Liver Transplant for Hepatocellular Carcinoma in the United States

Evolving Trends Over the Last Three Decades

Marc Puigvehí; Dana Hashim; Philipp K. Haber; Amreen Dinani; Thomas D. Schiano; Amon Asgharpour; Tatyana Kushner; Gaurav Kakked; Parissa Tabrizian; Myron Schwartz; Ahmet Gurakar; Douglas Dieterich; Paolo Boffetta; Scott L. Friedman; Josep M. Llovet; Behnam Saberi


American Journal of Transplantation. 2020;20(1):220-230. 

In This Article

Abstract and Introduction


Hepatitis C virus infection has been the most common etiology in HCC-related liver transplantation (LT). Since 2014, direct-acting antivirals (DAAs) have dramatically improved HCV cure. We aimed to study the changing pattern of etiologies and impact in outcome in HCC-related LT according to HCV treatment-era through retrospective analysis of the Scientific Registry of Transplant Recipients (SRTR) database (1987–2017). A total of 27 855 HCC-related liver transplants were performed (median age 59 years, 77% male). In the DAA era (2014–2017) there has been a 14.6% decrease in LT for HCV-related HCC; however, HCV remains the most common etiology in 50% of cases. In the same era, there has been a 50% increase in LT for NAFLD-related HCC. Overall survival was significantly worse for HCV-related HCC compared to NAFLD-related HCC during pre-DAA era (2002–2013; P = .031), but these differences disappeared in the DAA era. In addition, HCV patients had a significant improvement in survival when comparing the DAA era with IFN era (P < .001). Independent predictors of survival were significantly different in the pre-DAA era (HCV, AFP, diabetes) than in the DAA era (tumor size). HCV-related HCC continues to be the main indication for LT in the DAA era, but patients' survival has significantly improved and is comparable to that of NAFLD-related HCC.


Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related mortality worldwide.[1,2] At-risk populations are well defined and include patients with cirrhosis due to alcoholic liver disease (ALD), hepatitis B virus (HBV), hepatitis C virus (HCV), nonalcoholic fatty liver disease (NAFLD), and other chronic liver diseases.[3] Curative treatment options are available for patients with local disease and include ablation, resection, and liver transplantation (LT).[3] Particularly, patients with early stage HCC with cirrhosis, who are not eligible for surgical resection, represent ideal candidates for LT when the tumor burden is within Milan criteria.[4,5]

After the implementation of the Model for End-Stage Liver Disease (MELD) score in 2002, HCC patients were granted MELD exception points with the intent to balance the risk of tumor progression and subsequent dropout from the waiting list with death compared to non-HCC patients.[6] However, based on recent data demonstrating that the system advantaged HCC recipients compared to patients without HCC, the policy was modified in 2015 in order to decrease the priority awarded to HCC patients.[6] Overall, the organ allocation policies for HCC have evolved over the recent years to deprioritize HCC relative to other indications.[7]

Among the underlying etiologies of liver disease, HCV has been the most common indication for LT among HCC patients in the United States.[8] Treatment options of HCV have evolved tremendously in the recent years.[9] After November 2013, with the availability of interferon (IFN) free direct-acting antivirals (DAAs), sustained virologic response (SVR) rates of >90% in both pre- and post-LT settings and in patients with impaired liver function is achievable.[10,11] Prior to 2011, IFN and ribavirin (RBV) were the only available treatment for HCV that were associated with low SVR rates of only 20%-40% and significant side effects.[12] In 2011, the first generation of protease inhibitors was approved that improved the SVR rates to 50%-60%; however, they were still associated with side effects because they were combined with IFN/RBV.[13]

Although HCV treatment options have evolved considerably,[13] the growing obesity epidemic in the United States has led to an increased prevalence of NAFLD.[14] Current estimates indicate that 68% of US adults are overweight or obese, and between 75–100 million individuals likely have NAFLD.[15] Herein, it has been speculated that due to the DAAs, the relative burden of HCC arising from HCV will diminish and NAFLD eventually will become the leading indication for HCC-related LT.[16]

Patterns of underlying liver diseases giving rise to HCC and ultimately leading to LT are likely going to shift in the coming years, warranting a closer look at the etiologies. The recent changes in the MELD exception policies, the availability of DAAs to treat HCV, and the rise in the prevalence of obesity and fatty liver disease prompted us to study (a) the changing pattern of HCC-related LT etiologies over the past 30 years and (b) the impact of etiology in HCC-related LT outcomes, focusing on HCV treatment changes. In order to reflect both the changing patterns in etiology and the outcomes as treatment for HCV has advanced we defined four time intervals: the pre-MELD era (1987–2001), the IFN-only era (2002–2010), early IFN-DAA era (2011–2013), and the DAA-only era (2014–2017).