24 and during follow-up at weeks 4, 8, and 12.

Results

Twelve patients (3 with fibrosing cholestatic hepatitis and 9 with cirrhosis; median model for end-stage liver disease score 20) received sofosbuvir 400 mg/day + daclatasvir 60 mg/day, and 6 patients (50%) also received ribavirin 200–800 mg/day. Nine patients completed 24 weeks of treatment (75%), and all had undetectable hepatitis C virus RNA at week 24; 3 patients died (25%, liver failure, gastrointestinal bleeding and sepsis); 4 patients experienced severe liver disease-related adverse events. Post-treatment hepatitis C virus RNA was available for 5 patients (week 8, n = 2; week 4, n = 3) and was undetectable in all cases. Mean Child–Pugh score and albumin level improved significantly at week 24. No changes in immunosuppressant doses were needed.

Conclusion

All-oral sofosbuvir plus daclatasvir combination shows high virological efficacy in liver transplant recipients and does not interact with immunosuppressants. All adverse events were unrelated to study drugs. These data strongly suggest that this combination must be initiated before decompensation.

Introduction

Hepatitis C virus (HCV) infection is one of the leading indications for liver transplantation (LT) worldwide [1], [2]. Unfortunately, post-transplant recurrence of hepatitis C is almost universal, causing diminished post-transplantation survival compared to patients without HCV infection. Approximately 30% of HCV transplanted patients develop acute severe recurrent hepatitis progressing rapidly to liver cirrhosis [3], [4], and from 5% to 7% experience fibrosing cholestatic hepatitis (FCH), which will rapidly lead to death in the majority of patients [5]. Treatment of recurrent HCV infection with pegylated interferon (Peg-IFN) and ribavirin after LT is associated with low rates of sustained virological response (SVR), usually in the range of 15–35%, and with significant adverse effects [6]. The advent of triple treatment schedules with the addition of first-generation protease inhibitors (PI), such as boceprevir or telaprevir, to Peg-IFN and ribavirin backbone, has slightly improved the therapeutic efficacy compared to dual therapy, but at the cost of additional, and often severe, adverse events [7]. Moreover, triple therapy with PIs is not feasible in LT recipients with advanced HCV-related recurrent disease.

Sofosbuvir is a potent oral nucleotide analogue inhibitor of HCV polymerase activity, recently licensed by the Food and Drug Administration and by the European Medicines Agency for the treatment of HCV infection in combination with other antiviral drugs. The administration of sofosbuvir in association with ribavirin in liver transplant recipients with recurrent HCV infection has been reported to increase SVR to rates as high as 70% [8], [9]. Daclatasvir is a potent oral NS5A inhibitor, currently under investigation in combination with other antivirals [10]. The association of sofosbuvir and daclatasvir has been shown to have very high antiviral efficacy when administered, with or without ribavirin, to previously naïve or non-responder patients with chronic HCV infection [11]. Recently, a single experience of administration of sofosbuvir in combination with daclatasvir in a LT recipient with severe recurrent cholestatic hepatitis C has been reported, showing a favourable outcome and the lack of drug interactions with calcineurin inhibitors (CNI) [12]. The purpose of this study was to evaluate the virological and clinical efficacy and safety of the combination of sofosbuvir and daclatasvir, with or without ribavirin, in a wider population of LT recipients with advanced disease due to recurrent HCV infection.

Section snippets

Study design

This study was performed within the framework of two compassionate use programs of oral antivirals for LT patients with severe recurrence of HCV infection. Six hepatology centres participated in the study, including three Italian, one German, one Austrian and one in the United States. Written informed consent, approved by the Ethical Committees, was obtained for each patient.

Patients

The study included liver transplant recipients with severe disease recurrence due to persistent genotype 1 or 4 HCV

Results

Twelve patients (58% males, mean age 58 ± 7 years) were enrolled, including 3 with evidence of rapidly progressing FCH. Individual baseline features are reported in Table 1. Patients were treated with sofosbuvir and daclatasvir 3–60 months after LT (mean 20 ± 17 months). Most patients had been non-responders to pre-LT treatment with Peg-IFN plus ribavirin, but only one had received standard dual therapy after LT due to early severe disease recurrence.

Six patients were treated with sofosbuvir and

Discussion

Severe HCV recurrence is one of the main factors limiting the success of liver transplant for HCV-related end-stage liver disease, as up to 30% of transplanted patients develop cirrhosis within 5 years after transplantation [3], [4]. Regrettably, only few patients can tolerate treatment with interferon-based regimens and response rates are low. As many as 20–40% of patients withdraw from dual antiviral therapy due to the frequent development of adverse events [6].

Unfortunately, the association

Conflict of interest

None declared.

Acknowledgement

The authors wish to thank Ms. Serena Rotunno for English revision.

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