Elsevier

Journal of Hepatology

Volume 71, Issue 2, August 2019, Pages 265-273
Journal of Hepatology

Research Article
Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients

https://doi.org/10.1016/j.jhep.2019.03.027Get rights and content

Highlights

  • DAAs improve survival in patients with HCV-related early HCC that has been successfully treated.

  • The improvement in survival seems to be caused by a reduction in hepatic decompensation.

  • DAAs did not impact on HCC recurrence.

Background & Aims

The effectiveness of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), following successful treatment of early hepatocellular carcinoma (HCC), has been studied extensively. However, the benefit in terms of overall survival (OS) remains to be conclusively demonstrated. The aim of this study was to assess the impact of DAAs on OS, HCC recurrence, and hepatic decompensation.

Methods

We prospectively enrolled 163 consecutive patients with HCV-related cirrhosis and a first diagnosis of early Barcelona Clinic Liver Cancer stage 0/A HCC, who had achieved a complete radiologic response after curative resection or ablation and were subsequently treated with DAAs. DAA-untreated patients from the ITA.LI.CA. cohort (n = 328) served as controls. After propensity score matching, outcomes of 102 DAA-treated (DAA group) and 102 DAA-untreated patients (No DAA group) were compared.

Results

In the DAA group, 7/102 patients (6.9%) died, HCC recurred in 28/102 patients (27.5%) and hepatic decompensation occurred in 6/102 patients (5.9%), after a mean follow-up of 21.4 months. OS was significantly higher in the DAA group compared to the No DAA group (hazard ratio [HR] 0.39; 95% CI 0.17–0.91; p = 0.03). HCC recurrence was not significantly different between the DAA and No DAA groups (HR 0.70; 95% CI 0.44–1.13; p = 0.15). A significant reduction in the rate of hepatic decompensation was observed in the DAA group compared with the No DAA group (HR 0.32; 95% CI 0.13–0.84; p = 0.02). In the DAA group, sustained virologic response was a significant predictor of OS (HR 0.02; 95% CI 0.00–0.19; p <0.001), HCC recurrence (HR 0.25; 95% CI 0.11–0.57; p <0.001) and hepatic decompensation (HR 0.12; 95% CI 0.02–0.38; p = 0.02).

Conclusions

In patients with HCV-related cirrhosis who had been successfully treated for early HCC, DAAs significantly improved OS compared with No DAA treatment.

Lay summary

We aimed to determine whether direct-acting antivirals (DAAs) significantly improve overall survival in patients with hepatitis C virus-related compensated cirrhosis and a first diagnosis of hepatocellular carcinoma (HCC) which has been successfully treated with curative resection or ablation. Using propensity-score matched patients, we found that DAAs improved overall survival and reduced the risk of hepatic decompensation. However, the risk of HCC recurrence was not significantly reduced.

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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