Clin Mol Hepatol > Volume 30(3); 2024 > Article
Huang, Awad, Gal-Tanamy, and Yu: Unmet needs in the post-direct-acting antivirals era: The risk and molecular mechanisms of hepatocellular carcinoma after hepatitis C virus eradication

ABSTRACT

Hepatitis C virus (HCV) infection is one of the major etiologies of hepatocellular carcinoma (HCC) with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in chronic hepatitis C (CHC) patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the direct-acting antiviral (DAA) era and might be due to preexisting inflammatory and fibrotic liver backgrounds, immune dysregulation between host and virus interactions, as well as host epigenetic scars, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication in CHC patients.

INTRODUCTION

An estimated 60 million people are infected with hepatitis C virus (HCV). Chronic hepatitis C (CHC) is a global public health threat since 10–20% will develop liver complications including decompensated cirrhosis and hepatocellular carcinoma (HCC) [1]. HCC is the fifth most common cancer and the second most common cause of cancer death with approximately 30% of HCC being due to HCV infection [2]. The endorsement of the World Health Assembly and declaration of viral hepatitis elimination by 2030 set by the World Health Organization have facilitated HCV management in recent years. With the great innovation of direct-acting antivirals (DAAs), nearly 10 million CHC patients were treated with DAAs between 2015 and 2019 [3]. It is anticipated that a significantly increased number of CHC patients will be in post-curative status in the following decades, and how to deal with such post-sustained virological response (SVR) CHC patients is of great importance.
HCV eradication by antivirals greatly reduces the risk of HCC with up to 70% of HCC risk being reduced either by interferon-based regimens [4] or DAAs [5]. Nevertheless, HCC is still found in CHC patients who have achieved SVR. The annual incidence of HCC after HCV eradication ranges from 0.6% to 4.9% [6], of which the risk did not differ between those who received interferon-based regimens or DAAs after adjusting potential confounders [7]. However, unlike in the interferon era when more elderly patients with advanced liver disease were relatively contraindicated for antivirals, more CHC patients who possess the two HCC risk factors have been cured by DAAs [7]. As a consequence, the proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the DAA era; for example, in comparison to HCV-viremic HCC and non-HCV HCC, the percentage of post-SVR HCC increased from 3% between 2009 and 2012 to 16% between 2017 and 2019 in a Japanese study [8]. Taken collectively, it is critical to address the topic of post-SVR HCC due to the increasing health burden year-by-year. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication.

SCREENING TARGETS AND HCC SURVEILLANCE STRATEGIES

The recommendation for the HCC surveillance target population is based on cost-effectiveness analysis. Screening the population with an annual incidence of 1.5% or greater has been generally acceptable in the past [9]. A recent study has shown the incremental cost-effectiveness ratio would be >50,000 USD per quality-adjusted life-year, a traditional willingness-to-pay threshold, if the incidence is less than 1.32% [10]. Another study took the costs of surveillance harm into consideration by simulating 1 million patients with compensated cirrhosis. Biannual surveillance with ultrasonography plus alpha-fetoprotein (AFP) would be cost-effective for an HCC incidence rate >0.4% provided by surveillance adherence >19.5% if the willingness-to-pay threshold was set at USD 100,000 [11]. It should be noted that the cost-effectiveness analyses were based on the Markov model, but a prospective interventional study is lacking; furthermore, the analyses did not consider benefits or costs of emerging HCC treatment modalities as well. Importantly, the willingness-to-pay threshold is largely dependent on the support of the healthcare system, which tends to vary among regions. To this end, it is difficult to make a conclusion about defining the best candidates for post-SVR surveillance if the decision merely relies on cost-effective judgments.
All international societies agree that cirrhotic patients should receive HCC surveillance, although different recommendations are being suggested according to different regional consensus (Table 1) [6,12-15]. The Asian Pacific Association for the Study of the Liver (APASL) recommends screening all SVR patients with sonography and tumor markers, including AFP, protein induced by vitamin K absence or antagonist-II (PIVKA-II) and lectin-reactive AFP (AFP-L3). For patients with fibrotic stage 0–2, surveillance should be performed every 6 months for the first two years, then annually. For patients with fibrotic stages 3–4, surveillance should be performed every 6 months. The European Association for the Study of the Liver (EASL) recommends screening patients with fibrotic stages 3–4 every 6 months. EASL does not recommend using tumor markers as the screening tool due to potential false positivity. By contrast, the recent American Association for the Study of Liver Diseases guideline suggests screening cirrhotic patients every 6 months by sonography in addition to the tumor marker, AFP. The Taiwan Association for the Study of the Liver (TASL) has more stringent recommendations, which suggest screening for fibrotic stage 0–1 (F0–1) with HCC risk factors or fibrotic stage 2 every 6–12 months and fibrotic stage 3–4 every 3–6 months [6,12-15].
A controversy exists about whether patients with F3 could be discharged [10] or should receive regular post-SVR HCC surveillance since fibrosis regression after HCV eradication would also decrease HCC risk [16]. A meta-analysis showed that the incidence of HCC after HCV eradication by DAAs was 2.99 per 100 person-years and 0.47 per 100 person-years in cirrhotic and non-cirrhotic patients, respectively. For patients with F3, the incidence of HCC was 0.63 per 100 person-years. Based on the relatively low incidence of HCC, the authors concluded that screening HCC for F3 patients was not warranted [17]. Notably, the definition of each fibrotic stage was not universal across studies and misclassification would exist. APASL did not mention the definition of each fibrotic stage, and only EASL defined F3 by histology or liver stiffness measurement (transient elastography 10–13 kPa, Aixplorer 9–13 kPa or Acoustic Radiation Force Impulse 1.6–2.17 m/s) [18]. Accordingly, the management of SVR patients with advanced fibrosis should be individualized in terms of local healthcare policies.
For patients with mild fibrosis, those with comorbidities or ongoing risk behaviors (alcohol use, diabetes mellitus [DM], or obesity) shall be kept for HCC surveillance [12]. DM is well-recognized as the oncogenic factor of HCC through the mechanisms of the hyperinsulinemia-related PI3K/AKT/mTOR-signaling pathway, oxidative stress and chronic inflammation [19]. Pre-DM status has even been reported to carry a higher risk of HCC than normoglycemic status in SVR patients with mild fibrosis [20]. Meanwhile, metabolic syndrome (MS) has been shown to increase HCC risk in SVR patients with advanced fibrosis. Patients with MS, in particular those with DM, had a 3.03-fold higher risk of HCC compared to those without MS [21]. As increased body weight and hepatic steatosis have been reported after HCV eradication [22], the concurrence of steatotic liver disease should be incorporated with HCV infection with respect to holistic care in the post-SVR era [23] since it might be an independent risk factor for HCC after HCV eradication [24,25].

HOW LONG SHOULD POST-SVR HCC SURVEILLANCE BE MAINTAINED?

A study using a microsimulation model suggested that rather than lifelong monitoring, screening for post-SVR HCC is cost-effective up to age 70 in those with cirrhosis and up to age 60 in those with stable advanced fibrosis [26]. The aforementioned meta-analysis indicated a pooled HCC incidence after SVR in patients with cirrhosis was very high (2.99/100 person-years) but would decline as time went by after HCV eradication [17]. For example, the incidence of HCC was 6.17% for studies with a follow-up period less than 1 year and decreased to 1.83% for studies with a follow-up period greater than 3 years. Notably, HCC risk remains and persists up to decades after HCV eradication [27,28]. All three regional guidelines suggest post-SVR HCC surveillance should be maintained indefinitely for the recommended target populations [6,12,13].

RISK FACTORS AND PREDICTORS OF POST-SVR HCC

Plenty of risk factors or surrogate markers have been identified to predict post-SVR HCC [15]. As mentioned earlier, liver cirrhosis per se is the major risk factor predictive of post-SVR HCC. Liver fibrosis would augment after HCV eradication, and post-treatment liver fibrotic change could be more accurate than the pre-treatment status in predicting HCC [16]. Of the non-cirrhotic patients, several surrogate markers/predictors have been reported, which could be briefly divided into fibrosis-related (age, platelet count, aspartate aminotransferase [AST] to platelet ratio index [APRI], fibrosis-4 index [FIB-4], AST/alanine aminotransferase [ALT] ratio, albumin) or non-fibrosis-related (DM, HCV genotype 3, AFP and gamma-glutamyl transferase level) [20,27-33].
Developing an HCC prediction model by weighing and combining individual risk factors may help to promote risk stratification (Table 2). A web-based, model-guided strategy has been developed to facilitate HCC screening, of which age, platelet count, AST/ALT ratio, and albumin level were the four major determinants [33]. A dynamic transient elastography-based model has also been created to identify very low-risk patients [34], which helps to avoid unnecessary surveillance. An algorithm that combines age, liver stiffness measurement, alcohol consumption, albumin, and AFP in SVR patients with advanced liver chronic disease successfully stratified HCC risk [35], while an artificial intelligence-based prediction model using the recurrent neural network of age, sex, race, HCV genotype, and 24 laboratory tests has proven to be more accurate than using the traditional regression model [36]. A decision-tree algorithm combining gene score (TAS1R3, FOSL1, and ABCA3) and FIB-4 has also been created to predict post-SVR HCC [37]. Nevertheless, regarding all these contributions to the field, the “black box” of artificial intelligence-based study outcomes awaits further validation in clinical practice.

HCC RECURRENCE AFTER ACHIEVING SVR

Unlike CHC patients who received interferon-based therapy, an increased HCC recurrence risk was postulated in the early era of DAAs [38]. A large-scale study did not suggest a higher HCC recurrence rate in DAA-treated patients compared to those untreated [39]. Following this, pooled analysis also did not reveal a higher HCC recurrence risk [7,40]. Owing to the heterogeneity of patient characteristics and varying follow-up periods among published papers, Sapena et al. [41] conducted an individual patient data meta-analysis from 21 studies and found that the HCC recurrence rate did not differ between DAA-exposed (14.75 per 100 person-years) and DAA-unexposed (23.21 per 100 person-years) patients after a median follow-up period of 15 months. The result highlights the fact that the recurrence rate remained high even after HCV eradication, and CHC patients with curative HCC should receive close follow-up after achieving SVR. APASL recommended following SVR patients with HCC history every 4 months [6].

GENETIC POLYMORPHISM AND SOMATIC MUTATION SIGNATURES POST SVR

HCC is a multifactorial disease that is the result of genetic and epigenetic alterations, followed by the process of selection. Recent extensive sequencing of liver cancer samples identified genomic signatures and driver genes associated with HCC [42-47]. However, the genomic profile of liver genomes after SVR is currently poorly defined. A lower frequency of mutated ARID genes in HCV-SVR as compared to HCV-positive tumors was found [48]; mutations in this gene are specifically induced in HCV-related HCC [49]. In contrast, mutations in the KEAP1 and PREX2 genes were more frequently identified in HCV-SVR samples as compared to HCV-positive samples [48], and were previously reported in HCC [50]. We have summarized the mechanisms of post-SVR HCC in Table 3. These mutations result in resistance to oxidative stress while inducing metabolic transformation of cancer cells [51], and therefore, could be valid therapeutic and prognostic markers for HCC post-curation.
Recent findings show significant differences between HCV-related HCC following treatment with DAAs vs. IFN. In SVR patients, TP53 mutations as well as genomic abnormalities were significantly more frequent in DAA-treated patients as compared to IFN-treated patients [48], suggesting that mutations in TP53 result in genomic instability after SVR by DAAs and might serve as prognostic markers for post-cured HCC specifically after DAAs treatment. In contrast, in IFN-treated patients, a higher activation of the PI3K/AKT/mTOR pathway was observed and was associated with tumor aggressiveness and invasive phenotypes [48].
In addition to somatic mutations, several recent genome-wide association studies (GWAS) have shown high prevalence of alleles in specific loci in HCV-related HCC cases, which bear potential as markers for predisposition for HCC, also after SVR. For example, the 5’ flanking region of major histocompatibility complex (MHC) class I chain-related A (MICA) (6p21.33) in the MHC of class I region [52,53] and single nucleotide polymorphisms (SNPs) in the HLA-DQB1 locus [54] are associated with HCC. In SVR patients, a variant of tolloid-like 1 (tll1) gene on chromosome 4 (rs17047200), associated with the TGFβ signaling pathway, was suggested as a marker of increased risk for HCC [55]. Recently, a genetic risk score associated with hepatic steatosis, including patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), and glucokinase regulator (GCKR), was reported to be related to HCC development in cirrhotic patients [56]. Consequently, hepatic fat might be a prognostic marker for HCC development in patients cured by DAAs and a target for chemoprevention. Polymorphism in interferonλ3 (formerly known as interleukin-28B [IL28B]) was also found to be associated with increased risk for HCC pre- and post-SVR [57].
To summarize, genetic predictors for HCC, either genetic variants or somatic mutations in cirrhotic patients, could enable stratification of cured patients for personalized HCC monitoring. Since gene expression profiles encompass both the epigenetic landscape and genomic aberrations, more multi-omics studies are required to elucidate the relationship between the two and their relative contributions to cancer progression.

EPIGENETICS AND GENE EXPRESSION SCAR POST SVR

Epigenetics is the study of heritable events occurring in the genome that determine chromatin structure but not in the DNA sequence, including post-translation histone modifications (PTMs), DNA methylation and RNA-based mechanisms, and affects transcription programs [58,59]. These modifications may shift between active and silent states, resulting in activation or repression of gene expression [60]. They depend on the activity of specific enzymes such as histone acetyltransferase (HAT), Gcn5/PCAF and p300/CBP, histone deacetylase (HDACs), and histone methyltransferase enzymes (HMTs) [61,62].
Viruses can impose epigenetic changes that alter host transcription programs, thereby promoting their own propagation, and may contribute to cancer occurrence. We and others have recently shown that the altered epigenetic state associated with HCV infection persists, to some extent, even after cure following DAAs and IFN-based treatments [63-67]. This observation is consistent in various HCV infection models, including immortalized human liver and hepatoma cells, a human liver chimeric mouse model, and post-SVR human liver samples. In cell culture, HCV-induced changes in active chromatin markers H3K4Me3 and H3K9Ac and silent chromatin marker H3K9Me3 were associated with altered expression of genes involved in cancer-related pathways. A positive correlation was observed between chromatin modification and gene expression in HCV-infected cells, both before and after virus eradication by DAAs [63]. This persistent epigenetic imprint was recapitulated in pre- and post-SVR human liver samples, even years after virus eradication by DAAs. Interestingly, our data indicate more reversion of both RNA and epigenetic marker levels following IFN-based compared to DAAs-based treatment, which is in agreement with higher risk for HCC development in DAAs vs. IFN-cured patients reported in several publications [68-71]. Hamdane et al. [64] showed that chronic HCV infection induces genome-wide changes in active histone modification of H3K27Ac following SVR with DAA or IFN therapies, many of which persisted after HCV cure, depending on the liver fibrosis stage. These changes were found to be partly induced by direct HCV–hepatocyte interactions, as demonstrated in a HCV-infected human liver chimeric mouse model that did not develop inflammation or liver fibrosis. Collectively, the data demonstrated that both direct virus-mediated and indirect inflammation and fibrosis-mediated mechanisms contribute to the epigenetic changes in HCV-infected patients that are imprinted after cure with DAA [64]. Jühling et al. [65] found that both HCV- and non-alcoholic steatohepatitis (NASH)-related HCC have common epigenetic alterations, with a positive correlation between the epigenetic alteration in H3K27ac and transcriptomics, which mostly did not reverse after cure.
Imprint of global changes in HCV-induced DNA methylation has also been reported recently, where HCV-infected Hu1545-immortalized hepatocyte cells showed significant changes in DNA methylation that correlated with oncogenic gene expression after IFN- and DAAs-based treatments. The activated pathways were associated with disease development and HCC. Interestingly, IFN treatment in the absence of active HCV induced a similar epigenetic scar. Moreover, HCV was shown to persistently suppress innate immune pathways, including TLR3 activity, via epigenetic changes [66]. The effect of DNA methylation on transcription factors that regulate gene expression was also recently evaluated pre- and post-SVR, which remain dysregulated after HCV eradication [67].
HCV infection induces changes in host cell epigenetics and gene expression related to pathways that may be required for the virus life cycle but also contribute to carcinogenesis. Gene signatures associated with increased risk for HCC were found to intersect with epigenetic and gene expression scars [63,64,67]. These persistently altered genes and pathways are summarized in Table 3. Overall, these data all point to the involvement of the epigenetic scar in post-SVR hepatocarcinogenesis.

IMMUNE SCARS AND IMMUNOSURVEILLANCE POST-SVR

The nature of the immune response induced by HCV infection determines the outcome of infection, i.e., whether it resolves or progresses to chronic infection, and contributes to HCC development. Since complete viral elimination by DAAs is possible, HCV infection is a unique model to study the effect of infection and its eradication on immune responses and clinical outcomes. Due to the residual risk of liver diseases and HCC after cure with DAAs, it is important to understand whether the HCV-induced alterations in the immune response return to normal after viral eradication. Indeed, recent studies have reported that the altered characteristics and functions of various immune cells in chronic HCV infections persist to some extent as an immunological imprint after cure with DAAs; accordingly, the elimination of HCV by DAAs and its influence on the immune response could affect the development of hepatocarcinogenesis.
Overall, the innate immune response following HCV cure is only partially restored. A decrease in ISGs expression and type I IFN response in peripheral blood mononuclear cells in the liver was observed after DAAs treatment, therefore resulting in a weaker antitumor-immune state and contributing to hepatocarcinogenesis [72-75]. In patients with acute or chronic infection following virus elimination by DAAs treatment [76,77], and spontaneously resolved HCV infections [78], cytokines levels were decreased but still not returned to normal range. Yet, most of these studies were conducted within several months after treatment, and longer follow-up studies are still required.
NK cells play an important role in the innate anti-HCV immune response [79], but are damaged in chronic HCV infections [80,81]. Following HCV eradication by DAAs, some of the damaged phenotypes and functions of NK cells were reversed [82-84], while some functions persisted, such as decreased intra-individual NK cell diversity [85]. NK cells also bear antitumor activity, and their frequency is associated with HCC recurrence-free survival [86]. Downregulation of NK group 2D (NKG2D), which is important for NK cell antitumor activity, has been reported in association with HCC occurrence and recurrence post-DAA therapy [87,88]. In addition to NK cells, unique innate-like T-cells such as γδ T-cells and mucosa-associated invariant T (MAIT) cells were found to be impaired pre- and post-cure of chronic HCV infections [89-92] and may underlie pathologies and post-cure HCC development [93,94].
An imprinted adaptive immune response was also observed after HCV cure. Effective CD8+ and CD4+ T cell responses were associated with HCV clearance, while weak and exhausted responses were associated with chronic infection [95]. Persistent induction of T cells in chronic infection leads to T-cell exhaustion, which was only partially restored after cure with DAA- and IFN-based treatments [96-99]. Specifically, mitochondrial function [96] and transcription programs [100] of exhausted HCV-specific CD8+ T-cells were not fully recovered following cure and were associated with a distinct epigenetic signature [97,101-103] and post-cure HCC development [104]. Furthermore, CD4+ T cells remained impaired in chronic HCV infections after cure with DAAs [105].
The levels of circulating regulatory T cells (T regs) remain persistently high long after HCV cure with DAAs [106,107] and increase with HCC progression [108], suggesting that high T regs levels after DAAs treatment may be related to postcure HCC. T regs count correlates with myeloid-derived suppressor cell counts, which are increased in chronic HCV patients and remain high following cure with DAAs [109].
To summarize, although some functions of the innate and adaptive immune responses associated with HCV infections are normalized after HCV cure with DAAs, many persist after cure. These may lead to a pro-cancerous environment that may contribute to post-cure HCC. Understanding the molecular mechanisms that impact these immunological scars may set foundations for their prevention or reversion, though, for example, epigenetic drugs that revert the epigenetic scar in immune cells.

PROTEOMIC AND METABOLOMIC PROGNOSTIC MARKERS POST-SVR

The changes in the levels of cytokines and chemokines after achieving SVR have been proposed as predictors of HCC. Lu et al. [110] showed that downregulation of members of the TNF superfamily, including TNF-α and TNF-like weak inducer of apoptosis (TWEAK), increased the risk of HCC development. A strong prediction model for post-SVR HCC treated with either DAA or IFN-included FIB-4, hemoglobin A1c, and levels of TNF-α and TWEAK. An increase in TNF-α levels is associated with increased hepatic inflammation and HCC risk, suggesting that its pretreatment concentration predicts post-SVR HCC risk and an association between its persistently high expression after SVR and the development of HCC [111]. The sharp decline in TNF-α after cure may impair immune surveillance and inhibit antitumor response. Moreover, a correlation between high pretreatment serum levels of 12 immune mediators and posttreatment HCC development was identified [111,112], as well as high levels of IL-13 and IL-4 [113].
Circulating protein biomarkers of HCC, such as AFP, have also been suggested as prognostic markers. More specifically, higher pre- and post-treatment levels of AFP were associated with HCC development [24,114-116]. However, the accuracy, in particular the sensitivity of AFP, is an issue [117]. Other circulating protein biomarkers including wisteria floribunda agglutinin-positive Mac-2-binding protein [116], serum sphingolipids [118], VEGF, and angiopoietin-2 [119,120] also associated with post-curative HCV-related HCC occurrence. A large cohort study found that the MICA A allele and high serum MICA (sMICA) levels correlated with HCC development, but only in cirrhotic non-SVR patients [121]. A follow-up study found its levels to be lower and to gradually decline in non-HCC compared to HCC patients, while higher sMICA levels gradually increased in post-SVR HCC, but only in MICA GG, and not A allele, carriers [122].
Circulating microRNA (miRNA) profiles have also been suggested as biomarkers for HCC development. MiR-3197 was identified as a potential prognostic marker for HCC risk during DAA treatment [123]. Circulating miRNA levels of members of the Let-7 family were associated with fibrosis progression, were downregulated in HCV infection and lower in patients who developed HCC after SVR compared to those without HCC. This may be related to the antitumor activity of Let-7, which downregulates chronic inflammation [124].

MODULATION OF RISK GENE SIGNATURE WITH TARGETING AGENTS FOR HCC POST SVR

Identification of potentially reversible HCV-related alterations in epigenetics and gene expression might contribute to efforts to reduce risk of HCC post-SVR. The discovery of druggable targets requires the elucidation of molecular mechanisms that drive these altered signatures. Recently, specific molecular pathways were identified as inducers of the epigenetic state dysregulated by HCV and as potential targets for HCC chemoprevention. Nakagawa et al. [125] studied the pan-etiology PLS gene, which predicts the risk for HCC both before and after SVR. They identified the pro-fibrosis lysophosphatidic acid pathway as a potential chemoprevention target. Inhibition of this pathway by inhibitors AM063 and AM095 resulted in reversal of the altered expression of gene signature after SVR and fibrosis attenuation and prevented HCC development in animal and in vitro models [125]. Another potential druggable target is the EGFR, which is a cofactor for HCV entry into cells and is also activated by HCV and contributes to HCC development [126-128]. The EGFR inhibitor erlotinib induced reversion of the PLS genes altered expression and prevented progression of cirrhosis and HCC in animal models [126]. We found that erlotinib reversed gene expression and epigenetic signatures after HCV cure with DAAs [63]. In addition, the unfolded protein response (UPR) that is activated by HCV has been reported to contribute to HCV-induced epigenetic and transcriptional alterations; treatment with the UPR inhibitor BAPTA partially reversed this effect [65].
Targeting epigenetic enzymes as a genome-wide approach was recently demonstrated to efficiently reverse the epigenetic and gene expression signatures associated with HCV infection. We showed that the HAT p300/CBP inhibitor C646 reversed the persistent changes in H3K9Ac induced by HCV and the associated gene expression signature [63]. A panel of inhibitors targeting epigenetic enzymes, including HATs, bromodomain-containing proteins 3/4 (BRD3/4), mixed-lineage leukemia protein/WD repeat domain 5 complexes and HDACs, reversed the altered expression of the PLS genes in an HCV-infected cell culture model [65]. In addition, the authors observed common gene expression patterns between the HCC etiologies HCV and NASH, and the reversion of this signature following treatment with the BRD4 inhibitor as well as inhibition of cancer progression and liver inflammation in a NASH mouse model [65]. Further studies are urgently needed to identify additional druggable targets for prevention of liver disease and HCC development both pre- and post-SVR.

CHEMOPREVENTION OF POST-SVR HCC

Cigarette smoking is demonstrated as the risk of liver fibrogenesis and hepatocarcinogenesis, and smoking cessation may decrease the risk of HCC [129]. Whether quitting smoking reduces post-SVR HCC in CHC patients remains to be explored. Albeit DM is a risk factor for HCC, metformin use seemed to play a protective role in CHC-related HCC [130]. Tsai et al. [131] enrolled 7,249 Taiwanese CHC patients who achieved SVR, and the 5-year cumulative HCC incidence was 10.9% in diabetic non-metformin users and 2.6% in diabetic metformin users, compared to 3.0% in individuals without DM. Diabetic patients without metformin use had a 2.83-fold risk of HCC compared to non-diabetic patients, whereas the risk of HCC in diabetic patients who used metformin had reduced and had similar risk of HCC as with non-diabetic patients. Recent meta-analysis and pooled data has showed that statin and aspirin might reduce HCC risk as a whole [132,133], and while the role of aspirin in preventing post-SVR HCC in CHC is elusive. A Taiwanese cohort has demonstrated the chemopreventive effect of statin in reducing HCC risk in SVR patients [131].

IMPACT OF ANTIVIRAL THERAPY ON HCV VIREMIC HCC PATIENTS

Earlier reports have indicated an inferior SVR rate in HCC patients who received DAAs. A meta-analysis including 49 studies has shown a lower SVR rate of 73.1% in active HCC patients compared to that of 92.6% in inactive patients and of 93.3% in non-HCC patients [134]. Notably, much of the data came from the reports using suboptimal regimens in the early DAA era. With the current standard of care regimens, sofosbuvir/velpatasivir and glecaprevir/pibrentasvir used in two nationwide studies from Taiwan have validated similar treatment efficacy among patients with/without inactive or active HCC [135,136]. HCC is no longer an unfavorable factor associated with treatment failure with the application of more potent DAAs. Imperatively, long-term survival would be better for the viremic HCC patients receiving subsequent HCV eradication compared to those who remain persistently viremic [137,138]. A postulation is that HCC patients might benefit from viral eradication in terms of more preserved liver function, potentially allowing for salvage anti-cancer treatments once the patients encounter primary HCC treatment failure [138]. The result suggests that it is better-late-than-never to treat HCV. CHC patients with active HCC should be treated with DAAs aggressively unless a short life expectancy due to HCC is anticipated.
Lastly, HCV eradication significantly reduce hepatic vein pressure gradient. Recompensation occurs in a substantial proportion of decompensated patients. The benefit of HCC risk reduction in decompensated patients during the recovery of liver function reserve is controversial. The conduction of a prospective treated-versus-untreated controlled trial is unethical and impractical. Recently a meta-analysis including 4 retrospective studies have demonstrated a marginal benefit of 26% HCC risk reductions (95% confidence interval 0.52, 1.00; P=0.05) in DAA treated decompensated patients compared to untreated control [139].
In conclusion, post-SVR HCC remains as occurring in a subset of CHC patients due to preexisting inflammatory and fibrotic liver background, immune dysregulation as well as host epigenetic scar, genetic predispositions and alternations (Fig. 1). There are remaining unmet needs in post-SVR HCC surveillance and management (Table 4). By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations.

ACKNOWLEDGMENTS

Ming-Lung Yu would like to thank to the support of “Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.
Israel Science Foundation (grant number 2475/19).

FOOTNOTES

Authors’ contribution
Conception and design: Ming-Lung Yu. Manuscript drafting and critical revision: Chung-Feng Huang, Manar Hijaze Awad, Meital Gal-Tanamy and Min-Lung Yu. Approval of the final version of the manuscript: Ming-Lung Yu and Meital Gal-Tanamy.
Conflicts of Interest
Ming-Lung Yu: Research support (grant) from AbbVie, BMS, Gilead, Merck and Roche diagnostics. Consultant of AbbVie, BMS, Gilead, Roche and Roche diagnostics. Speaker of AbbVie, BMS, Eisai, Gilead, Roche and Roche diagnostics.
Chung-Feng Huang: Speaker for AbbVie, BMS, Gilead, Merck, and Roche.

Figure 1.
Scheme of molecular mechanisms of hepatocellular carcinoma after HCV eradication. Development of HCC pre- and post-SVR is related to impaired immune response and immune surveillance, epigenetic and gene expression alterations and genomic factors. Identified persistent mechanisms that remain impaired after HCV SVR and prognostic markers for HCC risk post SVR and HCC chemoprevention targets are shown. HCV, hepatitis C virus; SVR, sustained virological response; HCC, hepatocellular carcinoma; DAA, directly acting antiviral; IFN, interferon.

cmh-2024-0155f1.jpg
Table 1.
HCC screen targets and strategies among regional guidelines
Society APASL EASL AASLD TASL
Target population All patients (C2) F3, F4 (A1) F4 (B2) All patients (B1)
Screening for patients with mild fibrosis with comorbidities Yes (A1) Yes (A1) No (B2) Yes (B1)
Screen Interval F0-2: every 6 months for 2 years, then every 12 months Every 6 months Every 6 months F0-1 with HCC risk factors* and F2: every 6–12 months (B1)
F3-4: every 6 months (C2) indefinitely (A1) indefinitely (A1) F3-4: every 3–6 months (A1)
Modality Sonography+ tumor markers (AFP, PIVKA-II, AFP-L3) (A1) Sonography (B1) Sonography with AFP (B1) N/A

APASL, The Asian Pacific Association for the Study of the Liver; EASL, The European Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; TASL, Taiwan Association for the Study of the Liver; F0-2, fibrotic stage 0-2; F3, fibrotic stage 3; F4, fibrotic stage 4; cirrhosis. AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist-II; N/A, not available; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; ALT, alanine aminotransferase.

* Past HCC history, HBV/HCV dual infection, older age, male gender, presence of dysplastic nodule, alcohol consumption, diabetes mellitus, low albumin, low platelet count, high AFP post-treatment, high ALT post-treatment, and high g-GT level pre- and post-treatment.

Evidence grading denotes evidence quality (A: high, B: moderate, C: low) and recommendation (1: strong, 2: weak).

Table 2.
Selected HCC prediction model after achieving sustained virological response
Regimen Parameter Accuracy/discrimination power Note Reference
IFN; IFN plus DAA; DAA Major determinant: age, platelet count, AST/√ALT ratio and albumin level. Minor determinant: sex, race- ethnicity, HCV genotype, body mass index, hemoglobin and AFP Gonen and Heller’s κ-statistic 0.70–0.77 excellent correlation in patients with cirrhosis/SVR; no cirrhosis/no SVR; and no cirrhosis/SVR, and moderate correlation in patients with cirrhosis/no SVR [33]
DAA Baseline LSM, 1-year delta-LSM and albumin Harrell’s C: 0.77 Predict patients with very low risk of HCC to avoid unnecessary surveillance [34]
DAA Age, LSM, alcohol consumption, albumin and AFP Bootstrapped AUC 0.67–0.80 Stratify HCC risk in patients with compensated advanced chronic liver disease [35]
IFN; DAA FIB-4 and gene score including post- treatment TAS1R3, FOSL1 and ABCA3 AUC 0.91 in the gene score and 0.95 in the nomogram Decision-tree-based algorithms based on genetic alternations and clinical profile [37]

IFN, interferon; DAA, direct-acting antiviral; AST, aspartate aminotransferase; ALT, alanine aminotransferase; SVR, sustained virological response; LSM, liver stiffness measurement; AFP, alpha-fetoprotein; AUC, area under the curve; FIB-4, fibrosis-4 index.

Table 3.
Characteristics of persistently altered molecular mechanisms after HCV SVR
Molecular mechanisms Characteristics Reference
Genomic factors
Somatic mutations ARID Lower frequency of mutations in HCV-SVR as compared to HCV- positive tumors [48]
PREX2, KEAP1 More frequently identified in HCV-SVR samples as compared to HCV-positive samples and were previously reported in HCC [48]
TP53 More frequent in DAA-treated as compared to IFN-treated patients [48]
Genomic abnormalities
Genetic predisposition MICA Associated with reduced counts of NK and CD8+ T cells. Marker for predisposition for HCC [52]
TLL1 Associated with TGFβ signaling pathway. A variant is a marker for increases risk for HCC post SVR [55]
Genetic risk score: PNPLA3, TM6SF2, MBOAT7, GCKR Associated with hepatic fat. Specific variants are associated with predisposition for HCC pre and post SVR [56]
IFNL3 Polymorphism is associated with increases risk for HCC pre and post SVR [57]
Epigenetics and gene expression
Cytoskeleton, epithelial–mesenchymal transition, WNT, Development, Immune response, B-Raf, NGF, mTOR/MAPK, Lipid metabolism, TNFa, G2M checkpoint, cell cycle, phosphoinositide 3-kinase, Akt, Oncogenes (FGFR1, CCND2, MLLT3, MAML2) and Tumor suppressor genes (FANCC, TSC2) Genes and pathways persistently altered pre and post SVR by epigenetic dysregulation, identified by histone modifications markers and associated with HCC development [6365]
TLR3 and innate immune response genes, TFs (RXRA, KLF4, RUNX1, and RORA) Genes and TF persistently altered pre and post SVR by epigenetic dysregulation, identified by DNA methylation markers and associated with HCC development. [67]
Immune scar and immunosurveillance
Innate immunity ISGs expression and type I IFN response Decreased after DAAs treatment; reduce immune surveillance and increase risk for HCC post SVR. Partially persistent after SVR and spontaneously resolved infections [7275]
NK cells Damage of NK functions partially persist after SVR: decreased intra-individual NK cell diversity, decreased of NK group 2D (NKG2D), associated with HCC occurrence and recurrence post DAA [7788]
Innate- like T-cells (γδ T-cells MAIT) Impaired pre and post cure of chronic and acute HCV infections, associated with HCC development post cure [8992]
HCV-specific CD8 + T-cells Partial restoration of CD8 + T-cells exhaustion post cure with DAAs and IFN-based treatments, impaired mitochondrial function, transcription program, epigenetic signature and TF post cure [97,101103]
Adaptive immunity CD4+ T cells Impaired in chronic HCV infections post cure by DAAs [105]
T regs Remain persistently high long after HCV cure by DAAs, related to post cure HCC [109]
Prognostic markers
Cytokines and chemokines biomarkers TNF-α and TWEAK Downregulation after SVR increased the risk of HCC development [110]
FIB-4 with HbA1c, TNF-α and TWEAK Prediction model for post SVR HCC [37,110,111]
TNF-α Decline may affect immune surveillance and inhibit antitumor response. Persistent high expression after SVR is involved in HCC [111]
MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, IL21 High serum levels predict de novo HCC development post cure [111,112]
IL-13 and IL-4 High serum levels predict HCC development post cure [113]
Protein biomarkers AFP Higher levels pre and post treatment associated with HCC after SVR by DAAs [117]
Albumin and platelets High levels associated with risk of HCC following SVR by DAAs [33,35]
WFA and M2BP Sphingolipids Biomarkers associated with increased risk for de novo HCC post SVR by DAAs [116,118]
VEGF and ANGPT2 Increased circulating levels associated with occurrence and recurrence of HCC development after DAA treatment [119,120]
sMICA High serum levels correlated with HCC development, but only in cirrhotic non- SVR patients [121,122]
microRNA MiR-3197 Lower levels identified as a potential prognostic marker for HCC risk during DAA treatment [123]
Let-7 family Lower levels in patients who developed HCC after SVR compared to those without HCC [124]
Chemoprevention
Inhibition of signaling pathways LPA Inhibitors AM063 and AM095 reverse the altered expression of gene signature after SVR and fibrosis attenuation and prevented HCC development [125]
EGFR Erlotinib reversed HCV-induced gene expression and epigenetic signatures after HCV cure with DAAs [63,126128]
UPR BAPTA reversed HCV-induced gene expression and epigenetic signatures after HCV cure with DAAs [65]
Inhibition of epigenetic modifiers HATs BRD3/4 MLL/WDR5 inhibitors, HDACs Inhibitors reversed HCV-induced gene expression and epigenetic signatures after HCV cure with DAAs [63,65]

HCV, hepatitis C virus; SVR, sustained virological response; HCC, hepatocellular carcinoma; DAA, direct-acting antiviral; IFN, interferon.

Table 4.
Unmet needs for the post-SVR HCC
· Identify the target population for surveillance on the cost-effective basis
· Define the screen interval and duration after achieving SVR
· Adopt precise screening tools including image modalities and biomarkers
· Marginal benefit of HCC risk reduction in patients with decompensated liver cirrhosis
· Predict the high-risk population based on the pathophysiological mechanisms
· Construct a precision medicine-guided strategy that incorporates clinical and molecular surrogates

SVR, sustained virological response; HCC, hepatocellular carcinoma.

Abbreviations

AST
aspartate aminotransferase
AST
alanine aminotransferase
AFP
alpha-fetoprotein
CHC
chronic hepatitis C
DAA
direct-acting antiviral
FIB-4
fibrosis-4 index
HCV
hepatitis C virus
HCC
hepatocellular carcinoma
IFN
interferon
MICA
MHC class I chain-related A
SVR
sustained virological response
SNP
single nucleotide polymorphism

REFERENCES

1. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol 2013;10:553-562.
crossref pmid pdf
2. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019;16:589-604.
crossref pmid pmc pdf
3. Cui F, Blach S, Manzengo Mingiedi C, Gonzalez MA, Sabry Alaama A, Mozalevskis A, et al. Global reporting of progress towards elimination of hepatitis B and hepatitis C. Lancet Gastroenterol Hepatol 2023;8:332-342.
crossref pmid
4. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, FalckYtter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158(5 Pt 1):329-337.
crossref pmid
5. Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol 2018;68:25-32.
crossref pmid pmc
6. Kanda T, Lau GKK, Wei L, Moriyama M, Yu ML, Chuang WL, et al. APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation. Hepatol Int 2019;13:649-661.
crossref pmid pmc pdf
7. Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol 2017;67:1204-1212.
crossref pmid
8. Seko Y, Moriguchi M, Takahashi A, Yamaguchi K, Umemura A, Okuda K, et al. Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents. J Gastroenterol 2022;57:90-98.
crossref pmid pdf
9. Sarasin FP, Giostra E, Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis. Am J Med 1996;101:422-434.
crossref pmid
10. Farhang Zangneh H, Wong WWL, Sander B, Bell CM, Mumtaz K, Kowgier M, et al. Cost effectiveness of hepatocellular carcinoma surveillance after a sustained virologic response to therapy in patients with hepatitis C virus infection and advanced fibrosis. Clin Gastroenterol Hepatol 2019;17:1840-1849 e16.
crossref pmid
11. Parikh ND, Singal AG, Hutton DW, Tapper EB. Cost-effectiveness of hepatocellular carcinoma surveillance: an assessment of benefits and harms. Am J Gastroenterol 2020;115:1642-1649.
crossref pmid pmc
12. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: final update of the series. J Hepatol 2020;73:1170-1218.
crossref pmid
13. American Association for the Study of Liver Diseases (AASLD). HCV guidance: recommendations for testing, managing, and treating hepatitis C. AASLD web site, https://www.hcvguidelines.org/. Accessed 30 April 2023.

14. Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023;78:1922-1965.
crossref pmid
15. Yu ML, Chen PJ, Dai CY, Hu TH, Huang CF, Huang YH, et al. 2020 Taiwan consensus statement on the management of hepatitis C: part (I) general population. J Formos Med Assoc 2020;119:1019-1040.
crossref pmid
16. Huang CF, Yeh ML, Huang CI, Liang PC, Lin YH, Lin ZY, et al. Post-treatment fibrotic modifications overwhelm pretreatment liver fibrosis in predicting HCC in CHC patients with curative antivirals. Hepatol Int 2018;12:544-551.
crossref pmid pdf
17. Kim NJ, Vutien P, Cleveland E, Cravero A, Ioannou GN. Fibrosis stage-specific incidence of hepatocellular cancer after hepatitis C cure with direct-acting antivirals: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2023;21:1723-1738 e5.
crossref pmid pmc
18. D’Ambrosio R, Ioannou GN. Hepatocellular carcinoma risk, outcomes, and screening after hepatitis C eradication. Hepatol Commun 2021;5:1465-1468.
crossref pmid pmc pdf
19. Nakatsuka T, Tateishi R. Development and prognosis of hepatocellular carcinoma in patients with diabetes. Clin Mol Hepatol 2023;29:51-64.
crossref pmid pmc pdf
20. Huang CF, Yeh ML, Huang CY, Tsai PC, Ko YM, Chen KY, et al. Pretreatment glucose status determines HCC development in HCV patients with mild liver disease after curative antiviral therapy. Medicine (Baltimore) 2016;95:e4157.
crossref pmid pmc
21. Pelusi S, Bianco C, Colombo M, Cologni G, Del Poggio P, Pugliese N, et al. Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct-acting antivirals. Liver Int 2023;43:1593-1603.
pmid
22. Tokuchi Y, Suda G, Kawagishi N, Ohara M, Kohya R, Sasaki T, et al. Hepatitis C virus eradication by direct-acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low-density lipoprotein cholesterolemia without an increase in body weight. Hepatol Res 2023;53:595-606.
crossref pmid pdf
23. Fouad Y, Lazarus JV, Negro F, Peck-Radosavljevic M, Sarin SK, Ferenci P, et al. MAFLD considerations as a part of the global hepatitis C elimination effort: an international perspective. Aliment Pharmacol Ther 2021;53:1080-1089.
crossref pmid
24. Ji D, Chen GF, Niu XX, Zhang M, Wang C, Shao Q, et al. Non-alcoholic fatty liver disease is a risk factor for occurrence of hepatocellular carcinoma after sustained virologic response in chronic hepatitis C patients: a prospective four-years follow-up study. Metabol Open 2021;10:100090.
crossref pmid pmc
25. Peleg N, Issachar A, Sneh Arbib O, Cohen-Naftaly M, Harif Y, Oxtrud E, et al. Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response. J Viral Hepat 2019;26:1257-1265.
crossref pmid pdf
26. Mueller PP, Chen Q, Ayer T, Nemutlu GS, Hajjar A, Bethea ED, et al. Duration and cost-effectiveness of hepatocellular carcinoma surveillance in hepatitis C patients after viral eradication. J Hepatol 2022;77:55-62.
crossref pmid pmc
27. Ioannou GN, Beste LA, Green PK, Singal AG, Tapper EB, Waljee AK, et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology 2019;157:1264-1278 e4.
crossref pmid pmc
28. Yu ML, Huang CF, Yeh ML, Tsai PC, Huang CI, Hsieh MH, et al. Time-degenerative factors and the risk of hepatocellular carcinoma after antiviral therapy among hepatitis C Virus patients: a model for prioritization of treatment. Clin Cancer Res 2017;23:1690-1697.
crossref pmid pdf
29. Huang CF, Yeh ML, Tsai PC, Hsieh MH, Yang HL, Hsieh MY, et al. Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in noncirrhotic patients with successful hepatitis C virus eradication. J Hepatol 2014;61:67-74.
crossref pmid
30. Yu ML, Lin SM, Lee CM, Dai CY, Chang WY, Chen SC, et al. A simple noninvasive index for predicting long-term outcome of chronic hepatitis C after interferon-based therapy. Hepatology 2006;44:1086-1097.
crossref pmid
31. Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, et al. α-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology 2013;58:1253-1262.
crossref pmid
32. Tanaka Y, Ogawa E, Huang CF, Toyoda H, Jun DW, Tseng CH, et al. HCC risk post-SVR with DAAs in East Asians: findings from the REAL-C cohort. Hepatol Int 2020;14:1023-1033.
crossref pmid pdf
33. Ioannou GN, Green PK, Beste LA, Mun EJ, Kerr KF, Berry K. Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C. J Hepatol 2018;69:1088-1098.
crossref pmid pmc
34. Alonso López S, Manzano ML, Gea F, Gutiérrez ML, Ahumada AM, Devesa MJ, et al. A model based on noninvasive markers predicts very low hepatocellular carcinoma risk after viral response in hepatitis C virus-advanced fibrosis. Hepatology 2020;72:1924-1934.
crossref pmid pdf
35. Semmler G, Meyer EL, Kozbial K, Schwabl P, HametnerSchreil S, Zanetto A, et al. HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease. J Hepatol 2022;76:812-821.
crossref pmid
36. Ioannou GN, Tang W, Beste LA, Tincopa MA, Su GL, Van T, et al. Assessment of a deep learning model to predict hepatocellular carcinoma in patients with hepatitis C cirrhosis. JAMA Netw Open 2020;3:e2015626.
crossref pmid pmc
37. Lu MY, Liu TW, Liang PC, Huang CI, Tsai YS, Tsai PC, et al. Decision tree algorithm predicts hepatocellular carcinoma among chronic hepatitis C patients following viral eradication. Am J Cancer Res 2023;13:190-203.
pmid pmc
38. Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016;65:719-726.
crossref pmid
39. Singal AG, Rich NE, Mehta N, Branch A, Pillai A, Hoteit M, et al. Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study. Gastroenterology 2019;156:1683-1692 e1.
crossref pmid pmc
40. Saraiya N, Yopp AC, Rich NE, Odewole M, Parikh ND, Singal AG. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther 2018;48:127-137.
crossref pmid pmc pdf
41. Sapena V, Enea M, Torres F, Celsa C, Rios J, Rizzo GEM, et al. Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis. Gut 2022;71:593-604.
crossref pmid
42. Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Kato M, Shiraishi Y, et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet 2016;48:500-509.
crossref pmid
43. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012;44:760-764.
crossref pmid pdf
44. Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015;47:505-511.
crossref pmid pmc pdf
45. Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, et al. High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet 2011;43:464-469.
crossref pmid pdf
46. Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet 2014;46:1267-1273.
crossref pmid pdf
47. The Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 2017;169:1327-1341.e23.
pmid pmc
48. Imamura T, Okamura Y, Ohshima K, Uesaka K, Sugiura T, Ito T, et al. Hepatocellular carcinoma after a sustained virological response by direct-acting antivirals harbors TP53 inactivation. Cancer Med 2022;11:1769-1786.
pmid pmc
49. Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol 2020;72:215-229.
crossref pmid
50. Fine B, Hodakoski C, Koujak S, Su T, Saal LH, Maurer M, et al. Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science 2009;325:1261-1265.
crossref pmid pmc
51. Shibata T, Aburatani H. Exploration of liver cancer genomes. Nat Rev Gastroenterol Hepatol 2014;11:340-349.
crossref pmid pdf
52. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011;43:455-458.
crossref pmid pdf
53. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999;285:727-729.
crossref pmid
54. Lee MH, Huang YH, Chen HY, Khor SS, Chang YH, Lin YJ, et al. Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: a genome-wide association study. Hepatology 2018;67:651-661.
crossref pmid pdf
55. Matsuura K, Sawai H, Ikeo K, Ogawa S, Iio E, Isogawa M, et al. Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology 2017;152:1383-1394.
crossref pmid
56. Degasperi E, Galmozzi E, Pelusi S, D’Ambrosio R, Soffredini R, Borghi M, et al. Hepatic fat-genetic risk score predicts hepatocellular carcinoma in patients with cirrhotic HCV treated with DAAs. Hepatology 2020;72:1912-1923.
crossref pmid pdf
57. Chang KC, Tseng PL, Wu YY, Hung HC, Huang CM, Lu SN, et al. A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection. Clin Gastroenterol Hepatol 2015;13:1017-1024.
crossref pmid
58. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31:27-36.
crossref pmid pmc
59. Esteller M. Epigenetics in cancer. N Engl J Med 2008;358:1148-1159.
crossref pmid
60. Rothbart SB, Strahl BD. Interpreting the language of histone and DNA modifications. Biochim Biophys Acta 2014;1839:627-643.
crossref pmid pmc
61. Conte M, Altucci L. Molecular pathways: the complexity of the epigenome in cancer and recent clinical advances. Clin Cancer Res 2012;18:5526-5534.
crossref pmid pdf
62. Balasubramanyam K, Swaminathan V, Ranganathan A, Kundu TK. Small molecule modulators of histone acetyltransferase p300. J Biol Chem 2003;278:19134-19140.
crossref pmid
63. Perez S, Kaspi A, Domovitz T, Davidovich A, Lavi-Itzkovitz A, Meirson T, et al. Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet 2019;15:e1008181.
crossref pmid pmc
64. Hamdane N, Jühling F, Crouchet E, El Saghire H, Thumann C, Oudot MA, et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology 2019;156:2313-2329.e7.
crossref pmid pmc
65. Jühling F, Hamdane N, Crouchet E, Li S, El Saghire H, Mukherji A, et al. Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Gut 2021;70:157-169.
crossref pmid pmc
66. Hlady RA, Zhao X, El Khoury LY, Luna A, Pham K, Wu Q, et al. Interferon drives HCV scarring of the epigenome and creates targetable vulnerabilities following viral clearance. Hepatology 2022;75:983-996.
crossref pmid pmc pdf
67. Sugimachi K, Araki H, Saito H, Masuda T, Miura F, Inoue K, et al. Persistent epigenetic alterations in transcription factors after a sustained virological response in hepatocellular carcinoma. JGH Open 2022;6:854-863.
crossref pmid pmc pdf
68. Nagata H, Nakagawa M, Asahina Y, Sato A, Asano Y, Tsunoda T, et al. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol 2017;67:933-939.
crossref pmid
69. Nahon P, Layese R, Bourcier V, Cagnot C, Marcellin P, Guyader D, et al. Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs. Gastroenterology 2018;155:1436-1450.e6.
crossref pmid
70. Janjua NZ, Wong S, Darvishian M, Butt ZA, Yu A, Binka M, et al. The impact of SVR from direct-acting antiviral- and interferon-based treatments for HCV on hepatocellular carcinoma risk. J Viral Hepat 2020;27:781-793.
crossref pdf
71. Celsa C, Stornello C, Giuffrida P, Giacchetto CM, Grova M, Rancatore G, et al. Direct-acting antiviral agents and risk of Hepatocellular carcinoma: critical appraisal of the evidence. Ann Hepatol 2022;27 Suppl 1:100568.
crossref pmid
72. Alao H, Cam M, Keembiyehetty C, Zhang F, Serti E, Suarez D, et al. Baseline intrahepatic and peripheral innate immunity are associated with hepatitis C virus clearance during directacting antiviral therapy. Hepatology 2018;68:2078-2088.
crossref pmid pmc pdf
73. Amaddeo G, Nguyen CT, Maillé P, Mulé S, Luciani A, Machou C, et al. Intrahepatic immune changes after hepatitis c virus eradication by direct-acting antiviral therapy. Liver Int 2020;40:74-82.
crossref pmid pdf
74. Holmes JA, Carlton-Smith C, Kim AY, Dumas EO, Brown J, Gustafson JL, et al. Dynamic changes in innate immune responses during direct-acting antiviral therapy for HCV infection. J Viral Hepat 2019;26:362-372.
pmid
75. Sung PS, Lee EB, Park DJ, Lozada A, Jang JW, Bae SH, et al. Interferon-free treatment for hepatitis C virus infection induces normalization of extrahepatic type I interferon signaling. Clin Mol Hepatol 2018;24:302-310.
crossref pmid pmc pdf
76. Hengst J, Falk CS, Schlaphoff V, Deterding K, Manns MP, Cornberg M, et al. Direct-acting antiviral-induced hepatitis C virus clearance does not completely restore the altered cytokine and chemokine milieu in patients with chronic hepatitis C. J Infect Dis 2016;214:1965-1974.
crossref pmid
77. Khera T, Du Y, Todt D, Deterding K, Strunz B, Hardtke S, et al. Long-lasting imprint in the soluble inflammatory milieu despite early treatment of acute symptomatic hepatitis C. J Infect Dis 2022;226:441-452.
crossref pmid pmc pdf
78. Rosenberg BR, Depla M, Freije CA, Gaucher D, Mazouz S, Boisvert M, et al. Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection in patients with spontaneous viral clearance. PLoS Pathog 2018;14:e1007290.
crossref pmid pmc
79. Lunemann S, Schlaphoff V, Cornberg M, Wedemeyer H. NK cells in hepatitis C: role in disease susceptibility and therapy. Dig Dis 2012;30 Suppl 1:48-54.
crossref pmid pdf
80. Lunemann S, Malone DF, Hengst J, Port K, Grabowski J, Deterding K, et al. Compromised function of natural killer cells in acute and chronic viral hepatitis. J Infect Dis 2014;209:1362-1373.
crossref pmid
81. Golden-Mason L, Madrigal-Estebas L, McGrath E, Conroy MJ, Ryan EJ, Hegarty JE, et al. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut 2008;57:1121-1128.
crossref pmid
82. Serti E, Chepa-Lotrea X, Kim YJ, Keane M, Fryzek N, Liang TJ, et al. Successful interferon-free therapy of chronic hepatitis C virus infection normalizes natural killer cell function. Gastroenterology 2015;149:190-200.e2.
crossref pmid pmc
83. Golden-Mason L, McMahan RH, Kriss MS, Kilgore AL, Cheng L, Dran RJ, et al. Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment. Hepatol Commun 2018;2:364-375.
crossref pmid pmc pdf
84. Jiang HJ, Wang XX, Luo BF, Cong X, Jin Q, Qin H, et al. Direct antiviral agents upregulate natural killer cell potential activity in chronic hepatitis C patients. Clin Exp Med 2019;19:299-308.
crossref pmid pdf
85. Strunz B, Hengst J, Deterding K, Manns MP, Cornberg M, Ljunggren HG, et al. Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity. Nat Commun 2018;9:2275.
crossref pmid pmc pdf
86. Werner JM, Adenugba A, Protzer U. Immune reconstitution after HCV clearance with direct antiviral agents: potential consequences for patients with HCC? Transplantation 2017;101:904-909.
pmid
87. Chu PS, Nakamoto N, Taniki N, Ojiro K, Amiya T, Makita Y, 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.
crossref pmid pmc
88. Rosen HR, Golden-Mason L. Control of HCV infection by natural killer cells and macrophages. Cold Spring Harb Perspect Med 2020;10:a037101.
crossref pmid pmc
89. Ghosh A, Mondal RK, Romani S, Bagchi S, Cairo C, Pauza CD, et al. Persistent gamma delta T-cell dysfunction in chronic HCV infection despite direct-acting antiviral therapy induced cure. J Viral Hepat 2019;26:1105-1116.
crossref pmid pmc pdf
90. Hengst J, Strunz B, Deterding K, Ljunggren HG, Leeansyah E, Manns MP, et al. Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy. Eur J Immunol 2016;46:2204-2210.
crossref pmid pdf
91. Bolte FJ, O’Keefe AC, Webb LM, Serti E, Rivera E, Liang TJ, et al. Intra-hepatic depletion of mucosal-associated invariant T cells in hepatitis C virus-induced liver inflammation. Gastroenterology 2017;153:1392-1403.e2.
crossref pmid pmc
92. Khlaiphuengsin A, Chuaypen N, Sodsai P, Reantragoon R, Han WM, Avihingsanon A, et al. Successful direct-acting antiviral therapy improves circulating mucosal-associated invariant T cells in patients with chronic HCV infection. PLoS One 2020;15:e0244112.
crossref pmid pmc
93. Niehaus CE, Strunz B, Cornillet M, Falk CS, Schnieders A, Maasoumy B, et al. MAIT cells are enriched and highly functional in ascites of patients with decompensated liver cirrhosis. Hepatology 2020;72:1378-1393.
crossref pmid pdf
94. Mehta H, Lett MJ, Klenerman P, Filipowicz Sinnreich M. MAIT cells in liver inflammation and fibrosis. Semin Immunopathol 2022;44:429-444.
crossref pmid pmc pdf
95. Heim MH, Thimme R. Innate and adaptive immune responses in HCV infections. J Hepatol 2014;61(1 Suppl):S14-S25.
crossref pmid
96. Aregay A, Owusu Sekyere S, Deterding K, Port K, Dietz J, Berkowski C, et al. Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses. J Hepatol 2019;71:889-899.
crossref pmid
97. Tonnerre P, Wolski D, Subudhi S, Aljabban J, Hoogeveen RC, Damasio M, et al. Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nat Immunol 2021;22:1030-1041.
crossref pmid pmc pdf
98. Llorens-Revull M, Costafreda MI, Rico A, Guerrero-Murillo M, Soria ME, Píriz-Ruzo S, et al. Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy. PLoS One 2021;16:e0254243.
crossref pmid pmc
99. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol 2016;16:509-523.
crossref pmid pdf
100. Hensel N, Gu Z, Wieland D, Jechow K, Kemming J, et al. Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection. Nat Immunol 2021;22:229-239.
crossref pmid pdf
101. Yates KB, Tonnerre P, Martin GE, Gerdemann U, Al Abosy R, Comstock DE, et al. Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nat Immunol 2021;22:1020-1029.
crossref pmid pmc pdf
102. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 2019;571:265-269.
crossref pmid pdf
103. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 2013;14:1173-1182.
crossref pmid pmc pdf
104. Oltmanns C, Liu Z, Mischke J, Tauwaldt J, Mekonnen YA, Urbanek-Quaing M, et al. Reverse inflammaging: long-term effects of HCV cure on biological age. J Hepatol 2023;78:90-98.
crossref pmid
105. Hartnell F, Esposito I, Swadling L, Brown A, Phetsouphanh C, de Lara C, et al. Characterizing hepatitis C virus-specific CD4+ T cells following viral-vectored vaccination, directly acting antivirals, and spontaneous viral cure. Hepatology 2020;72:1541-1555.
crossref pmid pmc pdf
106. Ghosh A, Romani S, Kottilil S, Poonia B. Lymphocyte landscape after chronic hepatitis C virus (HCV) cure: the new normal. Int J Mol Sci 2020;21:7473.
crossref pmid pmc
107. Langhans B, Nischalke HD, Krämer B, Hausen A, Dold L, van Heteren P, et al. Increased peripheral CD4+ regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C. J Hepatol 2017;66:888-896.
crossref pmid
108. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007;132:2328-2339.
crossref pmid
109. Telatin V, Nicoli F, Frasson C, Menegotto N, Barbaro F, Castelli E, et al. In chronic hepatitis C infection, myeloid-derived suppressor cell accumulation and T cell dysfunctions revert partially and late after successful direct-acting antiviral treatment. Front Cell Infect Microbiol 2019;9:190.
crossref pmid pmc
110. Lu MY, Yeh ML, Huang CI, Wang SC, Tsai YS, Tsai PC, et al. Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication. World J Gastroenterol 2022;28:140-153.
crossref pmid pmc
111. Debes JD, van Tilborg M, Groothuismink ZMA, Hansen BE, Schulze Zur Wiesch J, von Felden J, et al. Levels of cytokines in serum associate with development of hepatocellular carcinoma in patients with HCV infection treated with direct-acting antivirals. Gastroenterology 2018;154:515-517.e3.
crossref pmid
112. Owusu Sekyere S, Port K, Deterding K, Cornberg M, Wedemeyer H. Inflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis C cirrhotic patients. United European Gastroenterol J 2021;9:486-496.
crossref pmid pmc pdf
113. Macek Jílková Z, Seigneurin A, Coppard C, Ouaguia L, Aspord C, Marche PN, et al. Circulating IL-13 is associated with de novo development of HCC in HCV-infected patients responding to direct-acting antivirals. Cancers (Basel) 2020;12:3820.
crossref pmid pmc
114. Watanabe T, Tokumoto Y, Joko K, Michitaka K, Horiike N, Tanaka Y, et al. AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy. BMC Cancer 2021;21:699.
crossref pmid pmc pdf
115. Yoshimasu Y, Furuichi Y, Kasai Y, Takeuchi H, Sugimoto K, Nakamura I, et al. Predictive factors for hepatocellular carcinoma occurrence or recurrence after direct-acting antiviral agents in patients with chronic hepatitis C. J Gastrointestin Liver Dis 2019;28:63-71.
crossref pmid pdf
116. Yasui Y, Kurosaki M, Komiyama Y, Takada H, Tamaki N, Watakabe K, et al. Mac-2 binding protein predicts early occurrence of hepatocellular carcinoma after sustained virologic response by direct-acting antivirals for hepatitis C virus. Hepatol Res 2018;48:1131-1139.
pmid
117. Biselli M, Conti F, Gramenzi A, Frigerio M, Cucchetti A, Fatti G, et al. A new approach to the use of α-fetoprotein as surveillance test for hepatocellular carcinoma in patients with cirrhosis. Br J Cancer 2015;112:69-76.
crossref pmid pmc pdf
118. Mücke VT, Thomas D, Mücke MM, Waidmann O, Zeuzem S, Sarrazin C, et al. Serum sphingolipids predict de novo hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virologic response. Liver Int 2019;39:2174-2183.
crossref pmid pdf
119. Faillaci F, Marzi L, Critelli R, Milosa F, Schepis F, Turola E, 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;68:1010-1024.
crossref pmid pmc pdf
120. Ramadan HK, Meghezel EM, Abdel-Malek MO, Askar AA, Hetta HF, Mahmoud AA, et al. Correlation between vascular endothelial growth factor and long-term occurrence of HCV-related hepatocellular carcinoma after treatment with directacting antivirals. Cancer Invest 2021;39:653-660.
crossref pmid
121. Huang CF, Huang CY, Yeh ML, Wang SC, Chen KY, Ko YM, et al. Genetics variants and serum levels of MHC class I chain-related A in predicting hepatocellular carcinoma development in chronic hepatitis C patients post antiviral treatment. EBioMedicine 2017;15:81-89.
crossref pmid pmc
122. Huang CF, Wang SC, Yeh ML, Huang CI, Tsai PC, Lin ZY, et al. Association of serial serum major histocompatibility complex class I chain-related A measurements with hepatocellular carcinoma in chronic hepatitis C patients after viral eradication. J Gastroenterol Hepatol 2019;34:249-255.
crossref pmid pdf
123. Pascut D, Cavalletto L, Pratama MY, Bresolin S, Trentin L, Basso G, et al. Serum miRNA are promising biomarkers for the detection of early hepatocellular carcinoma after treatment with direct-acting antivirals. Cancers (Basel) 2019;11:1773.
crossref pmid pmc
124. Tsai YS, Huang CI, Tsai PC, Yeh ML, Huang CF, Hsieh MH, et al. Circulating Let-7 family members as non-invasive biomarkers for predicting hepatocellular carcinoma risk after antiviral treatment among chronic hepatitis C patients. Cancers (Basel) 2022;14:2023.
crossref pmid pmc
125. Nakagawa S, Wei L, Song WM, Higashi T, Ghoshal S, Kim RS, et al. Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition. Cancer Cell 2016;30:879-890.
crossref pmid pmc
126. Liang D, Chen H, Zhao L, Zhang W, Hu J, Liu Z, et al. Inhibition of EGFR attenuates fibrosis and stellate cell activation in diet-induced model of nonalcoholic fatty liver disease. Biochim Biophys Acta Mol Basis Dis 2018;1864:133-142.
crossref pmid
127. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L, et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 2011;17:589-595.
pmid pmc
128. Ninio L, Nissani A, Meirson T, Domovitz T, Genna A, Twafra S, et al. Hepatitis C virus enhances the invasiveness of hepatocellular carcinoma via EGFR-mediated invadopodia formation and activation. Cells 2019;8:1395.
crossref pmid pmc
129. Marti-Aguado D, Clemente-Sanchez A, Bataller R. Cigarette smoking and liver diseases. J Hepatol 2022;77:191-205.
crossref pmid
130. Valenti L, Pelusi S, Aghemo A, Gritti S, Pasulo L, Bianco C, et al. Dysmetabolism, diabetes and clinical outcomes in patients cured of chronic hepatitis C: a real-life cohort study. Hepatol Commun 2022;6:867-877.
crossref pmid pmc pdf
131. Tsai PC, Kuo HT, Hung CH, Tseng KC, Lai HC, Peng CY, et al. Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan. J Hepatol 2023;78:281-292.
crossref pmid
132. Zeng RW, Yong JN, Tan DJH, Fu CE, Lim WH, Xiao J, et al. Meta-analysis: chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin. Aliment Pharmacol Ther 2023;57:600-609.
crossref pmid pmc pdf
133. Goh MJ, Sinn DH. Statin and aspirin for chemoprevention of hepatocellular carcinoma: time to use or wait further? Clin Mol Hepatol 2022;28:380-395.
crossref pmid pmc pdf
134. Ji F, Yeo YH, Wei MT, Ogawa E, Enomoto M, Lee DH, et al. Sustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: a systematic review and meta-analysis. J Hepatol 2019;71:473-485.
pmid
135. Cheng PN, Mo LR, Chen CT, Chen CY, Huang CF, Kuo HT, et al. Sofosbuvir/velpatasvir for hepatitis C virus infection: real-world effectiveness and safety from a nationwide registry in Taiwan. Infect Dis Ther 2022;11:485-500.
pmid
136. Huang CF, Kuo HT, Chang TS, Lo CC, Hung CH, Huang CW, et al. Nationwide registry of glecaprevir plus pibrentasvir in the treatment of HCV in Taiwan. Sci Rep 2021;11:23473.
pmid pmc
137. Yeh ML, Liang PC, Tsai PC, Wang SC, Leong J, Ogawa E, et al. Characteristics and survival outcomes of hepatocellular carcinoma developed after HCV SVR. Cancers (Basel) 2021;13:3455.
crossref pmid pmc
138. Toyoda H, Hiraoka A, Uojima H, Nozaki A, Shimada N, Takaguchi K, et al. Characteristics and prognosis of de novo hepatocellular carcinoma after sustained virologic response. hepatol commun 2021;5:1290-1299.
crossref pmid pmc pdf
139. Jongraksak T, Chuncharunee A, Intaraprasong P, Tansawet A, Thakkinstian A, Sobhonslidsuk A. Outcomes of direct-acting antivirals in patients with HCV decompensated cirrhosis: a systematic review and meta-analysis. Front Med (Lausanne) 2023;10:1295857.
crossref pmid pmc

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 1731
TOTAL : 1941569
Close layer