Impact of DAAs on liver transplantation: Major effects on the evolution of indications and results. An ELITA study based on the ELTR registry

Highlights

• DAAs have dramatically improved the outcome of cirrhotic patients with HCV infection.

• Since the advent of DAAs there has been a 50% decline in the number of liver transplants.

• At least 600 liver grafts every year can currently be allocated to indications other than HCV.

• Survival of LT recipients with HCV or HBV infection is currently comparable, because of DAAs.

Background & Aims

Direct-acting antivirals (DAAs) have dramatically improved the outcome of patients with hepatitis C virus (HCV) infection including those with decompensated cirrhosis (DC). We analyzed the evolution of indications and results of liver transplantation (LT) in the past 10 years in Europe, focusing on the changes induced by the advent of DAAs.

Methods

This is a cohort study based on data from the European Liver Transplant Registry (ELTR). Data of adult LTs performed between January 2007 to June 2017 for HCV, hepatitis B virus (HBV), alcohol (EtOH) and non-alcoholic steatohepatitis (NASH) were analyzed. The period was divided into different eras: interferon (IFN/RBV; 2007-2010), protease inhibitor (PI; 2011-2013) and second generation DAA (DAA; 2014-June 2017).

Results

Out of a total number of 60,527 LTs, 36,382 were performed in patients with HCV, HBV, EtOH and NASH. The percentage of LTs due to HCV-related liver disease varied significantly over time (p <0.0001), decreasing from 22.8% in the IFN/RBV era to 17.4% in the DAA era, while those performed for NASH increased significantly (p <0.0001). In the DAA era, the percentage of LTs for HCV decreased significantly (p <0.0001) from 21.1% (first semester 2014) to 10.6% (first semester 2017). This decline was more evident in patients with DC (HCV-DC, −58.0%) than in those with hepatocellular carcinoma (HCC) associated with HCV (HCV-HCC, −41.2%). Conversely, three-year survival of LT recipients with HCV-related liver disease improved from 65.1% in the IFN/RBV era to 76.9% in the DAA era, and is now comparable to the survival of recipients with HBV infection (p = 0.3807).

Conclusions

In Europe, the number of LTs due to HCV infection is rapidly declining for both HCV-DC and HCV-HCC indications and post-LT survival has dramatically improved over the last three years. This is the first comprehensive study of the overall impact of DAA treatment for HCV on liver transplantation in Europe.

Lay summary

After the advent of direct-acting antivirals in 2014, a dramatic decline was observed in the number of liver transplants performed both in patients with decompensated cirrhosis due to hepatitis C virus (HCV), minus 60%, and in those with hepatocellular carcinoma associated with HCV, minus 41%. Furthermore, this is the first large-scale study demonstrating that the survival of liver transplant recipients with HCV-related liver disease has dramatically improved over the last three years and is now comparable to the survival of recipients with hepatitis B virus infection. The reduction in HCV-related indications for LT means that there is a greater availability of livers, at least 600 every year, which can be allocated to patients with indications other than HCV.

Introduction

Viral hepatitis C has long been the most common indication for liver transplantation (LT) in Europe and in the US, with over 20% of all LT candidates on the waiting list having chronic hepatitis C virus (HCV) infection.[1], [2] Until recently, the expected survival rates for HCV infected liver graft recipients were the lowest among all indications, due to severe and rapid HCV recurrence with interferon (IFN)-based therapies giving low cure rates.[1], [2], [3] The approval of first generation direct-acting antiviral agents (DAAs), telaprevir and boceprevir, in 2011, marked the beginning of a new era. These protease inhibitors (PI) were more effective than the previous IFN-based regimens, but side-effects and frequent drug-drug interactions limited their use for patients with advanced liver disease. In 2014, more potent and better tolerated DAAs became available, and were offered first to patients with compensated and even decompensated cirrhosis. Most patients achieved a sustained virological response (SVR), allowing hepatic function to improve within months of completing treatment in the majority of patients with decompensated cirrhosis (DC) and a model for end-stage liver disease (MELD) score below 20. This resulted in one of four patients being removed from the waiting list.[4], [5], [6], [7], [8], [9], [10], [11], [12] Concurrently, the great majority of patients with compensated cirrhosis treated with DAAs did not progress to DC and avoided LT. To better understand the impact of the new DAAs pre and post-LT, we have interrogated the ELTR registry. The two main objectives of this study were to investigate whether DAAs had influenced indications for LT and improved post-LT outcome of HCV recipients. Only patients with HCV, hepatitis B virus (HBV), alcohol (EtOH) and non-alcoholic steatohepatitis (NASH) etiologies and listed for DC or for hepatocellular carcinoma (HCC) over the last decade were analyzed.