Interferon-free antiviral therapy for chronic hepatitis C among patients in the liver transplant setting

Abstract

Chronic hepatitis C (HCV) infection remains a major public health problem with many infected individuals worldwide. The revolutionary discovery of highly effective direct-acting antivirals (DAAs) makes chronic HCV infection a curable disease, even in patients with advanced liver disease. Liver function may improve shortly after initiation of antiviral therapy in patients on the waiting list and could even obviate the need for transplantation. However, whether these short term benefits also result in a favorable prognosis on the long-term remains to be seen and this fuels the discussion whether DAAs should be used prior to liver transplantation in all patients. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post-transplant setting may be better for certain patients. Furthermore, the discussion whether HCV positive organ donors should be used now viral eradication is achieved in almost all patients has regained interest.

Introduction

Chronic hepatitis C virus (HCV) infection is a major public health problem, with an estimated 130–150 million infected people worldwide [1]. Each year approximately three to four million people get infected and 350,000 individuals die from HCV-related disease [2]. HCV infection is the leading cause of chronic liver disease in both industrialized and developing nations. Chronic inflammation of the liver may cause formation of fibrosis, which eventually leads to cirrhosis in approximately 20% of infected individuals within 20 years following HCV acquisition [3]. Once cirrhosis is established, there is an increased risk of developing hepatocellular carcinoma or liver failure, and both these cirrhosis-related complications may result into liver-related death in absence of timely liver transplantation (LT) [4], [5], [6]. Patients with cirrhosis have a 1–5% annual risk of developing HCC and a 3–6% annual risk of experiencing liver failure. After a decompensating event, the risk of death in the following year is remarkably high with 15–20% [5].

As a consequence of aging of the HCV infected population, the proportion of patients with severe liver disease and HCC is increasing [7]. From 1996 to 2006 the prevalence of decompensated cirrhosis has doubled and the incidence of HCC has increased approximately 20-fold, and it is predicted the occurrence of these complication will continue to rise through 2030 [7], [8]. These numbers highlight the substantial disease burden of chronic HCV infection. In fact, chronic HCV infection is still the leading indication for LT in western countries, accounting for approximately 30% of all LTs in the United States [9].

Given the high prevalence, associated mortality and morbidity and the absence of a vaccine, effective treatment is of utmost importance for disease control. Viral eradication is defined as the absence of serum HCV RNA 12 or 24 weeks after antiviral treatment is completed and is described by the term sustained virologic response (SVR). Until recently, peg-interferon (peg-IFN) in combination with ribavirin (RBV) was the only option to cure patients from chronic HCV infection. However, the chance of achieving SVR with this combination was only around 30–80%, depending on fibrosis degree, genotype and comorbidity [10]. Moreover, treatment was associated with severe side effects and was therefore contraindicated in patients with advanced liver disease [11].

Patients with compensated HCV-induced liver disease in whom the virus was eradicated by IFN-based treatment showed improvements of their liver biochemistry, hepatic fibrosis and portal hypertension [12], [13]. Probably as a result, the risk of liver failure, HCC and LT was also lower among patients with SVR as compared to those without SVR [14], [15], [16], [17], [18]. In addition, the incidence of extra-hepatic disease manifestations, such as diabetes mellitus, cryoglubulinemia, cardiovasculair events and lymphoma, was lower after SVR [19], [20], [21]. Both the prevention of liver-related as well as liver-unrelated morbidity could thus explain the finding that SVR was significantly associated with an improved overall survival in HCV-infected patients in general and in those with cirrhosis specifically [15], [22].

The introduction of potent direct-acting antivirals (DAAs) in 2013 has changed the therapeutic landscape for HCV infection completely, with high response rates ∼95% in all patients with compensated liver disease using treatment regimens of only 12 weeks [23], [24], [25], [26], [27]. DAAs intervene on a specific point in the viral replication cycle and are classified according to their viral target protein: NS3/4A protease inhibitors, NS5B polymerase inhibitors and NS5A inhibitors. Importantly, the beneficial safety-profile enables also patients with advanced liver disease to undergo antiviral therapy and achieve viral eradication. Until now, it is, however, unclear whether and to what extent this particular population may experience actual clinical benefit from successful DAA treatment, on both the short term as well as on the long term. In case LT is required, HCV re-infection of the allograft occurs in virtually all HCV-infected liver transplant recipients and this is the leading cause of graft loss and death in this population [28]. DAAs also enable liver transplant patients to be treated effectively, whereas the peg-IFN regimens resulted in low SVR rates of ∼30% for genotype 1 and 60–75% for other genotypes. In addition, tolerability and safety were significant issues, and dose reductions and treatment discontinuations were common [28], [29].

In this review we will discuss the current results with DAA therapy of HCV-infected patients with an history of decompensated liver disease, both prior to LT as well as after LT. We will also discuss how these new treatment developments might affect the future of liver transplantation.