Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals

doi:10.1016/j.jhep.2016.06.015

Journal of Hepatology

Volume 65, Issue 4, October 2016, Pages 727-733

https://doi.org/10.1016/j.jhep.2016.06.015 Get rights and content

Background & Aims

Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA.

Methods

We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24 weeks. Fifty-nine patients had previous HCC.

Results

DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99–10.84): 17 of 59 patients (28.81%, 95% CI: 17.76–42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45–5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p = 0.03, OR: 4.18, 95% CI: 1.17–14.8) and history of HCC (p <0.0001, OR: 12.0, 95% CI: 4.02–35.74) resulted independently associated with HCC development. Among the 59 patients with previous HCC, younger age and more severe liver fibrosis were significantly associated with HCC recurrence, both at univariate and at multivariate analysis.

Conclusions

In patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumour recurrence, in the short term. For these reasons, all cirrhotic patients should be closely monitored and followed during and after antiviral therapy.

Lay summary

New direct-acting antivirals are able to eradicate HCV infection in over 90% of patients with advanced liver disease. Unfortunately, the occurrence of liver cancer is not reduced in effectively treated cirrhotic patients. In addition, patients previously treated for HCC have still a high risk of tumour recurrence in the short term, despite DAA treatment.

Graphical abstract

Introduction

Hepatitis C virus (HCV) infection is responsible for chronic hepatitis C, a necro-inflammatory process of the liver that progresses towards liver cirrhosis in about 20–30% of patients [1], [2]. When liver cirrhosis is established, liver cancer may occur at an average 3.5% annual rate [3], [4]. During the past decades, treatment of chronic hepatitis C with pegylated interferon (PegIFN) and ribavirin led to cure of HCV infection in about 50% of treated patients [5], [6]. A sustained virological response (SVR), as undetectable HCV RNA after therapy end, has been associated with a reduced risk of developing hepatocellular carcinoma (HCC) [7], [8], [9].

The recent introduction of new antiviral drugs, directly targeting HCV replication, allowed achieving SVR rates in over 90% of treated patients, irrespective of the liver fibrosis stage [10], [11], [12]. This has raised the hope of a drastic decline in HCC occurrence, and even a decline in recurring HCC in those patients who experienced liver cancer in the past, and went through effective surgical or ablative treatment of the neoplastic lesions.

The aim of this study was to evaluate the early occurrence of HCC in cirrhotic patients without history of liver cancer and the recurrence of HCC in cirrhotic patients with a history of previously treated HCC, systematically followed during and after treatment with direct-acting antivirals (DAA).

Section snippets

Patients and methods

In this retrospective cohort study, we analysed data from all the consecutive patients with advanced liver fibrosis who were prospectively enrolled for treatment with DAAs at our centres in the Bologna area, Italy, between March and September 2015. Data were first retrieved from the electronic regional registry database (Piattaforma SOLE). Then, all the additional data were obtained from the individual patient records.

Eligibility of each patient for treatment of hepatitis C with DAAs was

Results

We performed our analysis on the 344 consecutive adult patients, with HCV-related liver cirrhosis, who completed a full course of antiviral therapy with different DAA regimens between April and November 2015, and were systematically followed for 24 weeks after treatment completion. The principle baseline characteristics of the study population are reported in Table 1. In particular, most patients were males (60.2%), mean aged 63 years, with prevalent HCV genotype 1 infection (68.9%), and

Discussion

HCC is a possible serious complication in the natural history of chronic hepatitis C. The risk of developing HCC increases as liver fibrosis advances and in patients with advanced liver disease and cirrhosis the annual incidence rate averages 3.5% [3], [14]. Liver carcinogenesis is a long multistep process requiring chronic hepatic inflammation, progressive liver fibrosis, initiation of neoplastic clones, and progression of the malignant clones in a carcinogenic tissue environment [15].

Conflict of interest

The following disclosures were reported: LB (Bayer, BMS, MSD, Sirtex: advisory board/speaking bureau); PC (Gilead: speaking bureau, BMS: speaking bureau/scientific consultant); GV (BMS, Gilead, Abbvie, ViiV: advisory board; Gilead, MSD, BMS: speaking bureau); PA (Gilead, MSD, and Roche: research grants, Janssen, MSD, Roche, Gilead, BMS, Abbvie, and Intercept: advisory board); SB (Novartis, Gilead: research grants, Gilead, Janssen, MSD: advisory board). All other authors declared that they do

Authors contribution

FC (concept and design, data collection and procedures); FB (concept and design, data collection and procedures); AS (data collection and procedures); CC (data collection and procedures); LB (data collection and procedures); PC (data collection and procedures); FGF (data collection and procedures); ML (data collection and procedures); GM (data collection and procedures); GV (data collection and procedures); PA (concept and design, writing of article); SB (concept and design, writing of

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Major variations were observed in the two spectral regions i.e., 3500–2800 and 1800–900 cm-¹. IR spectral signatures of hepatocellular carcinoma were reliably different from healthy individuals. Principal component analysis – linear discriminant analysis and support vector machine models computed 100% accuracy for diagnosing hepatocellular carcinoma. To classify the non-angio-invasive hepatocellular carcinoma/ angio-invasive hepatocellular carcinoma status, diagnostic accuracy of 86.21% was achieved for principal component analysis – linear discriminant analysis. While the support vector machine showed a training accuracy of 98.28% and a cross-validation accuracy of 82.75%. External validation for support vector machine based classification observed 100% sensitivity and specificity for accurately classifying the freeze-dried sera samples for all categories.
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Citation Excerpt :
Additional study and patient characteristics are summarized in Tables 1 and 2. Quality assessment of articles indicated that 29 studies5,17,19-45 were of good quality with low risk of bias, and 2 studies16,18 were of fair quality with moderate risk of bias. Study definitions used to define cirrhosis, F3 fibrosis, and HCC screening before and after treatment, varied between studies (Table 2).
Hepatitis C virus (HCV) eradication with direct-acting antivirals reduces hepatocellular carcinoma (HCC) risk. Pooled HCC incidence rates by cirrhosis status and fibrosis stage have not been estimated using meta-analysis.
We searched PubMed, Web of Science, Embase, and Cochrane Library from January 1, 2014 to December 31, 2020 to identify studies assessing HCC incidence or outcomes by cirrhosis status, in adults with HCV who achieved sustained virologic response (SVR) after direct-acting antivirals. Pooled estimates were obtained using random-effects modeling. Subgroup, sensitivity, and meta-regression analyses were performed to evaluate heterogeneity.
We included 31 studies involving 27,711 patients with cirrhosis (mean follow-up, 2.1 years) and 11 studies involving 32,123 patients without cirrhosis (mean follow-up, 2.6 years). HCC incidence was 2.99/100 person-years (95% confidence interval [CI], 2.52–3.54; I² = 75%) in patients with cirrhosis, 0.47/100 person-years (95% CI, 0.32–0.70, I² = 71%) in patients without cirrhosis, and 0.63/100 person-years (95% CI: 0.34–1.20, I² = 0%) in stage 3 (F3) fibrosis. Among patients with cirrhosis, HCC incidence was highest in studies with <1 year of follow-up (6.17/100 person-years [95% CI, 3.73–10.19]) and progressively lower in studies with longer follow-up (1–2 years: 2.75/100 person-years [95% CI, 2.48–3.06]; 2–3 years: 2.90/100 person-years [95% CI, 1.90–4.44]; ≥3 years: 1.83/100 person-years [95% CI, 0.88–3.80]).
Pooled HCC incidence after SVR in patients with cirrhosis was very high (2.99/100 person-years) but may be declining as longer time accrues after SVR. In patients without cirrhosis, including F3 fibrosis, HCC incidence was lower than thresholds associated with cost-effective HCC screening. In patients with F3 fibrosis, the lack of between-study heterogeneity provides strong evidence that HCC screening may not be warranted.
Direct-acting antivirals sofosbuvir and daclatasvir attenuate carbon tetrachloride-induced liver fibrosis in mice
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Advanced liver fibrosis is a major risk for developing hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) patients. Direct-acting antivirals (DAAs) which are used for treating HCV infection, produce more than 90% cure rate but do not seem to diminish the rate of occurrence or recurrence of HCC. This study aimed to investigate the effect of DAAs sofosbuvir (SOF) and daclatasvir (DAC) on carbon tetrachloride (CCl₄)-induced fibrotic changes in mice.
Eighty adult male Swiss albino mice were randomly allocated into 8 groups (10 mice/group): normal control group, SOF group (receiving SOF 80 mg/kg body weight (BW), oral gavage, daily), DAC group (receiving DAC 30 mg/kg BW, oral gavage, daily), SOF + DAC group (receiving a combination of both, daily), CCl4 model group (receiving CCl₄ 2 mL/kg BW, intraperitoneal twice weekly) and three CCl₄-intoxicated groups receiving either SOF or DAC or their combination. All CCl₄ groups received CCl₄ for 12 weeks followed by DAAs for another 12 weeks.
CCl₄-induced a significant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and produced histopathological evidence of fibrosis and liver degeneration along with a significant increase (P ≤ 0.001) of the proliferation markers (proliferating cell nuclear antigen (PCNA) and Ki-67), hepatic stellate cells (HSCs) activation markers (alpha-smooth muscle actin (α-SMA) and glial fibrillary acidic protein (GFAP)), fibrosis marker (matrix metalloproteinase-9 (MMP-9)) and pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α)). CCl₄-intoxicated mice treated with SOF, DAC, or their combination revealed a significant amelioration (P ≤ 0.001) of CCl₄-induced elevation of liver enzymes, fibrotic changes, and liver degeneration along with a significant attenuation (P ≤ 0.001) of CCl₄-induced upregulation of all tested markers. The effects of SOF, DAC, and their combination on liver enzymes were comparable while the effect of SOF + DAC combination on mitigating CCl₄-induced upregulation of the proliferation and HSCs activation markers was significantly stronger than either SOF or DAC alone. As for MMP-9 and TNF-α, the effects of DAC and SOF + DAC combination were comparable and both were more significant than that of SOF alone.
SOF and DAC may possess an antifibrotic effect that is independent of their role as antiviral agents against CCl₄-induced liver injury. This might exclude the role of DAAs in early occurrence or accelerated recurrence of HCC through the progression of the HCV patients' pre-existing fibrosis. However, HCC patients treated with DAAs should be closely monitored with continuous HCC surveillance during and post-therapy.

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^†: These authors contributed equally as joint first authors.

^‡: These authors share senior authorship.

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Research ArticleEarly occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals

Background & Aims

Methods

Results

Conclusions

Lay summary

Graphical abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Conflict of interest

Authors contribution

Gastroenterology

Gastroenterology

Gastroenterology

Lancet Infect Dis

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

Cell

Adv Immunol

Natural history of chronic hepatitis C

Hepatology

Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression

Hepatology

Research Article
Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals