hr

Hot Keywords
non-alcoholic fatty liver disease epidemiology microenvironment nonalcoholic steatohepatitis transplantation cholangiocarcinoma direct-acting antiviral immunotherapy hepatitis B hepatitis C liver resection imaging cancer stem cell diagnosis gene cirrhosis biomarker recurrence

Top
Hepatoma Res 2022;8:28. 10.20517/2394-5079.2022.08 © The Author(s) 2022.
Open Access Review

Impact of direct-acting antivirals on the recurrence of hepatocellular carcinoma in chronic hepatitis C

1Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva 1211, Switzerland.

2Division of Clinical Pathology, Geneva University Hospitals, Geneva 1211, Switzerland.

Correspondence to: Dr. Nikoletta M. Tagkou, Division of Gastroenterology and Hepatology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, Geneva 1211, Switzerland. E-mail: Nikoletta.Tagkou@hcuge.ch

    Views:718 | Downloads:221 | Cited:0 | Comments:2 | :1
    Academic Editors: James Fung, Guang-Wen Cao | Copy Editor: Haixia Wang | Production Editor: Haixia Wang

    © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

    Abstract

    Chronic hepatitis C virus (HCV) infection is estimated to affect 56.8 million individuals globally and is a major and independent risk factor for the development of hepatocellular carcinoma (HCC). After the introduction of safe and potent direct-acting antivirals (DAAs), capable of curing HCV infection also in patients with advanced liver disease at high risk of HCC, the beneficial effect on a de novo HCC development after viral clearance has been established. However, studies addressing the relationship between DAA-induced eradication and risk of HCC recurrence (i.e., reappearance of HCC treated before starting antivirals) have produced contradictory data, suggesting either an increase or a decrease of HCC recurrence rate, while some report no effect of these treatments. Thus, there seems to be an unclear benefit of viral clearance in patients with a history of HCC curative treatment, where the recurrence rate remains worryingly high. This short review aims to summarize current evidence on the impact of DAAs on HCC recurrence rates, the pathogenic mechanisms and characteristics of HCC recurrence after DAA treatment, the predictors of tumor recurrence, and the impact of DAAs on overall survival.

    INTRODUCTION

    Hepatocellular carcinoma (HCC) represents the most frequent primary liver malignancy[1]. Being the fourth most common cause of cancer-related death worldwide, with a 5-year survival rate of 18%, liver cancer is an important global burden that is projected to cause more than one million deaths in 2030 according to the World Health Organization[2,3]. While HCC is the leading cause of mortality in patients with compensated cirrhosis, it rarely develops in those without an underlying chronic liver disease and advanced fibrosis[4]. Chronic hepatitis C virus (HCV) infection is estimated to affect 56.8 million individuals worldwide and is an independent risk factor for the development of HCC, through a complex mechanism that encompasses on the one hand chronic inflammation, fibrinogenesis, and eventually cirrhosis and on the other hand the direct carcinogenic effects of the virus[5]. Chronic HCV infection and the development of HCC often lack symptoms and physical signs, leading to a late diagnosis in advanced stages and a poor prognosis. Although there are many therapeutic options for HCC, the mainstay of curative treatment remains surgical resection of the liver, local ablation, and liver transplantation (LT). However, even after curative treatment, HCC presents a recurrence rate of up to 70%, which is unusually high compared to other malignant neoplasms[6]. Effective treatment of chronic HCV infection is believed to be the best strategy for the prevention of HCC occurrence in these patients. Until a few years ago, the mainstay of HCV treatments was interferon-alpha (IFN-α) and its long-acting form, pegylated IFN-α (Peg-IFN-α), in combination with ribavirin (RBV). These drugs were poorly tolerated, especially in patients with advanced liver disease, and achieved relatively low levels of sustained virologic response (SVR), defined as lack of detectable HCV RNA in serum 12-24 weeks after the end of therapy, which is tantamount to permanent viral clearance[7]. It was also nonetheless demonstrated that patients who had achieved SVR with IFN-α based treatments had a significantly reduced risk of developing HCC in comparison with the ones failing to do so[8]. Since the introduction of direct-acting antivirals (DAAs), the beneficial effect on de novo HCC has been further confirmed[9,10]. DAAs have been shown to have a better safety profile, shorter treatment period, and can be administered even in advanced liver disease stages including decompensated cirrhosis, achieving a markedly increased SVR rate of > 95%. Thus, since HCC represents a major complication of chronic hepatitis C, it is not surprising that the introduction of DAAs has been associated with high expectations of decreasing the risk of development of both occurent and recurrent HCC in patients with chronic HCV infection, thus improving their prognosis[11]. However, contradictory data have emerged from several studies evaluating the relationship of DAAs with the risk of HCC recurrence in the group of patients who have been previously cured for HCC[12-15]. On that account, some authors have suggested an increase, a decrease, or even no effect of DAA treatment on HCC recurrence[12-15]. Although meta-analyses have suggested that the risk of developing de novo HCC in patients without HCC at the start of antiviral therapy is decreased, there seems to be an unclear benefit in those with a history of treated HCC, where the recurrence rate remains worryingly high[7]. This short review aims to summarize current evidence on the impact of DAAs on HCC recurrence rates, the pathogenic mechanisms and characteristics of HCC recurrence after DAA treatment, the predictors of tumor recurrence, and the impact of DAAs on overall survival.

    DAAS AND HCC RECURRENCE

    Definition and categories of recurrence

    Although the definition of HCC occurrence may be simple, HCC recurrence still lacks a widely accepted definition. One simple definition for HCC recurrence is the reappearance of HCC in patients who have been treated with radical and potentially curative procedures, with the most effective being surgical resection. However, it remains a heterogeneous term as it can vary in terms of spatial (intra-hepatic or local versus distal recurrence) and temporal (early versus late recurrence) features[16]. According to a meta-analysis of seven studies, the significant variability in reported HCC recurrence rates can be partially explained by the case definition[17]. There are currently many hypotheses around the mechanisms of intra-hepatic HCC recurrence after curative treatment. Several authors have divided HCC recurrence in “early” and “late”, with two years from treatment serving as the cut-off. Considering the underlying mechanisms, “early recurrence” is thought to derive from microscopic (and therefore undetected) metastases of the primary tumor, while “late recurrence” is thought to be driven by the underlying liver cirrhosis and its carcinogenic properties[18]. However, there are very few studies evaluating the difference in carcinogenic processes and prognosis between “early” and “late” recurrence, which explains the lack of consensus concerning these terms. A study that aimed to address this exact issue suggested that 17 months after curative HCC surgical resection might be a more suitable cut-off value between early and late recurrence. Additionally, the authors reported different independent risk factors for early [alpha-fetoprotein (AFP) level > 100 ng/mL, multiple HCC, serosal invasion, and microvascular invasion] and late recurrence (liver cirrhosis)[19].

    Do DAAs Increase HCC recurrence rates?

    Some of the earliest studies suggested that DAA treatment can increase the recurrence rate of HCV-related HCC in previously cured patients [Tables 1 and 2]. One of the first studies that demonstrated a negative impact of DAAs on the risk of HCC recurrence was a retrospective multicenter study from Spain by Reig et al. in 2016[12]. The study included 58 patients with a mean follow-up of 5.7 months and reported a recurrence rate of 27.6%. The recurrence risk was particularly high (41.2%) in patients receiving DAAs < 4 months post HCC treatment, suggesting that timing of DAAs administration after HCC treatment could have an impact on the recurrence rate. The authors reported for the first time an unexpectedly high recurrence rate of HCC in patients receiving DAA therapy and although based in a small number of patients this study raised concerns about the benefit of this treatment in this sub-group of patients[12]. An almost simultaneous single-center cohort study by Conti et al. reported a similar trend, with 17 out of 59 patients with previously treated HCC (28.8%) experiencing tumor recurrence within a 24-week follow-up[13]. Younger age and more advanced liver fibrosis were found to be significantly associated with high rates of HCC recurrence[13]. Additionally, a multicenter cohort study that included 47 patients treated for HCC with surgical resection, ablation, or trans-arterial chemo-embolization (TACE) from five European centers reported that 77% and 58% of the patients were recurrence-free after six months and one year post DAA treatment, respectively. The recurrence was significantly associated with the time interval between HCC treatment and DAAs initiation[20]. A prospective cohort study from Egypt also showed that DAA-exposed patients can have up to four times increased HCC recurrence incidence rate compared to non-DAA-exposed patients (recurrence rate 37.7% in DAA-exposed vs. 25.4% in non-DAA-exposed patients)[21].

    Table 1

    Retrospective studies on HCC recurrence after treatment of chronic hepatitis C with DAA

    Author, year (reference)nHCC treatmentMedian time (range) from HCC treatment to DAA (months)SVR (%)Median FU (range) (months)HCC recurrence in DAA-exposed (%)HCC recurrence in controls (%)Cumulative HCC recurrence rate (%)Median time from DAA treatment to HCC recurrence (months)
    Reig et al., 2016[12]DAA: 58surgical resection, ablation, TACE11.2 (3.6-23.2)97.55.7 (0.4-14.6)27.6NANR3.5 (1.1–8)
    Nagata et al., 2017[14]Total: 143, IFN: 60 vs. DAA 83surgical resection, RFANRIFN 65 vs. DAA 96IFN: 81.6 (2.4-264) vs. DAA: 21.6 (1.2-92.4)2953At 5 years:
    DAA 45.1
    vs. IFN 54.2
    NR
    Mashiba et al., 2018[22]Total: 516, IFN 148 vs. DAA 368NR11.1 (0.5-167.9)IFN: 52.7 vs. DAA 94.2IFN 25.5 vs. DAA 7.7NRNRNRNR
    Singal et al., 2019[23]Total: 797, DAA: 383 vs. no DAA: 414surgical resection, RFA, TACE, other7.7 (3.6-14.1)DAA: 79.4NR54.650.7NRNR
    Nakamura et al., 2019[24]DAA: 312surgical resection, RFA9.992.328.543.2NA1-, 2- and 3-year: 18.3, 38.8 and 55.4NR
    Zou et al., 2019[25]DAA: 264liver transplant, surgical resection, ablation, TACE229223.3 ± 9.826.1NA1- and 2-year: 3.3 and 20.212.2 ± 8.0
    Kuo et al., 2020[26]DAA 82 vs. IFN 80 vs. Untreated 160surgical resection, RFA30.7NRNR26.8IFN 56.8, untreated 58.83- and 6-months: DAA: 4.8 and 15.5NR
    Ogawa et al., 2021[27]DAA: 326surgical resection, ablation, TACE, particle radiotherapy, PEIT, multimodal14.4 (3.6-188.4)NR32.4 (0-64.8)52.5NA3- and 5-year: curative treatment 40.8 and 51.4 vs. palliative treatment 66.5 and 73.7NR
    Elbaz et al., 2021[28]DAA: 523AblationNR83.75.320.1NArecurrence rate/100PY: 7.26NR
    Watanabe et al., 2021[29]DAA: 199NR20 ± 26922248.7NA4- and 6-month, 1-, 2- and 3-year: 9.0, 16.6, 29.8, 41.0, 53.410
    Tani et al., 2021[30]DAA: 130surgical resection, RFA, TACE, MTANRNR41 ± 13.963.8NA6-month, 1-, 2- and 3-year: 23.2, 32.5, 46.3, and 59.4NR
    Ochi et al., 2021[31]DAA 56 vs. no DAA 112surgical resection, RFA5.6 (1.6-11.4)NR4836.766.71-, 2-, 3-, 4-year: DAA vs. no DAA: 12.5 vs. 22.7, 27.8 vs. 41.1, 36.7 vs. 54.3, and 36.7 vs. 66.7NR
    Ahn et al., 2021[32]DAA: 100RFA, surgical resection, radiation therapy, TACE, multimodalNR8815.8 (4.4-29.9)37NA1-, 2-year: 28.4 and 61.3NR
    Table 2

    Prospective studies on HCC recurrence after treatment of chronic hepatitis C with DAAs

    Author, yearnHCC treatmentMedian time (range) from HCC treatment to DAA (months)SVR (%)Median FU (range) (months)HCC recurrence in DAA-exposed (%)HCC recurrence in controls (%)Cumulative HCC recurrence rate (%)Median time from DAA treatment to HCC recurrence (months)
    Pol et al., 2016[33]Total: 267, DAA: 189 vs. no DAA 78surgical resection, ablation, TACENRDAA: 91.920,212.720.5NRNR
    Cabibbo et al., 2017[34]DAA: 143surgical resection, ablation, TACE11 (1-126)968.7 (3-19)20.3NA6-, 12- and 18-month: 12, 26.6 and 29.1NR
    El Kassas et al., 2018[21]Total: 116, DAA: 53 vs. no DAA: 63RFA, MWA, PEIT, surgical resectionNRDAA: 77.4DAA 16 vs. no DAA 2337.725.4recurrence rate/100PM: DAA 4,06 vs. no DAA 1,0NR
    Ogawa et al., 2018[35]DAA: 152surgical resection, RFA, particle radiotherapy, multimodal14.4NR1717.1NA1-year: 6.5 non-cirrhosis vs. 23.1 cirrhosisNR
    Lleo et al., 2018[36]DAA: 161surgical resection, ablation, liver transplant, TACENR951223.6NA6-, 12-, and 18-month: 8.5, 20.9, and 26.920.7
    Nakano et al., 2019[37]DAA: 459surgical resection, ablationNRNR29.4 ± 6.847.2NA1‐, 2‐, and 3‐year:27.1, 43.4, and 50.834
    Cabibbo et al., 2019[38]DAA 163 vs. no DAA 328surgical resection, ablation2.1 (0.5-6)DAA: 83DAA: 21.4 vs. no DAA: 17.527.537.36-month, 1-, 2- and 3-year: DAA vs. no DAA 6 vs. 9, 15 vs. 20, 27 vs. 40 and 70vs57 NR
    Sangiovanni et al., 2020[39]DAA: 124NR11 (1-188)951532NAmean yearly incidence 29.9/100PY and 2-year: 42.9NR
    Chi et al., 2021[40]DAA: 199 DAA (127 prospective, 72 retrospective), DAA 107 vs. IFN 42surgical resection, liver transplant, RFA, PEIT, TACE, Yttrium-90, target therapyDAA 8.2 (0.1-133.3) vs. IFN 3.8 (0.1-33.5)DAA 95 vs. IFN 64.3DAA 26.9 (6.0-147.6) vs. IFN 64.4(13.0-126.6)NR40.3NRDAA 29.3 vs. IFN 39.2

    Are HCV-Related HCC recurrence rates unaffected by DAAs?

    Subsequent studies came to question this association between DAAs and HCC recurrence, reporting no effect of DAAs on HCC recurrence rates. Several studies suggested that patients who achieve SVR with IFN-α-based or DAA treatments have similar HCC recurrence risk[21,22,41]. A recent multicenter retrospective study from Japan that included 338 patients found no significant difference in cumulative HCC recurrence rates in 1-, 2-, and 3-year survival (20.6%, 27.4%, and 34.6% in the IFN group vs. 19.2%, 32.3%, and 43.0% in the DAA group, P = 0.332) and overall survival (OS) rates (OS rates in one, two, and three years: 100%, 98.3%, and 96.6% in the IFN-α group vs. 100%, 98.4%, and 96.4% in the DAA group, P = 0.132). The authors found a homogenous HCC recurrence pattern between the two groups that were distinguished by similar tumor characteristics and serum AFP levels at HCC recurrence[42]. A recent study from Taiwan suggested that DAAs cannot increase the risk for HCC recurrence and tumor progression. The authors compared a DAA and an IFN-α-treated arm, and they found no difference in median recurrence-free survival (RFS) counting from either antiviral (29.3 months vs. 39.2 months, P = 0.764) or curative HCC treatment (65.8 months vs. 44.0 months, P = 0.130)[40]. Another recent case–control study showed that DAA-treated patients had similar rates of recurrence (41% vs. 35%, P = 0.7904), time to progression (12[9-16] months G1 vs. 14[8-21] months G2, P = 0.7688), and HCC pattern at recurrence [assessed with Barcelona Clinic Liver Cancer Stage (BCLC)] compared to untreated patients. However, these authors suggested that the time interval between HCC treatment and antiviral therapy can have a significant role in HCC recurrence rate, discouraging DAA initiation < 12 months after HCC cure[43]. Additionally, in a prospective study, Cabibbo et al. compared a DAA-exposed and a non-DAA-exposed group of patients and reported a similar HCC recurrence rate (HR = 0.70; 95%CI: 0.44–1.13, P = 0.15). Notably, they demonstrated that DAA-exposed patients had significantly reduced hepatic decompensation (HR = 0.32; 95%CI: 0.13–0.84, P = 0.02)[38]. In addition, Nakamura et al. reported one-, two-, and three-year HCC recurrence rates of 18.3%, 38.8%, and 55.4%, respectively, comparable to those reported before the advent of DAAs, suggesting that DAA therapy may not be associated with tumor development[24]. A systematic review, meta-analysis, and meta-regression that included 17 studies on HCC recurrence found no association between DAA therapy and HCC recurrence, after adjusting for study follow-up and age (RR = 0.62, 95%CI: 0.11–3.45, P = 0.56)[44]. Similarly, Sapena et al., in a large meta-analysis of 21 studies of HCV-related cirrhosis and HCC that included 977 DAA-treated patients and 328 DAA-unexposed patients from the ITA.LI.CA cohort as controls, observed no significant difference in recurrence rate between DAA-exposed and DAA-unexposed patients (RR = 0.64, 95%CI: 0.37-1.1; P = 0.1)[45].

    Do DAAs decrease HCV-Related HCC recurrence rates?

    Recently, several studies have supported that DAA therapy can even decrease the HCC-recurrence risk in patients who have previously undergone curative treatment. A study from Japan compared two patient cohorts with history of HCV-related HCC who were DAA-exposed or non-DAA-exposed, after matching for age, gender, and BCLC staging, and found that DAA therapy significantly decreased recurrence rate when it was performed after initial HCC therapy (one- and two- year recurrence rates of 18.1% and 25.0% in DAA vs. 21.8% and 46.5% in non-DAA, P = 0.003)[15]. Additionally, a multicenter retrospective study on Child–Pugh A class patients who fulfilled the Milan criteria reported a significantly lower recurrence rate in the DAA group compared to the non-DAA group (36.7% vs. 66.7%, HR = 0.46; 95%CI: 0.27-0.77, P = 0.003). DAA treatment was also shown to significantly improve survival rate and lower median albumin-bilirubin (ALBI) score[31]. A meta-analysis of six studies that included a total of 1105 patients exposed to DAAs versus 1912 controls who were either non-treated or treated with peg-IFN-α-based regimens, with a follow-up ranging from 1.25 to 4 years, found that DAA therapy decreased HCC recurrence by 64% compared to untreated controls (OR = 0.36, 95%CI: 0.27-0.47, P < 0.00001)[46].

    Do DAAs affect the dropout rate from the liver transplant waiting list?

    While HCV eradication after DAA treatment has been shown to improve MELD and Child-Pugh scores and lead to a delisting of almost one third of liver transplant candidates with chronic HCV without oncological complications[47,48], the effect of DAAs administration and timing on waitlisted patients with HCC history is not fully elucidated. A single center case–control study from Italy showed that the DAA-treated and control groups had similar drop-out rates due to tumor progression (8.7 vs. 4.3%, respectively, P = 0.9)[49]. Additionally, a retrospective study of 149 LT candidates with locally treated HCV-related HCC suggested that DAAs have no effect on HCC recurrence, while they can reduce the risk of delisting due to HCC progression[50]. Neutral results concerning the effect of DAA treatment on the waitlist drop-out due to tumor progression and post-LT HCC recurrence were also reported by Emamaullee et al.[51]. On the contrary, a retrospective cohort that compared DAA-treated, IFN-treated, and untreated groups of HCC patients awaiting LT showed that SVR achieved with DAAs before LT was associated with increased post-LT HCC recurrence, compared to no-treatment[52]. Undoubtedly, there is a need for optimization of DAA administration timing in HCV-related HCC patients awaiting LT in order to benefit from the positive effects of SVR on liver function preservation while avoiding any possible risk of tumor progression acceleration or recurrence that would induce a waitlist drop-out. A recent multicenter study that aimed to address this question suggested 0-3 months post-LT as the ideal time frame for DAA administration in patients with history of HCV-associated HCC[53].

    TIME ASSOCIATION BETWEEN DAA TREATMENT AND HCC RECURRENCE

    Several studies observed that there might be a time association between DAAs administration and HCC recurrence. In a large multicenter study, Singal et al. compared patients treated with DAAs to untreated controls and suggested that early tumor recurrence could be associated with the timing of DAA therapy[23]. Specifically, they reported that HCC recurred less in patients who delayed DAA treatment > 6 months after tumor complete response (CR) (HR = 0.56, 95%CI: 0.22-1.38), although this difference was not statistically significant[23]. Additionally, Warzyszyńska et al. suggested that patients with previously treated HCC may be at a higher risk of accelerated tumor relapse when receiving DAA therapy[54]. By recruiting 19 patients receiving DAAs after tumor and the non-DAA group had a recurrence rate of 42.1% and 65.6%, respectively (P = 0.058), with a recurrence time that was significantly shorter in DAA-treated patients (265 vs. 632 days after surgery, P = 0.033)[54]. In fact, several studies have reported that the time elapsing from HCC treatment to DAA exposure may significantly increase the risk of tumor relapse[20,25,32,35]. More specifically, patients treated with DAAs less than 12 months following HCC treatment are shown to exhibit increased HCC recurrence rates[32,35].

    PATHOGENIC MECHANISMS OF HCC RECURRENCE AFTER DAA TREATMENT

    Different hypotheses have been suggested regarding the underlying mechanisms of HCC recurrence following HCV treatment with DAAs that imply immunological and epigenetic mechanisms.

    The immunological surveillance theory

    Even though the exact mechanism of action remains unclear, IFN-α is known to have immune-mediated anti-proliferative properties as well as anti-angiogenic effects. DAAs act in a different manner, by dramatically suppressing viral replication from the initial days of treatment. This may lead to a phenomenon that has been characterized as dysregulation in the surveillance of the immune system[55]. It is known that HCV-infected hepatocytes produce Type I, II, and III IFNs that act on tumor, immune, and endothelial cells and may decelerate cancer genesis and progression. Recent in vitro studies have demonstrated that effective DAA treatment rapidly downregulated IFN-stimulating gene expression and Type II and III IFN production, which could affect the risk of developing HCC occurrence or recurrence after therapy[56]. Natural killer (NK) cells are crucial components in microenvironment tumor surveillance and have a direct anti-tumor immune-mediated cytotoxic effect[57]. Chronic HCV infection is known to modify NK cells phenotype by causing them to produce fewer antiviral cytokines and exhibit an increased cytotoxic function. Several studies have suggested that DAAs alter NK cells’ functional phenotype rapidly after administration by downregulating NK cell cytotoxicity receptors and impairing their cytotoxic anti-tumor function, which potentially enables hepatocarcinogenesis[58-60]. Moreover, DAA treatment modifies mucosal-associated invariant T (MAIT) liver cell function while inducing changes in macrophage-derived cytokines. MAIT cells are activated in chronic HCV infection and significantly decrease in situations of liver inflammation and fibrosis[61]. A recent report shows that DAA induced HCV eradication does not restore MAIT cell function, which further supports the persistent immune dysfunction after DAA treatment[62].

    Epigenetic factors

    Few epigenetic factors have been studied in the context of HCC development after DAA therapy. Highly activated neo-angiogenesis is demonstrated to play a significant role in hepatic tumor growth. Angiopoietin-2 and vascular endothelial growth factor, as angiogenesis pathway markers, can be present in higher concentrations in liver tissue of DAA-treated patients and are related to HCC occurrence and recurrence[63,64]. miR-122 is a serum biomarker that is involved in HCV replication and its loss has been associated with HCC development. Santangelo et al. observed that DAA-treated patients have a decreased level of liver-specific miR-122, which is potentially linked to a higher HCC recurrence risk[65]. Additionally, a recent study that explored the effect of sofosbuvir and daclatasvir in HCC-derived cell lines demonstrated possible off-target effects that ultimately lead to modulation of tumor cell proliferation and migration. These findings suggest that transcriptomic and epigenetic changes may justify reported cases of more aggressive recurrence[66]. Sofosbuvir, which is used as a backbone in DAA-based therapies, has also been shown to increase epidermal growth factor receptor expression and phosphorylation, leading to pro-survival reprogramming of hepatoma cells[67].

    PREDICTORS OF HCC RECURRENCE

    Many of the studies addressing HCC recurrence post DAAs aim to report predictors of that event [Table 3]. Nakamura et al. suggested that multiple HCC nodules at the first HCC treatment, history of multiple treatments for HCC, and Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) ≥ 10% at the initiation of DAA therapy are positively associated with the risk HCC recurrent development after DAAs[24]. AFP level before DAA therapy (P = 0.0047) and the number of curative procedures for HCC before antiviral treatment (P < 0.0001) were also found to be associated with HCC recurrence in another large multicenter prospective study from Japan[37]. Interestingly, Mashiba et al. found in univariate analysis that duration from last HCC treatment to starting antiviral therapy was significantly associated with early recurrence of HCC in patients who achieved SVR, irrespectively of the type of antiviral therapy (IFN or DAA therapy)[22]. This finding was confirmed in a multivariate analysis[22]. In addition, El Kassas et al. demonstrated that HCC recurrence was associated with DAA exposure with an incidence rate ratio of 3.83 (95%CI: 2.02-7.25), while Child-Pugh score and the presence of gastroesophageal varices were predictors of that recurrence[21].

    Table 3

    Predictors of HCC recurrence in DAA treated patients

    Author, yearPredictors
    Cabibbo et al., 2017[34]Main tumor size, history of prior HCC recurrence
    Nagata et al., 2017[14]Pre-treatment AFP, post-treatment WFA + M2BP
    El Kassas et al., 2018[21]Exposure to DAAs, Child-Pugh score, presence of gastroesophageal varices
    Ogawa et al., 2018[35]Higher baseline AFP level, cirrhosis, time from previous HCC treatment to initiation of DAA, number of HCC nodules, therapeutic procedures
    Mashiba et al., 2018[22]AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, number of treatments
    Lleo et al., 2019[36]Lack of SVR, AFP > 10 ng/dL
    Nakamura et al., 2019[24]Multiple tumors at the first HCC treatment, a history of multiple treatments for HCC, AFP-L3 ≥ 10% at the initiation of DAA therapy
    Nakano et al., 2019[37]AFP level before DAA therapy, number of curative treatments for HCC before DAA therapy
    Zou et al., 2019[25]Non-curative HCC treatment, shorter duration between HCC treatment completion and DAA initiation, no SVR
    Cabibbo et al., 2019[38]Lack of SVR
    Sangiovanni et al., 2020[39]History of alcohol abuse, history of HCC recurrence
    Watanabe et al., 2021[29]Male gender, no SVR, history of more > 2 treatments for HCC
    Tani et al., 2021[30]Palliative treatment prior to DAA treatment, AFP at SVR
    Ochi et al., 2021[31]DAA, tumor size
    Ahn et al., 2021[32]Last HCC treatment durability (< 12 months)
    Chi et al., 2021[40]no SVR
    Sapena et al., 2022[45]AFP logarithm, HCC recurrence history pre-DAA initiation, performance status, tumor burden pre-HCC treatment
    Ogawa et al., 2022[27]For late recurrence: cirrhosis, number of HCC nodules (≥ 2), previous palliative HCC treatment; For early recurrence: AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC CR to DAA initiation (< 1 year), number of HCC treatments necessary to achieve CR (≥ 2)

    POST HCC DAA TREATMENT AND IMPACT ON OVERALL SURVIVAL

    Although the hypothetical association between DAAs and HCC recurrence has been extensively studied, only a few studies aimed to assess their impact on overall survival. To investigate the predictors of HCC recurrence and the causes of mortality in this group of patients, more case–control studies recruiting untreated HCV patients as control arms would be necessary, raising major ethical objections. In a prospective observational study that recruited 328 patients with HCV-related cirrhosis and early-stage HCC who had completely responded to curative treatments, Cabibbo et al. demonstrated that hepatic decompensation was a stronger driver of mortality than HCC recurrence. Using a time-dependent Cox regression analysis, patients who had hepatic decompensation within 12 months of follow-up as first event had about 7.5 times higher risk of mortality (HR = 7.52, 95%CI: 1.23-13.48, P < 0.0001) in comparison with patients having early HCC recurrence as a first event that had only 2.5 (HR = 2.50, 95%CI: 1.23-5.05, P = 0.0110)[68]. The authors concluded that DAAs could improve overall survival (OS) of patients with HCV-related cirrhosis and successfully treated HCC by long-term preservation of liver function[68]. Additionally, a large multicenter cohort that included 797 patients with HCV-related HCC [304 (38.3%) DAA-treated vs. 489 (61.7%) untreated] from 31 hospitals demonstrated that patients that achieved SVR after DAA therapy had a significantly reduced death risk (HR = 0.29, 95%CI: 0.18-0.47). Interestingly, the same association was not present in DAA-treated patients without an SVR. The one- and two-year risk of mortality for DAA treated patients was 5.5% and 11.8%, respectively[23]. Kamp et al. retrospectively analyzed data from 969 HCC patients and reported similar results[69]. Specifically, patients who received DAAs had a significantly higher OS in comparison to the non-DAA group (71.8 months vs. 11.6 months, P <  0.0001), while patients who achieved SVR at 12 weeks (SVR12) after DAA treatment also significantly improved their survival compared to the ones who received DAAs but without reaching SVR12 (75.6 months vs. 26.7 months, P  <  0.0001)[69]. Recently, Ochi et al. reported a higher survival rate at 48 months of follow-up in a DAA-treated group compared to the untreated group (91.0% vs. 68.7%, HR = 0.33, 95%CI: 0.13-0.84, P = 0.021)[31]. The above-mentioned results point to the direction that DAAs potentially improve the overall survival of HCV-related HCC patients.

    HCC SURVEILLANCE IN PATIENTS WITH A HISTORY OF HCC AND DAA-INDUCED SVR

    According to the recommendations of the European Association for the Study of the Liver (EASL), patients with complete response to HCC therapy should be treated for their HCV infection according to the same general recommendations as for patients without HCC. Furthermore, as patients with complete response to HCC therapy who achieve SVR have a continued risk of HCC recurrence, indefinite post SVR HCC surveillance is recommended[70]. Similarly, the American Association for the Study of Liver Diseases (AASLD) suggested that treating HCV infection with DAAs in patients with HCC history should be performed after HCC is completely treated with no evidence of recurrence after an observation period of 3-6 months. According to the guidance statements, SVR achieved after DAA treatment lowers the risk of HCC for cirrhotic HCV patients without reducing it to zero and therefore cirrhotic patients with treated HCV should continue to undergo surveillance. Surveillance should be performed with liver ultrasound (US) with or without AFP every six months[71]. On the contrary, the Asian Pacific Association for the Liver (APASL) clinical practice guidelines that were published in 2017 state that, in HCV-related HCC patients having received curative therapy, IFN-α-based regimes may decrease recurrence risk and improve survival rates, while there is no such evidence for DAA-induced SVR. These authors recommend surveillance at four-month intervals for HCC by US and tumor markers for SVR patients with previous HCC history[72,73].

    CONCLUSIONS

    Undoubtedly, the emergence of DAAs has revolutionized anti-HCV treatment, with more than 95% of patients achieving SVR regardless of genotype and liver disease severity, from low liver fibrosis stages to decompensated cirrhosis. This will eventually lead to large SVR cohorts of aging patients under surveillance programs with a persisting important risk of HCC development, despite viral eradication. While these treatments were initially expected to improve outcomes by decreasing both the development of de novo and recurrent liver malignancy, the first studies on the subject reported conflicting results. Nevertheless, recent studies and meta-analyses point to the direction that DAAs ultimately do not increase HCV-related HCC recurrence risk, leading to the conclusion that, to properly assess the impact of DAA treatment on HCC recurrence, methodological issues of previous published studies should be taken into account. Firstly, study design heterogeneity should be considered. Some studies are retrospective, some have a control group that could be untreated or IFN-treated, and some lack a control group. Simultaneously, baseline patient and tumor characteristics can differ among studies. Additionally, studies are characterized by heterogeneity when it comes to type and number of curative treatments, history of prior HCC recurrences, definition of HCC recurrence (in temporal and locoregional terms), and follow-up schedule. Radiological assessment of complete response after curative HCC treatment or HCC recurrence can also be a methodological issue as it may be influenced by subjective observations. Another important fact is the lack of randomized control trials (RCTs) given the fact that DAAs represent nowadays the standard of care for HCV infected patients, and therefore these RCTs would be considered unethical. Ultimately, the poor understanding of the pathogenic mechanisms of HCC recurrence after DAA treatment contributes to the uncertainty of the issue. Conversely, it is known that DAA treatment and subsequent SVR reduces the risk of hepatic decompensation, which could eventually improve the overall survival. In fact, a recent study showed that hepatic decompensation is a stronger driver of mortality than HCC recurrence. In addition, the improvement of liver function could render early HCC curative treatments more feasible, resulting in prolonging overall survival. In conclusion, based on the lack of compelling evidence of negative effects of DAAs in patients with previously treated HCC and the benefit of preserving liver function on overall survival, the use of DAAs in these patients should be encouraged.

    DECLARATIONS

    Authors’ Contributions

    Write and finalize the manuscript and accepte the final version: Tagkou NM, Goossens N, Negro F

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship

    None.

    Conflicts of interest

    All authors declared that there are no conflicts of interest.

    Ethical approval and consent to participate

    Not applicable.

    Consent for publication

    Not applicable.

    Copyright

    © The Author(s) 2022.

    References

    • 1. Villanueva A. Hepatocellular carcinoma. N Engl J Med 2019;380:1450-62.

      DOIPubMed
    • 2. Organisation WH. Projections of mortality and causes of death, 2016 to 2060.

    • 3. Jemal A, Ward EM, Johnson CJ, et al. Annual report to the nation on the status of cancer, 1975-2014, featuring survival. J Natl Cancer Inst 2017:109.

      DOIPubMed PMC
    • 4. Cabibbo G, Celsa C, Cammà C, Craxì A. Should we cure hepatitis C virus in patients with hepatocellular carcinoma while treating cancer? Liver Int 2018;38:2108-16.

      DOIPubMed
    • 5. Blach S, Terrault NA, Tacke F, et al. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study. The Lancet Gastroenterology & Hepatology 2022;7:396-415.

      DOIPubMed
    • 6. Tampaki M, Papatheodoridis GV, Cholongitas E. Intrahepatic recurrence of hepatocellular carcinoma after resection: an update. Clin J Gastroenterol 2021;14:699-713.

      DOIPubMed
    • 7. Sahakyan Y, Lee-Kim V, Bremner KE, Bielecki JM, Krahn MD. Impact of direct-acting antiviral regimens on mortality and morbidity outcomes in patients with chronic hepatitis c: Systematic review and meta-analysis. J Viral Hepat 2021;28:739-54.

      DOIPubMed
    • 8. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158:329-37.

      DOIPubMed
    • 9. Spârchez Z, Mocan T. Hepatocellular carcinoma occurrence and recurrence after antiviral treatment in HCV-related cirrhosis. Are outcomes different after direct antiviral agents? J Gastrointestin Liver Dis 2017;26:403-10.

      DOIPubMed
    • 10. Shiha G, Mousa N, Soliman R, Nnh Mikhail N, Adel Elbasiony M, Khattab M. Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: a prospective study. J Viral Hepat 2020;27:671-9.

      DOIPubMed
    • 11. AASLD-IDSA HCV Guidance Panel. Hepatitis C guidance 2018 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. Clin Infect Dis 2018;67:1477-92.

      DOIPubMed PMC
    • 12. Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016;65:719-26.

      DOIPubMed
    • 13. Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016;65:727-33.

      DOIPubMed
    • 14. Nagata H, Nakagawa M, Asahina Y, et al. Ochanomizu Liver Conference Study Group. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol 2017;67:933-9.

      DOIPubMed
    • 15. Ikeda K, Kawamura Y, Kobayashi M, et al. Direct-acting antivirals decreased tumor recurrence after initial treatment of hepatitis C virus-related hepatocellular carcinoma. Dig Dis Sci 2017;62:2932-42.

      DOIPubMed
    • 16. Celsa C, Stornello C, Giuffrida P, et al. Direct-acting antiviral agents and risk of Hepatocellular carcinoma: critical appraisal of the evidence. Ann Hepatol 2022;27 Suppl 1:100568.

      DOIPubMed
    • 17. Cabibbo G, Petta S, Barbàra M, et al. ITA. LI.CA study group. A meta-analysis of single HCV-untreated arm of studies evaluating outcomes after curative treatments of HCV-related hepatocellular carcinoma. Liver Int 2017;37:1157-66.

      DOIPubMed
    • 18. Gao X, Zhan M, Wang L, Ding Y, Niu J. Timing of DAA initiation after curative treatment and its relationship with the recurrence of HCV-related HCC. J Hepatocell Carcinoma 2020;7:347-60.

      DOIPubMed PMC
    • 19. Yamamoto Y, Ikoma H, Morimura R, et al. Optimal duration of the early and late recurrence of hepatocellular carcinoma after hepatectomy. World J Gastroenterol 2015;21:1207-15.

      DOIPubMed PMC
    • 20. Kolly P, Waidmann O, Vermehren J, et al. Hepatocellular carcinoma recurrence after direct antiviral agent treatment: a European multicentre study. J Hepatol 2017;67:876-8.

      DOIPubMed
    • 21. El Kassas M, Funk AL, Salaheldin M, et al. Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C-infected Egyptian cohort: a comparative analysis. J Viral Hepat 2018;25:623-30.

      DOIPubMed
    • 22. Mashiba T, Joko K, Kurosaki M, et al. Does interferon-free direct-acting antiviral therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC? PLoS One 2018;13:e0194704.

      DOIPubMed PMC
    • 23. Singal AG, Rich NE, Mehta N, et al. Direct-acting antiviral therapy for hepatitis c virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma. Gastroenterology 2019;157:1253-1263.e2.

      DOIPubMed PMC
    • 24. Nakamura S, Nouso K, Okada H, et al. Hepatocellular carcinoma recurrence in HCV patients treated with direct-acting antivirals after curative treatment. Hepatoma Res 2019;5:16.

      DOI
    • 25. Zou WY, Choi K, Kramer JR, et al. Risk of hepatocellular cancer recurrence in hepatitis C virus + patients treated with direct-acting antiviral agents. Dig Dis Sci 2019;64:3328-36.

      DOIPubMed PMC
    • 26. Kuo YH, Wang JH, Chang KC, et al. The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment. Invest New Drugs 2020;38:202-10.

      DOIPubMed
    • 27. Ogawa E, Nakamuta M, Furusyo N, et al. Kyushu university liver disease study (KULDS) group. Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals. J Gastroenterol Hepatol 2022;37:190-9.

      DOIPubMed
    • 28. Elbaz T, Waked I, El-Akel W, et al. Impact of successful HCV treatment using direct acting antivirals on recurrence of well ablated hepatocellular carcinoma. Expert Rev Anti Infect Ther 2022;20:307-14.

      DOIPubMed
    • 29. Watanabe T, Tokumoto Y, Joko K, et al. AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy. BMC Cancer 2021;21:699.

      DOIPubMed PMC
    • 30. Tani J, Senoh T, Moriya A, et al. Long-term outcomes and evaluation of hepatocellular carcinoma recurrence after hepatitis C virus eradication by direct-acting antiviral treatment: all kagawa liver disease group (AKLDG) study. Cancers (Basel) 2021;13:2257.

      DOIPubMed PMC
    • 31. Ochi H, Hiraoka A, Hirooka M, et al. Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria. J Gastroenterol 2021;56:90-100.

      DOIPubMed PMC
    • 32. Ahn YH, Lee H, Kim DY, et al. Independent risk factors for hepatocellular carcinoma recurrence after direct-acting antiviral therapy in patients with chronic hepatitis C. Gut Liver 2021;15:410-9.

      DOIPubMed PMC
    • 33. collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Electronic address: stanislas.pol@aphp.fr. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J Hepatol 2016;65:734-40.

      DOI
    • 34. Cabibbo G, Petta S, Calvaruso V, et al. Rete Sicilia Selezione Terapia - HCV (RESIST-HCV). Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? Aliment Pharmacol Ther 2017;46:688-95.

      DOIPubMed
    • 35. Ogawa E, Furusyo N, Nomura H, et al. Kyushu University Liver Disease Study (KULDS) Group. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment. Aliment Pharmacol Ther 2018;47:104-13.

      DOIPubMed
    • 36. Lleo A, Aglitti A, Aghemo A, Maisonneuve P, Bruno S, Persico M. collaborators. Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals. Dig Liver Dis 2019;51:310-7.

      DOIPubMed
    • 37. Nakano M, Koga H, Ide T, et al. Predictors of hepatocellular carcinoma recurrence associated with the use of direct-acting antiviral agent therapy for hepatitis C virus after curative treatment: a prospective multicenter cohort study. Cancer Med 2019;8:2646-53.

      DOIPubMed PMC
    • 38. Cabibbo G, Celsa C, Calvaruso V, et al. Rete Sicilia Selezione Terapia – HCV (RESIST-HCV) and Italian Liver Cancer (ITA.LI.CA.) Group. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J Hepatol 2019;71:265-73.

      DOIPubMed
    • 39. Sangiovanni A, Alimenti E, Gattai R, et al. Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis. J Hepatol 2020;73:593-602.

      DOIPubMed
    • 40. Chi CT, Chen CY, Su CW, et al. Direct-acting antivirals for patients with chronic hepatitis C and hepatocellular carcinoma in Taiwan. J Microbiol Immunol Infect 2021;54:385-95.

      DOIPubMed
    • 41. Nishibatake Kinoshita M, Minami T, Tateishi R, et al. Impact of direct-acting antivirals on early recurrence of HCV-related HCC: comparison with interferon-based therapy. J Hepatol 2019;70:78-86.

      DOIPubMed
    • 42. Tahata Y, Sakamori R, Urabe A, et al. Clinical outcomes of direct-acting antiviral treatments for patients with hepatitis C after hepatocellular carcinoma are equivalent to interferon treatment. Hepatol Res 2020;50:1118-27.

      DOIPubMed
    • 43. Adhoute X, Penaranda G, Raoul JL, et al. Hepatocellular carcinoma recurrence in hepatitis C virus-related cirrhosis treated with direct-acting antivirals: a case-control study. Eur J Gastroenterol Hepatol 2018;30:368-75.

      DOIPubMed
    • 44. Waziry R, Hajarizadeh B, Grebely J, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol 2017;67:1204-12.

      DOIPubMed
    • 45. Sapena V, Enea M, Torres F, et al. Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis. Gut 2022;71:593-604.

      DOIPubMed
    • 46. Lui FH, Moosvi Z, Patel A, et al. Decreased risk of hepatocellular carcinoma recurrence with direct-acting antivirals compared with no treatment for hepatitis C: a meta-analysis. Ann Gastroenterol 2020;33:293-8.

      DOIPubMed PMC
    • 47. Belli LS, Berenguer M, Cortesi PA, et al. European Liver and Intestine Association (ELITA). Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study. J Hepatol 2016;65:524-31.

      DOIPubMed
    • 48. Ferrarese A, Germani G, Gambato M, et al. Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: a single-center study. World J Gastroenterol 2018;24:4403-11.

      DOIPubMed PMC
    • 49. Zanetto A, Shalaby S, Vitale A, et al. Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals. Liver Transpl 2017;23:1103-12.

      DOIPubMed
    • 50. Huang AC, Mehta N, Dodge JL, Yao FY, Terrault NA. Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. Hepatology 2018;68:449-61.

      DOIPubMed PMC
    • 51. Emamaullee JA, Bral M, Meeberg G, et al. HCV eradication with direct-acting antivirals does not impact HCC progression on the waiting list or HCC recurrence after liver transplantation. Can J Gastroenterol Hepatol 2019;2019:2509059.

      DOIPubMed PMC
    • 52. Lim N, Singh D, Jackson S, Lake JR. Recurrence of hepatocellular carcinoma in hepatitis C virus (HCV) liver transplant recipients treated with pretransplant direct-acting antiviral (DAA) therapy. Gastrointest Tumors 2020;7:134-43.

      DOIPubMed PMC
    • 53. Turgeon MK, Shah SA, Delman AM, et al. Optimal timing of administration of direct-acting antivirals for patients with hepatitis C-associated hepatocellular carcinoma undergoing liver transplantation. Ann Surg 2021;274:613-20.

      DOIPubMed PMC
    • 54. Warzyszyńska K, Jonas M, Wasiak D, Kosieradzki M, Małkowski P. Accelerated hepatocellular carcinoma recurrence rate after postoperative direct-acting antivirals treatment - preliminary report. Clin Exp Hepatol 2017;3:194-7.

      DOIPubMed PMC
    • 55. Reig M, Boix L, Mariño Z, Torres F, Forns X, Bruix J. Liver cancer emergence associated with antiviral treatment: an immune surveillance failure? Semin Liver Dis 2017;37:109-18.

      DOIPubMed
    • 56. Sung PS, Shin EC. Immunological mechanisms for hepatocellular carcinoma risk after direct-acting antiviral treatment of hepatitis C virus infection. J Clin Med 2021;10:221.

      DOIPubMed PMC
    • 57. Sung PS, Jang JW. Natural killer cell dysfunction in hepatocellular carcinoma: pathogenesis and clinical implications. Int J Mol Sci 2018;19:3648.

      DOIPubMed PMC
    • 58. Easom NJW, Stegmann KA, Swadling L, et al. IL-15 Overcomes hepatocellular carcinoma-induced NK cell dysfunction. Front Immunol 2018;9:1009.

      DOIPubMed PMC
    • 59. Chu PS, Nakamoto N, Taniki N, et al. On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C. PLoS One 2017;12:e0179096.

      DOIPubMed PMC
    • 60. Golden-Mason L, McMahan RH, Kriss MS, et al. Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment. Hepatol Commun 2018;2:364-75.

      DOIPubMed PMC
    • 61. Bolte FJ, O'Keefe AC, Webb LM, et al. Intra-Hepatic depletion of mucosal-associated invariant T cells in hepatitis C virus-induced liver inflammation. Gastroenterology 2017;153:1392-1403.e2.

      DOIPubMed PMC
    • 62. Hengst J, Strunz B, Deterding K, et al. Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy. Eur J Immunol 2016;46:2204-10.

      DOIPubMed
    • 63. Villani R, Facciorusso A, Bellanti F, et al. DAAs rapidly reduce inflammation but increase serum vegf level: a rationale for tumor risk during anti-HCV treatment. PLoS One 2016;11:e0167934.

      DOIPubMed PMC
    • 64. Faillaci F, Marzi L, Critelli R, et al. Liver angiopoietin-2 Is a key predictor of de novo or recurrent hepatocellular cancer after hepatitis C virus direct-acting antivirals. Hepatology 2018;68:1010-24.

      DOIPubMed PMC
    • 65. Santangelo L, Bordoni V, Montaldo C, et al. Hepatitis C virus direct-acting antivirals therapy impacts on extracellular vesicles microRNAs content and on their immunomodulating properties. Liver Int 2018;38:1741-50.

      DOIPubMed
    • 66. Giovannini C, Fornari F, Indio V, et al. Direct antiviral treatments for hepatitis C virus have off-target effects of oncologic relevance in hepatocellular carcinoma. Cancers (Basel) 2020;12:2674.

      DOIPubMed PMC
    • 67. Bojkova D, Westhaus S, Costa R, et al. Sofosbuvir activates EGFR-dependent pathways in hepatoma cells with implications for liver-related pathological processes. Cells 2020;9:1003.

      DOIPubMed PMC
    • 68. Cabibbo G, Petta S, Barbara M, et al. Italian Liver Cancer (ITA.LI.CA) group. Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma. J Hepatol 2017;67:65-71.

      DOIPubMed
    • 69. Kamp WM, Sellers CM, Stein S, Lim JK, Kim HS. Impact of direct acting antivirals on survival in patients with chronic hepatitis c and hepatocellular carcinoma. Sci Rep 2019;9:17081.

      DOIPubMed PMC
    • 70. Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu., Clinical Practice Guidelines Panel: Chair:., EASL Governing Board representative:., Panel members:. EASL recommendations on treatment of hepatitis C: final update of the series. J Hepatol 2020;73:1170-218.

      DOI
    • 71. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases. Hepatology 2018;68:723-50.

      DOIPubMed
    • 72. Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11:317-70.

      DOIPubMed PMC
    • 73. Kanda T, Lau GKK, Wei L, et al. APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation. Hepatol Int 2019;13:649-61.

      DOIPubMed PMC

    Cite This Article

    Tagkou NM, Goossens N, Negro F. Impact of direct-acting antivirals on the recurrence of hepatocellular carcinoma in chronic hepatitis C. Hepatoma Res 2022;8:28. http://dx.doi.org/10.20517/2394-5079.2022.08

    Views
    718
    Downloads
    221
    Citations
     0
    Comments
    2

    1

    Comments

    Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.

    • Kiesha Allen   
      My first time meeting with a Psychic medium and I have to say, it's really worth it. It had been 6months since my husband left me without saying anything.All thanks to Dr Adoda I was able to connect with my husband again with his powerful reunion love spell and now he loves me more than he used to. Eternally grateful with The Great Dr Adoda! I highly recommend,  His contact details adodalovespelltemple440ATgmail . com 

      24 Jun 2022 23:57

       0

    • Theresa May   
      You can think of a herpes outbreak not as something disgusting and shameful, but instead as a signal to take great care of yourself.   I had all the signs of  STD Virus but I was not too sure as to which one. I did a lot of online research and I WAS scared myself for a whole week before going to see the nurse. She took one look at my genital part and first said that it could just be the anatomy of my body, then she said it looked like genital warts and that I MAY have herpes. I was devastated. She gave me some medicine for the herpes and some cream for the warts. I was also tested for every single STD including herpes. I went home and cried searching the web for all sorts of cures for herpes and awaiting my results. I saw a post whereby Dr. Razor cured Herpes and other diseases, I copied his contacts after visiting his website 
      https://herbalistrazorherb.wixsite.com/drrazorherbalhome and decided to reach him for help. The next day my test result was ready and I confirmed  Herpes positive. I told Dr. Razor about my health problems and he assured me of a cure. He prepared his herbal medicine and sent it to me. I took it for 18 days . Before the completion of the 18 days in which I completed the dose, the Blisters and Warts that were on my body were cleared. I went back for a check-up and I was told I'm free from the virus. Dr. Razor cures all types of diseases and viruses with the help of his herbal medicine. You can reach Dr. Razor via his email address on (drrazorherbalhome@gmail.com)  Tel/Whatsapp him via +2349065420442

      17 Jun 2022 23:17

       0

    Article Access Statistics

    • Viewed: 718
    • Downloaded: 221
    • Cited: Crossref0

    Share This Article

    See Updates

    © 2016-2022 OAE Publishing Inc., except certain content provided by third parties