Recurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: Literature review and risk analysis

doi:10.1016/j.dld.2018.08.001

Digestive and Liver Disease

Volume 50, Issue 11, November 2018, Pages 1105-1114

https://doi.org/10.1016/j.dld.2018.08.001 Get rights and content

Abstract

Although studies suggest decreased incident hepatocellular carcinoma (HCC) after treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, data are conflicting regarding risk and aggressiveness of recurrence in patients who have a history of treated HCC. This review analyses data available in literature in order to elucidate the impact of DAAs on the risk of HCC recurrence after successful treatment of the tumor. Overall 24 papers were identified. The available data cannot be considered definitive, but the initial alarmist data indicating an increased risk of recurrence have not been confirmed by most subsequent studies. The suggested aggressive pattern (rapid growth and vascular invasion) of tumor recurrence after DAAs still remains to be confirmed. Several limitations of the available studies were highlighted, and should drive future researches. The time-to-recurrence should be computed since the last HCC treatment and results stratified for cirrhosis and sustained viral response. Any comparison with historical series is of limited interest because of a number of biases affecting these studies and differences between enrolled patients. Prospective intention-to-treat analyses will be probably the best contribution to drive clinical practice, provided that a randomized trial can be difficult to design.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide [1]. In the last decades, a growing incidence of HCC was observed in most developed countries, being hepatitis C virus (HCV)-related hepatitis one of the main determinant of this phenomenon [2]. The introduction of second-generation directly-acting antivirals (DAAs) has dramatically changed the scenario of HCV infection. DAAs can achieve sustained virological response (SVR) rates in a percentage of cases as high as 95–98% [3]. Their extensive adoption is expected to lead to a progressive decrease in HCV-related HCC, even if an initial cumulative increase of HCC incidence could be observed because of the lower risk of liver decompensation and the higher survival expectancy of cirrhotic patients with SVR [4], [5].

Two contemporary retrospective studies have advanced the hypothesis that successful treatment with the new DAAs may be associated with higher incidence and recurrence rates of HCC [6], [7]. Moreover, an unusual increase of infiltrating tumors has been reported by these authors. Subsequently, controversial data have been published and several biomolecular hypotheses have been suggested [8]. These findings have been object of debate and could have major implications in the management of HCC patients. An urgent clarification is needed to drive clinical practice.

This review analyses the data available in the literature in order to clarify the impact of DAAs on the risk of HCC recurrence after successful treatment of the tumor.

Section snippets

Literature search

A systematic search of PubMed, Science Citation Index, and Embase databases was performed for articles published between January 2014 and January 2018 (cut-off date February 1, 2018) relevant to recurrence of HCC after DAAs. English language articles were selected using the keywords ‘hepatocellular carcinoma’; ‘HCC’; ‘HCV’; ‘DAA/directly-acting antivirals’ and ‘recurrence’ to identify all reports that may pertain to the review issue. Manual cross-referencing was performed; and relevant

Literature selection

Overall, 24 papers (with 25 cohorts of patients) [6], [7], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30] reporting on HCC recurrence after DAAs treatment in patients with previously and successfully treated HCC (liver resection, ablation or trans-catheter arterial chemoembolization — TACE) were identified. Two papers only considered patients with HCC recurrence [25], [27], two included also patients who

Discussion

The potential risks and benefits of DAA therapy in patients with a history of HCC are still a matter of debate. Some authors suggested a reduction of the recurrence risk in comparison to patients with untreated HCV infection, although these conclusions must be interpreted in the context of the clinical heterogeneity within and between studies and methodological limitations of current data. However, all these indirect comparisons with historical data suffer from biases favoring (immortal bias)

Conclusions

The available data about the risk of HCC recurrence after DAAs treatment in HCV patients cannot be considered definitive, but the initial alarmist data indicating an increased risk of recurrence have not been confirmed by most subsequent studies. Nonetheless, since there are no clear evidences of a detrimental effect of DAAs on HCC recurrence, we believe that DAAs should not be denied to these patients, as well as, it is mandatory to maintain an active surveillance for HCC.

Conflict of interest

None declared.

Acknowledgements

We thank the other members of Special Interest Group on “Hepatocellular carcinoma and new anti-HCV therapies” of the Italian Association for the Study of the Liver (AISF): Alessandro Vitale, Francesco Paolo Russo, Umberto Cillo, Patrizia Burra, Claudia Mescoli, Martina Gambato from Padua University Hospital. Anna Sessa from Dept. of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples “Federico II”, Naples, Italy. Giuseppe Cabibbo from Section of Gastroenterology, DIBIMIS,

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With the introduction of DAAs, tremendous cure rates were recorded. Unfortunately, some studies related the use of DAAs with tumor development in CHC patients (Butt et al., 2018; Guarino et al., 2018; Ida et al., 2017). One of the suggested mechanisms linked to HCC development is the production of proangiogenic factors and cytokines.
Suspect has been directed towards some direct acting antivirals (DAAs) due to their reported association with hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients. The mechanisms behind HCC development, following CHC treatment, were not well understood and may be linked to genetic variabilities in different patients which affect several cytokine productions involved in angiogenesis and inflammation. Of these variabilities, is the genetic polymorphisms in the interleukin-17 (IL-17) A receptor gene. Being an important pleiotropic cytokine, this study aimed to investigate the association between haplotypes in IL-17A receptor rs2275913 and rs3819024 and development of HCC in CHC patients treated with either triple therapy (sofosbuvir (SOF), pegylated interferon-alpha-2a (Peg-IFNα-2a) & ribavirin(RBV)) or with dual therapy (Peg-IFNα-2a&RBV). A cohort of 100 CHC patients was recruited in this study. Samples were tested for single nucleotide polymorphism (SNPs) in IL-17A receptor (rs2275913 and rs3819024) using TaqMan Genotyping assay. Our results showed that the presence of G-G haplotype in IL-17A (rs2275913& rs3819024) is inversely associated with HCC development in patients receiving triple therapy. While, high serum AFP levels are directly associated with HCC development in patients receiving triple therapy. However, in patients receiving dual therapy, HCC development was only associated with high serum alpha fetoprotein (AFP) levels and was not correlated to any specific allele in our studied SNPs. Such results highlight the importance of IL17A receptor gene haplotyping in the prediction of HCC development in patients receiving triple therapy. These results will aid in performing tailored, personalized strategy for CHC treatment.
Absence of impact of direct acting antivirals for hepatitis C virus on recurrent hepatocellular carcinoma tumor growth in the AFEF/ANRS CO22 Hepather cohort
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This is the first study on a small number of patients showing that DAA therapy significantly reduced the recurrence rate of HCC and improved survival without recurrence. Finally, Guarino et al., in a meta-analysis of data available (24 papers) in order to elucidate the impact of DAAs on the risk of recurrence after successfull treatment of HCC did not confirm an increasing risk of HCC recurrence associated with DAAs [23]. One Japanese study investigating the influence of HCV eradication by DAA therapy on the development of HCC strongly suggests that DAA do not enhance the development of HCC [30].
Although it has now been excluded that direct-acting antivirals (DAA) are associated with a significant risk of hepatocellular carcinoma (HCC) in HCV-infected patients, a possible effect of DAA on tumor growth is still a subject of debate. We performed a blind comparison of the kinetics of HCC recurrence in patients after HCV treatment with or without DAA to evaluate the potential aggressiveness of HCC after DAA treatment.
Thirty-nine HCV-infected patients from the AFEF/ANRS CO22 Hepather cohort who experienced HCC recurrence after so-called curative treatment were evaluated. Contrast-enhanced CT and/or MR images were read blindly 6 months before HCC recurrence and during the follow-up period. Seventeen patients who received DAA (DAA + ) before HCC recurrence were compared to the 22 who did not receive (DAA−), according to the LiRads and mRECIST criteria.
There were 28 men and 11 women, median age 62 years old, 37 (95%) with cirrhosis. DAA+ patients had a lower median MELD score (8 ± 2 vs. 10 ± 4, P = 0.0286) than DAA− patients. The median time to HCC recurrence (time from the date of curative treatment to the diagnosis of recurrence) was not different (20 vs. 18 months) (P = 0.73) between the two groups. There was no difference between the 2 groups in the overall survival and/or transplantation-free survival (P = 0.71) and for the mRECIST time to progression (P = 0.25).
This blinded analysis of HCC recurrence after HCC treatment does not support any negative impact of DAA therapy on the severity or progression of recurrent HCC.
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However, our finding of the highest recurrence rate of HCC at 7.7 months from the onset of antiviral therapy, to be followed by a decline in incidence, suggests the enrolment of patients with unrecognized residual HCC cells or the presence of untreated small foci of tumor cells that quickly progress to overt HCC. Future studies are necessary to establish whether these events are favored by changes in the liver microenvironment consequent to treatment with DAA.12,14,15,40 Along this line, it is important to highlight that in our cohort there was an association between likelihood of HCC recurrence and history of alcohol abuse, which points to the multifactorial etiology of liver cancer and the difficulty of interpreting all biological events linked to malignant transformation of the liver.
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An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness.
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¹: Both the authors equally contributed to the manuscript.

²: Study Group Members: Alessandro Vitale, Francesco Paolo Russo, Umberto Cillo, Patrizia Burra, Claudia Mescoli, Martina Gambato, Anna Sessa, Giuseppe Cabibbo, Mauro Viganò, Giovanni Galati, Erica Villa, Massimo Iavarone, Giuseppina Brancaccio, Maria Rendina, Luigi G. Lupo, Francesco Losito, Fabio Fucilli, Marcello Persico, Roberta D’Ambrosio, Angelo Sangiovanni, Alessandro Cucchetti, Franco Trevisani e Matteo Renzulli, Luca Miele, Antonio Grieco, Gian Lodovico Rapaccini, Maurizio Pompili, Antonio Gasbarrini, Giovanni Battista Levi Sandri, Fabio Melandro, Massimo Rossi, Ilaria Lenci, Tommaso Maria Manzia, Raffaella Tortora, Giovan Giuseppe Di Costanzo, Rodolfo Sacco, Davide Ghinolfi, Erion Rreka, Paola Carrai, Natalia Simonetti, Carlo Sposito, Sherrie Bhoori, Stefano di Sandro, Francesco Giuseppe Foschi, Andrea Casadei Gardini, Daniele Nicolini, Susanna Mazzocato, Alba Kostandini, Paola Violi, Umberto Baccarani, Riccardo Pravisani, Valter Vincenzi.

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Review ArticleRecurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: Literature review and risk analysis

Abstract

Introduction

Section snippets

Literature search

Literature selection

Discussion

Conclusions

Conflict of interest

Acknowledgements

Dig Liver Dis

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

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Review Article
Recurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: Literature review and risk analysis