Research ArticleDirect-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients
Graphical abstract
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death globally, and the leading cause of mortality in cirrhotic patients, with hepatitis C virus (HCV) being the major risk factor in the Western world and Japan.1 Orthotopic liver transplantation (OLT) is the definitive treatment for HCC and cirrhotic liver, but this approach cannot be offered to all patients due to limited graft availability and rigorous selection criteria.2 Alternative curative treatment options for patients with compensated cirrhosis are surgical resection and loco-regional ablation of early HCC (i.e. Barcelona Clinic Liver Cancer [BCLC] stage 0/A).2
Unfortunately, hepatic decompensation of underlying cirrhosis, the major driver of death, and tumour recurrence contribute to long-term mortality after successful treatment of early HCC.3 A recent meta-analysis showed that, among HCV-infected compensated cirrhotic patients in whom early HCC was successfully treated, who remained unexposed to direct-acting antivirals (DAAs), the 2-year actuarial pooled HCC recurrence rate was 47.0% and the 3-year actuarial pooled survival rate was 79.8%.4 These data indicate that there is an urgent need for an effective adjuvant strategy given the prior failures of other adjuvant treatments, including sorafenib.5
DAAs improve HCV infection outcomes, even in patients with advanced liver disease,[6], [7] with a good safety profile and a sustained virologic response (SVR) rate exceeding 90% in clinical practice. In 2016, an alarm signal was released about a potentially increased risk of early HCC recurrence after DAA therapy, raising concerns about the safety of DAA use in patients with previously treated early HCC.[8], [9] Since then, several prospective studies[10], [11], [12], [13] and 2 meta-analyses[14], [15] have provided evidence that the risk of HCC recurrence after treatment with DAAs in patients with history of successful treatment of early HCC is similar, if not lower, than that observed in interferon-treated or DAA-unexposed controls. However, field-practice prospective studies that prove the benefit of DAAs on overall survival and hepatic decompensation are lacking, and the longer-term effect of DAAs on mortality remains to be established. Since DAAs are the accepted standard of care even in patients with previously treated early HCC, randomized controlled trials (RCTs) comparing DAAs to No DAAs are not feasible, ethical or timely. Therefore, we analysed our observational data, as an attempt to emulate a randomized trial, outlining a framework for comparative effectiveness using observational data.16 For this reason, an appropriately matched control group of DAA-unexposed patients is needed to assess the benefit of DAA treatment on hepatic decompensation, HCC recurrence and finally overall survival.
The main aim of this prospective multicentre study was to estimate whether DAAs prolong overall survival in patients with HCV-related compensated cirrhosis and a first diagnosis of early HCC (without history of HCC recurrence before DAA treatment) who had achieved a complete radiologic response after curative resection or ablation. We used an appropriately matched control group of patients who had not received DAAs for this comparison. As secondary outcomes we considered the impact of DAAs on HCC recurrence and on hepatic decompensation.
Section snippets
DAA-treated patients after successful treatment of HCV-related early HCC
This multicentre prospective cohort study used data from the RESIST-HCV (Rete Sicilia Selezione Terapia HCV), a web-based regional network (for more details, see Supplementary File 1).[17], [18] We analysed data from all consecutive HCV-infected cirrhotic patients, who had previously cured HCC, that were treated with DAAs and included in the RESIST-HCV database from March 1, 2015 to March 27, 2018. The study included all consecutive patients with HCV-related compensated cirrhosis and complete
Baseline features of patients
The baseline characteristics of the 163 patients treated with DAAs (DAA-treated) and 328 patients who had not received DAAs (DAA-untreated) are shown in Table 1. Most of the DAA-treated patients were male (63%) and Child-Pugh class A (84%). Oesophageal varices were present in 60% of patients. Eighty-two percent had monofocal HCC at the time of tumour diagnosis. The HCC treatment received by the majority of patients (59.5%) was thermal ablation. In DAA-treated patients, intention-to-treat
Discussion
This prospective real-world multicentre observational study involved a cohort of patients with HCV-related cirrhosis who had received treatment with DAAs after curative resection or ablation of early HCC. According to methods for comparative effectiveness, we used our observational data to emulate a hypothetical randomized trial by comparing DAA-exposed versus DAA-unexposed patients.[16], [26] Its results show that patients treated with DAAs had significantly better OS and lower hepatic
Financial support
The RESIST-HCV is funded by unrestricted grants from Gilead, MSD, Abbvie and BMS.
Conflict of interest
Marco Distefano: participated in advisory board for Abbvie. Gaetano Scifo: participated in advisory board for Abbvie. Vincenza Calvaruso: participated in advisory board for Abbvie. Salvatore Petta: advisory board and/or speaker for Abbvie, Gilead, MSD, Intercept. Vito Di Marco: research support from Abbvie, BMS, Gilead, Merck/MSD. Participated in advisory boards for Abbvie, BMS; MSD/Merck. Antonio Craxì: Research support from Abbvie, BMS, Gilead, Merck/MSD, Intercept, provided consultancy,
Authors’ contributions
All the authors had full control of the study design, data analysis and interpretation, and preparation of article. All authors were involved in planning the analysis and drafting the article. All authors approved the final version of the manuscript.
Acknowledgments
MEMBERS OF THE RESIST-HCV GROUP
PALERMO A.O.U.P. Paolo Giaccone, Palermo: U.O.C. di Gastroenterologia e Epatologia (A. Craxì, V. Di Marco, C. Cammà, G. Cabibbo, V. Calvaruso, S. Petta, C. Celsa, B. Magro, M. Rossi, F. Rini, E. Conte); U.O.C. di Malattie Infettive (P. Colletti, G. Mazzola), U.O.C. di Medicina Interna (A. Licata, L. Giannitrapani). ARNAS Civico-Di Cristina-Benefratelli, Palermo: U.O.C. di Malattie Infettive (S. Corrao, T. Prestileo, F. Di Lorenzo, R. Fecarotta, P. Sanfilippo) A.O.
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These authors equally contributed to this work.