Elsevier

Journal of Hepatology

Volume 65, Issue 4, October 2016, Pages 719-726
Journal of Hepatology

Research Article
Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy

https://doi.org/10.1016/j.jhep.2016.04.008Get rights and content

Background & Aims

The success of direct-acting antivirals (DAA) against hepatitis C is a major breakthrough in hepatology. Until now, however, there are very few data on the effect of hepatitis C virus (HCV) eradication in patients who have already developed hepatocellular carcinoma.

Methods

The study included patients with HCV infection and prior history of treated hepatocellular carcinoma who achieved complete response and lacked ‘non-characterized nodules’ at the time they underwent anti-HCV treatment with all-oral DAAs in 4 hospitals. Patients receiving interferon as part of the antiviral regimen were excluded. The baseline characteristics, laboratory and radiologic tumor response were registered in all patients before starting antiviral therapy and during the follow-up according to the clinical practice policy.

Results

Between 2014 and 2015, 103 patients with prior hepatocellular carcinoma received DAA, 58 of them met the inclusion criteria. After a median follow-up of 5.7 months, 3 patients died and 16 developed radiologic tumor recurrence (27.6%). The pattern of recurrence was: intrahepatic growth (3 patients), new intrahepatic lesion (1 nodule in 5 patients, up to 3 nodules less or equal to 3 cm in 4 cases and multifocal in one patient) and infiltrative ill-defined hepatocellular carcinoma and/or extra-hepatic lesions in 3 patients.

Conclusions

Our data show an unexpected high rate and pattern of tumor recurrence coinciding with HCV clearance and, although based in a very small cohort of patients, should be taken as a note of caution and prime a large scale assessment that exceeds the individual investigators capacity.

Lay summary

High rate of cancer recurrence after DAA treatment in patients with prior hepatocellular carcinoma. Disruption of immune surveillance may facilitate the emergence of metastatic clones.

Introduction

Treatment of hepatitis C virus (HCV) infection has experienced a major advancement with the advent of the new direct-acting antivirals (DAA). Current HCV infection cure rates exceed 90% and this has occurred in a very short time. Different studies have shown rates of sustained virological response (SVR) around 95–97% in compensated cirrhosis [1], [2], [3] and 85–90% in patients with more advanced liver disease including those awaiting liver transplantation [4], [5]. More importantly, these high efficacy results have been shown to be also reproducible in large real-life cohorts [6], [7], [8] reporting improvements in disease severity (Child-Pugh score, MELD) in some patients early after treatment.

This clinical reality has raised several expectations: i) the evolution of infected patients into cirrhosis and the need of transplant would decrease sharply in one decade; ii) the incidence of liver cancer would also decrease as a result of the abrogation of the chronic inflammation related to viral infection, ultimately leading to cirrhosis and oncogenic damage. These predictions are all well grounded on a population basis, but in some specific populations, the impact of viral infection cure with sudden changes in the relationship between inflammatory status and immune stimulation may induce the emergence of events that were totally unpredicted.

This may be the case in patients with HCV-related hepatocellular carcinoma (HCC) that have been successfully treated for their cancer and, later on received effective antiviral therapy. We started the treatment of such patients when approval was granted for the indication (2014). Due to the large number of cases attending in the liver cancer unit (BCLC) and the viral hepatitis unit, we detected some unfortunate patients in whom antiviral therapy and HCV eradication was followed by the detection of HCC recurrence. The recognition of more cases with recurrent disease with a clear-cut temporal association between antiviral therapy and HCC recurrence, prompted us to carefully review the clinical experience that was part of a prospective health plan in viral hepatitis, and to involve other groups in such an effort, who had the same clinical experience and concerns. This is particularly relevant since data from real-life antiviral experience with DAA [6], [7], [8] regarding HCC incidence or HCC outcomes are absent or heterogeneous, and do not allow extraction of any clear recommendation. Indeed, the indications on antiviral therapy for virus-related HCC patients remains incomplete in most clinical guidelines [9].

In this study we expose the findings from a well-defined population of patients with chronic HCV infection and HCC that were treated with DAA after reaching complete tumor response after treatment for their tumor.

Section snippets

Patient evaluation

The study included patients with HCV infection and complete radiologic response after a prior history of HCC treated by ablation, resection or chemoembolization between 13th October 2014 and 15th December 2015, and who had received treatment with all-oral DAA in four Spanish referral hospitals (Hospital Clinic de Barcelona, Hospital Universitario Puerta de Hierro, Clínica Universidad de Navarra and Hospital Universitario Central de Asturias). Cases were identified in each hospital registry and

Baseline characteristics of patients

Between October 2014 and December 2015, 103 HCC patients with prior HCC and a HCV infection received treatment with DAA. A total of 98 patients had a history of HCC treatment before starting DAA. Eighty-six of them were confirmed to have a complete radiologic response following the validated EASL criteria that take into account tumor necrosis. To avoid confounders because of HCC understaging, 8 out of the 86 with complete radiologic response were excluded because the existence of

Discussion

Until recently, therapeutic eradication of chronic HCV infection has required the use of injectable IFN formulations, which are associated with a significant number of side effects and suboptimal efficacy in terms of viral eradication. The current scenario with several available combinations of DAA has completely changed the landscape of HCV therapy. While these represented a major breakthrough because of the high efficacy and optimal safety profile, there is still a need to collect further

Financial support

MR: received support in part by Instituto de Salud Carlos III (PI15/00145); XF: received support in part by Instituto de Salud Carlos III (PI15/00151), Ministerio de Economía y Competitividad, co-funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa. XF also received a grant from Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (grant 2014_SGR_605). CIBERehd is funded by the Instituto de Salud Carlos III; JB: received support in

Conflict of interest

MR: Advisory boards, conferences, travel grants from Bayer; ZM: Speaker fees from Abbvie, Gilead, Janssen; MI: Conferences, travel grants from Bayer; SL: Speaker fees from Abbvie, Gilead, MSD, Janssen; Advisor for Gilead and Janssen; MV: Advisory boards, conferences, travel grants from Bayer; BS: Speaker and/or consulting fees from Astra Zeneca, Bayer Healthcare, BMS, BTG, Medimmune, Novartis, Onxeo, and Sirtex; JLC: Speaker and consultant: MSD, Gilead, Abbvie, Janssen; XF: Unrestricted Grant

Authors contributions

MR: concept and design, database, analysis writing of article; ZM: concept and design, database, analysis writing of article; CP: database, analysis writing of article; MI: database, analysis writing of article; AR: database, analysis writing of article; SL: database, analysis writing of article; AD: analysis writing of article; RV: database, analysis writing of article; AD: database, analysis writing of article; MV: database, analysis writing of article; BS: analysis writing of article; JLC:

Acknowledgments

The authors thank Dr. Ignacio Herrero from Clínica Universitaria de Navarra for his help in collecting all data.

References (33)

  • E. Lawitz et al.

    Efficacy and safety of ombitasvir, paritaprevir, and ritonavir in an open-label study of patients with genotype 1b chronic hepatitis C virus infection with and without cirrhosis

    Gastroenterology

    (2015)
  • F. Poordad et al.

    ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis

    N Engl J Med

    (2014)
  • K.R. Reddy et al.

    Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis

    Hepatology

    (2015)
  • F. Poordad et al.

    Daclatasvir with sofosbuvir and ribavirin for HCV infection with advanced cirrhosis or post-liver transplant recurrence

    Hepatology

    (2016)
  • M.S. Sulkowski et al.

    Effectiveness of simeprevir plus sofosbuvir, with or without ribavirin, in real-world patients with HCV genotype 1 infection

    Gastroenterology

    (2015)
  • N. Terrault et al.

    (HCV-TARGET) – Treatment outcomes with 8, 12 and 24 week regimens of ledipasvir/sofosbuvir for the treatment of hepatitis C infection: analysis of a multicenter prospective, observational study

    Hepatology

    (2015)
  • Cited by (0)

    Guest editor: Didier Samuel

    These authors contributed equally as joint first authors.

    These authors share senior authorship.

    View full text