Elsevier

Journal of Hepatology

Volume 67, Issue 3, September 2017, Pages 585-602
Journal of Hepatology

Review
ELITA consensus statements on the use of DAAs in liver transplant candidates and recipients

https://doi.org/10.1016/j.jhep.2017.03.006Get rights and content

Summary

The advent of safe and highly effective direct-acting antiviral agents (DAAs) has had huge implications for the hepatitis C virus (HCV) transplant field, and changed our management of both patients on the waiting list and those with HCV graft re-infection after liver transplantation (LT). When treating HCV infection before LT, HCV re-infection of the graft can be prevented in nearly all patients. In addition, some candidates show a remarkable clinical improvement and may be delisted.

Alternatively, HCV infection can be treated post-LT either soon after the transplant, taking advantage of the removal of the infected native liver, or at the time of disease recurrence, as was carried out in the past. In either case, some DAAs have a limited use because of their drug to drug interactions with various immunosuppressants as well as the many other drugs liver transplant recipients are often prescribed. In addition, some DAAs should be avoided in case of severe renal failure, which is not an unusual complication after LT.

The present document provides a series of consensus statements on the LT issues that have not been extensively addressed previously. These statements have been developed to support physicians and other stakeholders in charge of LT candidates and recipients when deciding to treat HCV, especially in difficult situations.

Introduction

Chronic hepatitis C virus (HCV) infection related advanced liver disease is the most common indication for liver transplantation (LT), which accounts for about 10% to 50% of LTs performed in Northern and Southern Europe, respectively (www.ELTR.org). Until very recently, all HCV recipients who underwent LT had detectable viremia. Virtually all of them had HCV re-infection shortly after transplant. Between 10% to 30% developed cirrhosis within 5 years from LT and 40% presented signs of liver decompensation within 1 year from the diagnosis of recurrent cirrhosis.[1], [2], [3] The combination of pegylated interferon (PegIFN) and ribavirin (RBV) has been the only therapeutic option available for the last 20 years but it was rarely effective, particularly in patients with more advanced graft hepatitis. Due to the high risk of severe disease recurrence, re-transplantation was controversial because of the risk of HCV-induced graft failure. These factors clarify why HCV infected recipients had a reduced survival rate by at least 10% after 5 years of follow-up, compared to non-HCV infected individuals.4

The advent of safe and highly effective direct-acting antiviral agents (DAA) has had huge implications for the HCV transplant field, and changed the management of both patients on the waiting list and those with HCV graft re-infection after LT. When treating HCV infection before LT, some candidates show a remarkable clinical improvement and may be delisted. If not, HCV re-infection of the graft may be prevented in nearly all patients when a HCV RNA negative status is achieved by DAAs at least 4 weeks before transplantation (>95%).

Alternatively, HCV infection can be treated post-LT either soon after the transplant, taking advantage of the removal of the infected native liver, or at the time of disease recurrence, carried out in the past. In either case, some DAAs have a limited use due to their drug to drug interactions (DDI) with various immunosuppressants (IS), as well as the many other drugs often prescribed to liver transplant recipients. In addition, some DAAs should be avoided in cases of severe renal failure, which is not an unusual complication after LT.

Finally, anti-HCV positive donors with favourable histological features are likely to become an important additional resource for the donor pool, particularly in areas where anti-HCV positive donors are more prevalent. The potential recipients of these grafts should be selected beforehand and treated after LT.

In the middle of this therapeutic revolution, two monothematic European Liver and Intestine Transplant Association (ELITA) conferences were held in Milan in March 2015 and April 2016, where a selected number of European experts discussed the many unsolved issues regarding the use of DAAs before and after LT. The present document provides the conclusions of these conferences, which are presented as the ELITA statements.

Section snippets

Methods

These ‘‘Consensus statements’’ were elaborated following a slightly modified Appraisal of Guidelines for Research & Evaluation methodology.5 In brief, the promoter of this initiative was ELITA, whose governing body selected a scientific board of experts in charge of organizing the two conferences held in Milan and of writing this document. The two conferences were endorsed by the Italian Association for the study of the Liver (AISF) and by the European Association for the Study of the Liver

Background

DAAs should be used with caution in LT candidates with severely impaired liver function (Child-Pugh B and C) or with severe renal dysfunction (estimated glomerular filtration rate [eGFR] <30 ml/min) as both conditions may affect the metabolism of some DAAs.

Facts

  • a)

    Impairment of liver function affects the exposure of various DAAs which is typically measured by the area under the curve (AUC) (Table 2).

    Simeprevir (SIM): AUC increased by 2.5-fold in Child-Pugh B and 5.2-fold in Child-Pugh C.

    Paritaprevir/r

Conclusions

Data accumulated over the last 3 years on the use of DAAs pre- and post-LT opened the door to considerable changes in the treatment of HCV infection in the liver transplantation field. ELITA therefore decided to compile this series of consensus statements, which focus primarily on very specific LT issues that had not been extensively addressed previously. These consensus statements are a starting point and will be updated regularly, because of the rapid changes in knowledge availability of new

Financial support

The ELITA consensus meetings were supported by Gilead International, Gilead Italy, BMS Italy, AbbVie Italy, Biotests France, Kedrion Italy.

Conflict of interest

LSB, grants from Gilead, AbbVie and MSD outside the submitted work. CD, grants and/or personal fees from Gilead, Novartis and Chiesi outside the submitted work. TB, grants and/or personal fees from AbbVie, Gilead, BMS, Janssen, Roche Vertex and Tibotec outside the submitted work. MS, grants from Gilead, grants from AbbVie, personal fees from Bayer, outside the submitted work. SF, grants or personal fees from Gilead, BMS, AbbVie, and MSD, outside the submitted work. SK, nothing to disclose. GPP,

Authors’ contributions

LSB organized the ELITA monothematic conferences, manuscript writing, critical review for intellectual content and approval of the manuscript. CD organized the ELITA monothematic conferences, manuscript writing, critical review for intellectual content and approval of the manuscript. TB expert at the 2 ELITA monothematic conferences, critical review for intellectual content and approval of the manuscript. MS expert at the 2 ELITA monothematic conferences, critical review for intellectual

Acknowledgments

The first version of these Consensus statements was presented at the “ELITA Symposium” held in Brussels on September 13, 2015. ELITA board members: René Adam, William Bennet, Gabriela Berlakovich, Giacomo Germani, Silvio Nadalin, Martin Oliverius, Roberto Troisi, Wojtek Polak, and Krzysztof Zieniewics. Without the support and contribution of these ELITA board members this initiative could not have been completed.

The authors and the working group thank Gilead International, Gilead Italy, BMS

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      Citation Excerpt :

      HCV reinfection post-transplant in the form of fibrosing cholestatic hepatitis C (FCH) has historically been an ominous sign and a significant cause of patient and graft loss. The fear of this aggressive form of recurrence has prompted many to treat patients before LT [14,19–22]. However, DAAs have proven extremely successful in post-LT viral clearance and can be utilized before damage to the allograft has occurred and even in cases of rapidly progressing FCH [4,5,14–17].

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    These authors contributed equally as co-ordinators and joint first authors.

    These authors acted as expert contributors to the manuscript.

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