The Association Between Hepatocellular Carcinoma and Direct-acting Anti-viral Treatment in Patients With Decompensated Cirrhosis

Ali Jibran Mecci; Polychronis Kemos; Clifford Leen; Adam Lawson; Paul Richardson; Salim I. Khakoo; Kosh Agarwal; David Mutimer; William M. Rosenberg; Graham R. Foster; William L. Irving; on behalf of HCV Research UK

Disclosures

Aliment Pharmacol Ther. 2019;50(2):204-214. 

In This Article

Abstract and Introduction

Abstract

Background: Direct-acting anti-viral therapy (DAA) has transformed hepatitis C virus (HCV) care, particularly in patients with decompensated cirrhosis. However, their impact on hepatocellular carcinoma (HCC) remains unclear.

Aim: To use a national registry of patients with advanced liver disease to explore the relationship between DAA therapy and HCC.

Methods: All patients with de novo HCC post DAA therapy were frequency matched with patients who did not develop HCC. Demographic, clinical and laboratory data were obtained. Cross-sectional imaging and multidisciplinary team reports were reviewed for dates of HCC diagnosis and HCC progression. Patients were categorised by treatment outcome and time of HCC development. Data were examined by multivariable analysis and Kaplan-Meier estimation.

Results: Eighty patients with HCC were compared with 165 patients without HCC, treated between June 2014 and September 2015. Mean follow-up from start of DAA therapy was 32.4 months. Twenty-eight patients were diagnosed with early HCC (within 6 months of therapy) and 52 presented late. Baseline nonmalignant lesions (HR: 1.99), thrombocytopaenia (HR: 1.59) and diabetes (HR: 1.68) increased likelihood of HCC. Response to therapy was reduced in patients who developed liver cancer (SVR in patients with HCC = 54/80 (68%), SVR in patients without HCC = 143/165 (87%), P < 0.001, OR: 3.13, 95% CI: 1.64-5.99). We found no difference between tumour size, progression or survival between viraemic and nonviraemic patients.

Conclusion: There is no alteration in prognosis or cancer progression following HCC development after HCV treatment. However, baseline nonmalignant liver lesions, diabetes and thrombocytopaenia increase the risk of HCC, and HCC is associated with a decreased SVR rate.

Introduction

Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC), the second most frequent malignant cause of death worldwide.[1] With the advent of direct-acting anti-viral (DAA) therapy for HCV, treatment options and curative rates have been transformed with high rates of sustained virological response (SVR).[2,3] These agents have also facilitated the treatment and cure of patients with advanced liver disease who remain at risk of HCC[4] and are therefore recommended to continue lifelong surveillance.[5,6]

There is controversy around patients with cirrhosis who have cleared virus (ie achieved an SVR) on DAAs and their ongoing risk of developing HCC. Conti et al reported an increased incidence of HCC following DAA treatment with 3.16% (95% CI 1.45-5.90) of 285 patients developing an HCC within 24 weeks of therapy.[7] Supporting this Ravi et al found an unusually high risk (9%) of patients developing de novo HCC following DAA treatment.[8] Conversely, multiple studies have shown no increase in HCC occurrence[9] following viral clearance and a large American cohort of 62 354 patients with and without cirrhosis showed that although patients with cirrhosis who had cleared virus with DAA therapy did develop malignancy, the frequency was not increased.[10] These studies have suggested that alcohol consumption, diabetes mellitus, lower platelet count and higher aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio[11] are baseline characteristics that predict HCC development.

In addition to the impact of HCV clearance on HCC development, there is controversy regarding the impact of HCC on HCV treatment outcome. Prenner et al showed a greatly reduced SVR rate of 58% for patients with an HCC present on treatment initiation, with this rising to 97% in patients with a previous history of treated HCC prior to DAA commencement.[12] This implies that the presence of HCC may reduce the response to treatment though this study includes patients post-liver transplantation.

The prognosis following the diagnosis of HCC in patients with HCV and cirrhosis is poor with a median survival as low as 0.7-0.9 years.[13] In the SHARP trial of sorafenib in patients with advanced HCC, time to progression on imaging regardless of the initial cause was 2.8 months in the placebo group.[14] It is still not known whether clearance of HCV impacts tumour progression, but anecdotal evidence has suggested that it may slow evolution.

In light of these uncertainties, we examined the NHS England early access programme (EAP), which provided access to 12 weeks of all-oral DAA therapy for patients with advanced liver disease. Patients in this programme remain on surveillance, and here, we report the incidence and factors predictive of de novo malignancy in patients developing HCC early (within 6 months) or late (after 6 months) after the onset of DAA therapy, the impact of HCC on DAA treatment response and the progression of cancers in viraemic and nonviraemic patients.

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