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Review  |  Open Access  |  15 Feb 2023

Hepatocellular carcinoma after treatment of hepatitis C with direct-acting antivirals: a critical re-appraisal

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Hepatoma Res 2023;9:4.
10.20517/2394-5079.2022.35 |  © The Author(s) 2023.
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Soon after introducing direct-acting antiviral agents (DAAs) for chronic hepatitis C treatment, there began a debate over the possibility of hepatocellular carcinoma (HCC) after viral clearance. Although several reports suggested that the question has been answered negatively, other reports suggested the opposite. The present review presents data in favor and against the null hypothesis and analyzes the scientific background of the possible participation of DAAs in HCC development. The reasons for the discrepancy among studies are presented. These include heterogeneity of patient selection, the nature of the studies, and the tumors themselves are responsible for varying results. Exogenous factors like alcohol consumption or metabolic syndrome confound these findings and suggest the need for statistical adjustments. The need for careful attention to the statistical details is exemplified, and the significant points of almost universal agreements are identified. The conclusion is that the definitive study is impossible for ethical and scientific reasons, and the physician should not ignore even simple personal observations and screening of all patients with extensive fibrosis in HCC, irrespective of sustained virologic response, until a robust, reliable prognostic model can be invented.


Hepatocellular carcinoma, direct-acting antivirals, incidence, recurrence


Direct-acting antivirals (DAAs) have changed the treatment approach to chronic hepatitis C (HCV) as they achieve high sustained virological response rates (SVRs) in cirrhotic patients and prolong overall survival with few side effects[1-3].

The first therapeutic efforts of chronic HCV were based on interferon (IFN) with or without ribavirin. Even then, there was a significant risk of HCC or recurrence after SVR; a yearly incidence of 1.13% was reported[4]. DAA treatment did not change these earlier observations, and incidences between 1.5 and 3.6/100 patient-years were not uncommon[5-7], mainly in cirrhotics with substantial portal hypertension[8]. However, soon after the introduction of DAAs, a debate started on the possibility of higher-than-expected occurrence and recurrence of HCC in patients after SVR[9,10]. Many studies supporting or disputing the initial reports were published. These findings conflict, and the debate continues[11]. A meta-analysis reported that an increased effect of DAAs on HCC recurrence could not be confirmed or refuted because of the extreme heterogeneity of studies[12]. Nevertheless, a commentary on this paper declared an end to the debate, claiming that the matter was settled and DAAs are not associated with HCC recurrence[13].

In this report, we present the evidence in favor and against the increased association of DAAs with HCC and review the possible underlying mechanisms of HCC complicating viral clearance. We focus on the reasons behind the profound diversity of the results published to date and summarize the facts that are beyond dispute by almost all investigators.

In favor of increased HCC after DAAs

Observational studies

Early after the introduction of DAAs, many observational studies reported an alarmingly higher-than-expected occurrence or recurrence of previously-treated HCC after DAA administration. These were uncontrolled reports without a control arm. Nonetheless, these findings could not be ignored, and a heated debate began[9,10,14-17].

An early meta-analysis showed high HCC recurrence rates of 7.4% after six months and 47.0% after two years in untreated patients after an initial curative resection or ablation of HCC, but also extreme variability in recurrence risk and survival[18]. An uncontrolled, real-world Spanish retrospective study confirmed the initial high HCC recurrence rates[19]. Similar unexpectedly high occurrence and recurrence rates were reported in more uncontrolled prospective and retrospective studies[20-25]. A critical observation was that de novo development and HCC recurrence appeared early after DAAs administration[26]. Another essential observation was made by a large retrospective study reporting an increased observed HCC occurrence associated with the time of DAAs introduction and the presence of uncharacterized liver nodules[27]. Early HCC occurrence and increased recurrence in patients with undefined nodules after DAAs treatment was confirmed in a prospective study[28].

Interestingly, the modality used for HCC treatment was associated with the recurrence rate after DAAs. Thus, patients treated with Ttrans arterial chemoembolization (TACE) had a much greater recurrence than other modalities[29]. This observation was confirmed in a multicenter retrospective study that assessed risk factors of late HCC recurrence 24 weeks after SVR with DAAs. The five-year cumulative HCC recurrence rates for the previous curative and palliative treatment groups were 45.4% and 65.7%, respectively[30].

DAAS vs. no treatment

A higher recurrence rate after liver transplantation was reported in patients treated with DAAs than in untreated patients[31]. Increased recurrence was also reported in a large group of patients from a liver transplantation registry in a prospective cohort using untreated patients as the control arm[32]. HCC aggressivity was increased after DAAs treatment compared to treatment-naïve patients[33].

DAAs vs. IFN

Several studies compared DAAs with IFN. A Belgian retrospective study compared DAAs with IFN administration but failed to find differences because the control arm was DAAs plus IFN. Nevertheless, they confirmed an earlier development of HCC in the DAAs-only arm[34]; a retrospective controlled study with IFN as the control arm confirmed this result[35]. An initial analysis of the ANRS CO12 CirVir study showed more HCC in patients treated with DAAs than IFN; however, they attributed the difference to patient characteristics and screening protocols[36]. A large retrospective study analyzed a liver transplant registry and showed that patients during the IFN period had a reduced HCC occurrence rate compared to patients during the DAAs period[37].

Two studies assessed HCC recurrence rates in DAAs-treated patients and compared them with two control groups (IFN administration and no treatment). In the first study, there was a strong trend toward an increased HCC recurrence in transplanted patients who received DAAs before transplantation compared with viremic patients without any treatment, while no difference was observed between DAAs and IFN[38]. In contrast, another study reported a higher recurrence rate in DAAs-treated patients than in IFN-treated patients; however, no difference was found between DAAs and viremic untreated patients[39]. Controlled studies showed similar results. Higher recurrence or occurrence rates were reported in patients treated with DAAs compared with IFN treatment[40-42].

Additional studies

A prospective study found that patients treated with DAAs before radical HCC therapy had a higher and earlier recurrence rate than patients not exposed to DAAs. Recurrence rates were significantly higher in those treated with arterial chemoembolization than in curative treatment[43].

A compelling finding was reported in a prospective Italian study where an earlier occurrence was observed in sofosbuvir-based treatment compared to patients who received ribavirin as part of the treatment protocol[44]. Finally, a prospective study of genotype 3-infected patients compared four sofosbuvir-based treatments with or without ribavirin and IFN. Earlier and higher occurrence rates were observed in cirrhotics without IFN[45].

Table 1 summarizes the studies reporting a higher or earlier HCC development after DAAs administration. It should be noted that the authors of 31% of the studies declared a conflict of interest due to some support by the pharmaceutical companies.

Table 1

Studies reporting increased development of HCC after HCV viral cure

Reig et al.[9]2016RetrospectiveRecurrenceNoUnexpected high
Rinaldi et al.[10]2016RetrospectiveRecurrenceNoUnexpected high
Conti et al.[14]2016RetrospectiveOccur-RecurNoUnexpected high
Kozbial et al.[15]2016RetrospectiveOccurrenceNoUnexpected high
Cardoso et al.[17] 2016RetrospectiveOccurrenceNoUnexpected high
Yang et al.[31]2016RetrospectiveRecurrenceNo treatHigher in DAAs
Ravi et al.[16]2017ProspectiveOccurrenceNoUnexpected high
Worns et al.[158]2017Systematic reviewOccur-RecurrIFNHigher in DAAs
Bielen et al.[34]2017RetrospectiveOccur-RecurIFNSimilar occurrence
Higher recurrence
Calleja et al.[19]2017RetrospectiveRecurrenceNoUnexpected high
El Kassas et al.[32]2018ProspectiveRecurrenceNo treatHigher in DAAs
Kwong et al.[37]2018RetrospectiveOccurrenceNo DAAsHigher in DAAs
Nahon et al.[36]2018RetrospectiveOccurrenceIFNHigher in DAAs
Rinaldi et al.[44]2019RetrospectiveOccurrenceSOF vs. SOF + RibHigher in SOF
Nakano et al.[22]2019ProspectiveRecurrenceNoHigh recurrence
Lashen et al.[20]2019RetrospectiveOccur-RecurNoHigh Recur-Occur
Marino et al.[27]2019RetrospectiveOccurrenceNoUnexpected high
Degasperi et al.[26]2019RetrospectiveOccur-RecurNoHigh Occur-Recur
Kuo et al.[39]2020RetrospectiveRecurrenceIFN-No treatHigher in DAAs vs. IFN. Similar DAAs vs. No treat
Lim et al.[38]2020RetrospectiveRecurrenceIFN- viremicNo difference vs. IFN
DAAs SVR higher than viremic
Tayyab et al.[45]2020ProspectiveOccurrence4 DAAs schemesBetter when IFN added
Fatima et al.[35]2020RetrospectiveAggressivenessIFNSimilar but earlier HCC in DAAs
Sandgiovani et al.[28]2020ProspectiveOccur-RecurNoHigh Occur-Recur
Teng et al.[40]2019RetrospectiveRecurrenceIFNHigher in DAAs
Hassany et al.[21]2020ProspectiveOccurrenceNoUnexpected high
Chan et al.[23]2020RetrospectiveOccur-RecurNoHigh Occur-Recur
Ji et al.[42]2021ProspectiveOccurrenceIFNHigher in DAAs
Fouad et al.[33]2021RetrospectiveAggressivenessNo treatMore aggressive in DAAs
Ahn et al.[24]2021RetrospectiveRecurrenceNoHigh recurrence
Tani et al.[29]2021RetrospectiveRecurrenceNoTACE higher recurrence;
Similar survival recur-non recur
Kamal et al.[25]2021RetrospectiveRecurrenceNoUnexpected high
Karbeyaz et al.[41]2021RetrospectiveOccurrenceIFNHigher in DAAs
Lithy et al.[43]2022ProspectiveRecurrenceNo DAAsHigher in DAAs. Less after radical than palliative. Earlier in DAAs
Ogawa et al.[30]2022RetrospectiveRecurrenceNoHigh late recurrence. Less after radical than palliative

Against an increase of HCC after DAAs

Papers supporting that DAAs did not report an increased occurrence or recurrence of HCC after broadly separating patients into three groups: Those comparing DAAs with no treatment, those comparing SVR and no SVR after DAAs, and those comparing DAAs with IFN-based treatment. There are also some observational papers without any control group for comparison.

DAAs vs. no treatment

The first direct answer to early studies supporting the lack of DAAs implication in HCC development came from two simultaneously published studies. The first was a prospective observational study reporting that treated and untreated patients had similar HCC occurrences[46]. The second study reported that the recurrence rates were similar between those treated with DAAs and those without treatment[47]. In both studies, overall survival was similar between treated and untreated patients, although treatment reduced liver complications. No differences between treated and untreated patients were reported in several subsequent studies, usually using statistical adjustments[12,48-51]. In contrast to the two initial reports, there were studies suggesting that, in addition to similar recurrence rates, the improvement in survival was significant in the treated group[52,53].

A similar recurrence rate was reported in a large retrospective study from North America[54]. This study was heavily criticized for the high heterogeneity of patients and HCC curative treatments despite a high rate of 46% in the first year after the HCC cure[55,56].

Similar results were found when different DAAs regimens were used[57] or after transplantation on HCV-related HCC[58]. As should be expected, there were also papers reporting a reduced HCC recurrence risk after DAAs treatment, always compared to untreated patients[59,60]with[61,62] or without improved survival[63].

SVR vs. no SVR

The second group of papers compared DAAs-treated patients achieving SVR with those still viremic at the end of treatment. Many reported that SVR patients had lower hepatoma occurrence or recurrence rates. However, there was an agreement that several patients, even after SVR, developed HCC[5,64-67]. A study, however, reported that recurrence rates were similar between SVR and viremic patients, but the survival was better after SVR[68] in contrast to a previous paper where no difference in survival was found between SVR and viremic patients[69].

A notable exception is a report indicating that DAAs eradicating HCV in patients with precancerous liver lesions did not increase or decrease HCC occurrence compared with viremic patients[70].

DAAs vs. IFN

In the third group, all comparisons of occurrence between DAAs and IFN were retrospective by necessity. By contrast, recurrence studies were prospective and retrospective with a variable follow-up time, and all but two small studies showed a considerable recurrence rate of around 30% in the DAAs arm.

One study reported a lower recurrence rate in the DAAs arm than in IFN and untreated arms; however, their Kaplan-Meier curves showed no differences among the three arms[71]. Similarly, a propensity score-matched analysis found no difference in occurrence or recurrence between DAAs- and IFN-treated patients[72]. The same conclusions appeared in a meta-analysis from Australia. However, their figures reveal that occurrence and recurrence after DAAS appear earlier[73]. Strong criticism of statistical problems due to the heterogeneity of studies in this meta-analysis was also published[74]. Several additional papers agreed that there was no difference between DAAs and IFN[6,7,75-83].

A compelling finding was confirmed in several studies. Despite the insignificant difference between DAAs and IFN eradication in HCC occurrence and recurrence, the tumors appeared much earlier after DAAs than after IFN[84-87]. In addition, reports demonstrated that occurrence and recurrence are reduced after DAAs compared to IFN[88,89]. In a meta-analysis[89], three additional papers were presented showing lower recurrence rates of HCC in the DAAs group than IFN[76,82,87]; however, this finding is not justified by actual comparisons [Table 2].

Table 2

Studies reporting no higher development of HCC after HCV viral cure

Cheung et al.[46]2016ProspectiveOccurrenceNo treatNo difference. Mortality similar
ANRS study[47]2016RetrospectiveRecurrenceNo treatNo difference. Mortality similar
Minami et al.[71]2016RetrospectiveRecurrenceIFN-No treatNo difference
Kanwal et al.[5]2017RetrospectiveOccurrenceNo SVRReduced in SVR
Wasiry et al.[73]2017Meta-analysisOccur-RecurIFNNo difference
Nagata et al.[72]2017RetrospectiveOccur-RecurIFNNo difference
Ikeda et al.[59]2017RetrospectiveRecurrenceNo treatBetter in DAAs
Li et al.[75]2018RetrospectiveOccurrenceIFNNo difference
Romano et al.[64]2018ProspectiveOccurrenceNo SVRSVR lower
Calvaruso et al.[65]2018ProspectiveOccurrenceNo SVRSVR reduced
Innes et al.[86]2018RetrospectiveOccurrenceIFNNo difference
Ioannou et al.[84]2018RetrospectiveOccurrenceIFNNo difference
Singer et al.[88]2018RetrospectiveOccurrenceNo treat-IFNBetter than IFN
Mettke et al.[48]2018Prosp-RetroOccurrenceNo treatNo difference
Mashiba et al.[85]2018RetrospectiveRecurrenceIFNSimilar, BUT earlier in DAAs
Finkelmeier et al.[6]2018RetrospectiveOccurrenceIFNNo difference
Huang et al.[66]2018Meta-analysisOccur-RecurDAAs-No DAAsLower with DAAs
Mecci et al.[69]2019RetrospectiveOccurrenceNo SVRNo difference. Similar survival
Nishibatake et al.[76]2019RetrospectiveRecurrenceIFNNo difference (P = 0.43)
Nagaoki et al.[87]2019RetrospectiveRecurrenceIFNNo difference (P < 0.37)
Cabibbo et al.[52]2019ProspectiveRecurrenceNo treatNo difference
Carrat et al.[49]2019ProspectiveOccurrenceNo treatNo difference
Mun et al.[57]2019RetrospectiveOccurrenceMultiple DAAsNo difference
Singal et al.[54]2019RetrospectiveRecurrenceNo treatNo difference
Jain et al.[67]2019RetrospectiveRecurrenceNo DAAsBetter after SVR No DAAs better than noSVR
Toyoda et al.[68]2019ProspectiveOccurrenceNo SVRNo difference
Rutledge et al.[7]2019Meta-analysisOccurrenceIFNNo difference
Pinero et al.[58]2020RetrospectiveRecurrenceNo treatReduced in treat
Janjua et al.[78]2020RetrospectiveOccurrenceIFNNo difference? DAAs 6.9/1000PY IFN 1.8/1000PY
Imai et al.[79]2020RetrospectiveRecurrenceIFNNo difference
Shiha et al.[91]2020ProspectiveOccurrenceNoReduced? HCC incidence was 2.917/100PY in cirrhosis NO
Lin et al.[53]2020RetrospectiveRecurrenceNo treatNo difference
Miuma et al.[50]2020RetrospectiveRecurrenceNo treatNo difference
Tahata et al.[80]2020RetrospectiveRecurrenceIFNNo difference
Gorgen et al.[77]2020RetrospectiveRecurrenceIFN-no treatNo difference. Better than no treatment but similar mortality
Lui et al.[60]2020Meta-analysisRecurrenceNo treatBetter after SVR
Tani et al.[92]2020ProspectiveOccurrenceNoLow incidence?
Hamoir et al.[93]2021ProspectiveOccurrenceNoLow incidence
Wu et al.[81]2021RetrospectiveRecurrenceIFNNo difference
Chi et al.[82]2021ProspectiveRecurrenceIFNNo difference (P = 0.13)
Frazzoni[89]2021Meta-analysisRecurrenceIFNDAAs are better than IFN. DAAs early recurrence. Differences among countries
Ismail et al.[83]2021RetrospectiveRecurrence LTIFNNo difference
Ochi et al.[61]2021RetrospectiveRecurrenceNo treatBetter DAAs
Minami et al.[168]2021RetrospectiveOccurrenceIFNNo difference
Toyoda et al.[68]2021RetrospectiveRecurrenceSVR-No SVRNo difference
Sapena et al.[12]2022RetrospectiveRecurrenceNo treatNo difference but no firm conclusions
Chen et al.[63]2022RetrospectiveRecurrenceNo treatBetter in DAAs. Similar survival
Kuromatsu et al.[51]2022RetrospectiveRecurrenceNo treatReduced in treat
Ikenaga et al.[62]2022RetrospectiveRecurrenceNo DAAsBetter after SVR

Observational studies

It has been reasonably argued that this form is the only currently feasible study due to ethical and logistic reasons. It avoids many but not all statistical perplexities[90]. Nevertheless, once again, there are discrepancies among studies. All prospective observational studies compared DAAs-treated to untreated patients; some had no control arm. Most conclusions are that they do not increase or decrease occurrence[91-93].

It should be stressed, however, that in any attempt to evaluate heterogeneous studies with complex designs, investigators should remember that a non-significant P-value does not mean that the null hypothesis is confirmed. As Altman and Bland put it, “absence of evidence is not evidence of absence”[94].

Table 2 summarizes the studies reporting that DAAs administration is not associated with increased development of HCC. It should be noted that the authors of 61% of the studies declared a conflict of interest due to some support by the pharmaceutical companies.

An explanation for increased HCC after DAAS

All these studies, whether positive or negative, agree that the risk of HCC development is real despite SVR. Various explanations have been proposed.

The pathogenesis of HCC in HCV infection is multifactorial. There is a fundamental difference between HCV-related HCC and other cancers. Sequential mutations of oncogenes and tumor suppressor genes are necessary for developing tumors such as colorectal cancer (Vogelstein-type). This phenomenon may or may not be necessary for HCV-related HCC, where core protein expression contributes to the induction of HCC, even without a complete set of genetic aberrations required for carcinogenesis (non-Vogelstein-type)[95]; they usually cause epigenetic alterations and dysregulation of signaling pathways. A report summarized histone modifications, DNA methylation abnormalities of 18 gene targets, and various signaling pathways[96]. A multi-gene transcription profile was identified in HCV-associated cirrhosis that may be used as a prognostic biomarker of HCC development[97-99]. Factors associated with HCC in HCV were reviewed[100,101].

DAAs treatment can remove the HCV patient serum; however, epigenetic abnormalities in cells persist despite the absence of the virus[102]. Reig et al. proposed an immunological explanation based on a rapid fall in antigenic load during DAAs eradication leading to hypo-responsiveness of memory T cells and, therefore, a possible breakdown of immune surveillance[103]. The finding supports this proposition that immune surveillance by CD8+ T lymphocytes was reduced after HCV eradication by DAAs, possibly mediated through IL-12[104]. An analysis of immune cells before and after DAAs revealed the long-term persistence of immune exhaustion, possibly causing an irreversible defect in the immune system[105].

Epigenetic alterations are associated with an increased risk of HCC and form an “epigenetic signature” of eight genes persisting after DAAs treatment. Drugs that inhibit epigenetic modifying enzymes suppress this signature[106-108]. Epigenetic alterations regulate the expression of genes leaving the nucleotide sequence unaffected. Viral proteins are responsible for hyper and hypo-DNA methylation affecting the natural killer cell-dependent innate immune response[109,110].

Additional factors are involved in the pathogenesis of HCV-associated HCC. The gut microbiota may be causally associated with HCC through inflammation and fibrosis. HCV clearance with DAAs in patients with cirrhosis modifies the gut microbiota but does not influence the dysregulated intestinal barrier function[111]. A compelling finding was the overexpression of human endogenous retroviruses (HERV)-H-pol and HERV-K-pol proteins that persisted after DAAs eradication of HCV, suggesting that overexpression of HERVs (which constitute 8% of the human genome) may predispose to HCC[112].

Other factors not restored in liver tissue after DAAs treatment that may contribute to HCC are the decrease of microRNA-122 and the upregulation of oncogenic transcriptomic profiles like CYR61[113-115]. Moreover, a reduction of mucosal-associated invariant T cell cytotoxicity, possibly caused by rapid phenotyping changes of these cells after DAAs treatment, attenuates their action against cancer cells. SVR achieved after DAAs does not correct the increased frequency of regulatory T cells observed in chronic HCV infection, leading to a local immunosuppressive environment inhibiting the clearance of cancer cells[116]. A detailed overview of immunological factors not restored after DAAs obtained SVR[117].

Non-immunological factors were also investigated. HCV infection causes endoplasmic reticulum stress responses, degradation of p53 in lysosomes, and dysregulation of autophagy. These abnormalities are corrected after IFN-induced HCV eradication but not after DAAs[118-120]. Given this, many HCV patients have non-alcoholic fatty liver disease features, which may be partly responsible for HCC occurrence or recurrence after SVR[121]. Neo-angiogenesis may also favor HCC development, and markers of angiogenesis, like VEGF and angiopoietin-2, either increase or persist during or after DAAs administration[122,123]. Another explanation for HCC recurrence and occurrence after DAAs was proposed after the finding that SVR achievement with DAAs was accompanied by a high prevalence of occult HCV persistence in peripheral blood mononuclear cells[124,125]. This occult persistence was not observed when ribavirin was added to the DAAs scheme[126].

In contrast, there have been reports that the development of HCC after DAAs eradication is genetically associated with a single-nucleotide polymorphism identified using genome-wide analysis[127]. Potential mechanisms for HCC recurrence after DAAs treatment have been reviewed[128-130]. It should be noted, however, that there is no direct evidence of incriminating DAAs in hepatic carcinogenesis.

Reasons for problems

Papers described the many variables that influence every attempt to clarify the problem of HCC after DAAs eradicate HCV infection. They found an extreme variation in HCC occurrence or recurrence among reported studies ranging between 0 and 7.4% for occurrence and 0% to 54.4% for recurrence[100,131].

We analyzed the explanations for discrepancies among published studies.

Heterogeneity of studies

A review of the problem noted that the heterogeneity of studies was significant irrespective of the primary outcome and pointed to the difficulty of comparisons, particularly when an untreated group is used as the control[18]. A meta-analysis reported high geographical differences in HCC development after DAAs. Recurrence rates increased when moving from Europe (23%) to the US (34%) to Egypt (37%) and Asia (33%). These studies showed extreme heterogeneity (I² = 84.7%)[89]. The reason for these differences is not apparent.

Most studies use simple classification based on clinical parameters to distinguish patient groups. One study reported that the development of HCC depended on the response to treatment. Other biochemical predictors were found in patients without SVR compared with those with SVR. They classified their patients into eight phenotypes according to HCC risk. However, patients without SVR but a good liver biochemical profile were found to have similar low five-year incidence to those with SVR[132].

Other studies suggested that fibrosis and the previous tumor burden are more critical than the type of treatment for HCC occurrence or recurrence. However, estimation of the degree of fibrosis is challenging without a liver biopsy; even among cirrhotics, the degree of fibrosis is not identical. The same is true for accurately estimating the tumor burden[133]. In addition, the diagnosis of cirrhosis in most studies is based on elastography findings or indirect scores like FIB4 or APRI (with all the problems associated with these tests). Definite diagnosis based on liver biopsy is rare. The severity of cirrhosis should also be considered. Unfortunately, no accurate clinical marker can be used to that end. Albumin is not directly related to the severity of cirrhosis, and many studies show either no difference among groups or very low significance. Currently, the best indicator of the severity of cirrhosis appears to be the hepatic venous pressure gradient; unfortunately, this index is rarely, if ever, available.

Heterogeneity of HCCs

Several lines of evidence suggest that all hepatocellular carcinomas are not similar, and several publications addressed a variety of risk indicators, including genetic single-nucleotide polymorphisms[134]. The increased heterogeneity of HCCs is a problem in many other aspects of HCC and is not unique in HCC occurrence or recurrence after DAAs. Heterogeneity is present even when the Child classification is used as many studies include only Child A cirrhotics, while others include both Child B and sometimes Child C patients.

Liu et al. demonstrated that a viral exposure signature predicts HCC in at-risk patients with long-term follow-up for HCC development[135]. These data suggest a new approach to grading cancer risk that, combined with established parameters, could become the clue to define the absence of HCC risk[135].

The CRAFITY score, based on the estimations of CRP and alpha-fetoprotein levels, was validated as HCC biomarkers associated with survival, allowing for a much better classification of patients about to receive immunotherapy[136]. There was some criticism of the retrospective design and lack of comparisons with other available tests[137]. Nevertheless, these studies occurred during the era of individualized medicine[138].

A possible revolution is expected in the classification of HCC that will affect future clinical trials and predict the development of the tumors or the response to therapies. Most advances are due to the progress of the so-called “omics” technologies.

Immunogenomics identified six tumor subtypes with different microenvironments[139]. Transcriptomics identified three subtypes associated with three hepatocellular metabolic pathways: the WNT/β-catenin pathway, telomere maintenance, and several subtype-specific genes[140,141]. Proteomics also classified subtypes of HCC while integrating with transcriptomic data and identified two genes associated with poor survival in addition to 18 tumorigenesis genes[142,143]. Integration of data also revealed that changes caused by the MYC oncogene were implicated in vascular invasion[144]. The new molecular and genetic classifications of HCC have been reviewed[145,146].

The tumor cell population is highly heterogeneous between tumors and within a tumor. New data are also emerging from single-cell technology, allowing for more accurate classification of HCC sub-groups. Inter- and intratumoral differences can be identified using this technology to better understand HCC biology[147]. The single-cell analysis demonstrated that an upregulation of the inhibitor of apoptosis MLX interacting protein-like (MLXIPL) was related to poor survival in HCC[148]. HCC survival was also deceased in association with a proliferating cell type identified in HCC tumors[149].

Combined data from genomics and transcriptomics allowed for classifying HCC into three subtypes, CTNNB1-mutated, proliferative, and metabolic disease-associated, with different molecular characteristics[150].

HCC molecular signatures have been rarely used in clinical decision-making as they are not widely available, and some are cumbersome. However, their generalized use will completely change our clinical perception of HCC behavior[151].

Efforts to correct for heterogeneity include statistical tests like multivariate analysis or propensity score matching to account for confounding factors. However, the exclusion of selection bias is highly doubtful, as discussed[84].

The heterogeneity of methods, patients, and tumor variability may lead to studies reporting disparate results. Nevertheless, not all discrepancies are due to bias and statistical imputation[90]. Unfortunately, there are many more problems.

Time of DAAs treatment after HCC treatment

It was suggested that the interval between the curative intervention and the initiation of DAAs treatment is essential for the recurrence of HCC[152]. Thus, the interval was significantly higher in patients without recurrence than in those with recurrence (36 months and seven months, respectively)[153]. This was true even when hepatectomy was used as the modality of complete HCC treatment before DAAs initiation[154].

An essential time association between IFN-free treatment and HCC development was reported as HCC appeared earlier in the IFN-free treated than in the IFN-treated patients[90]. This observation has been repeatedly confirmed, and most studies report an interval between 6 months and one year for the recurrence of HCC after DAAs[24,27,76,155,156].

Based on these observations, experts suggested that after curative treatment of HCC by liver resection or ablation, the initiation of DAAs should be deferred. The precise timing remains debatable[157].

The German Alliance for Liver Cancer proposed that DAAs initiation should start 6-12 months after HCC curative intervention[158]. The American Gastroenterology Association suggests that DAAs initiation can be deferred for 4-6 months after HCC curative treatment[155]. A six-month delay was recommended in another systematic review[159].

However, a study of transplanted patients with HCV-related HCC recommended that a delay should be avoided, and treatment should begin within 0-3 months after transplantation[160].

It should be expected that, with such heterogeneity of studies, conflicting results would appear. Reports have demonstrated that the delay time is not critical for HCC recurrence[161]. Another report supported this finding where there was no significant difference between those with delayed treatment and those with early administration. However, more patients (41%) with early initiation developed HCC recurrence than 30% with delayed administration. The lack of significance was obviously due to the small number of patients[26].

Time of follow-up

The evidence suggests that the follow-up time for HCC recurrence should exceed one year if late recurrence is to be identified[162]. Moreover, a report showed that the median time between SVR and the occurrence of HCC was 28.1 months, suggesting that shorter follow-up times may underestimate the occurrence rate[163]. Nevertheless, there is at least one well-documented case of HCC occurrence eight years after liver transplantation[164]. In many studies, there was a shorter duration of follow-up in DAAs-treated patients than in IFN-treated patients, which might affect the comparison of HCC occurrence; however, in most studies, the occurrence of HCC occurs earlier after DAAs.

The role of alcohol

There are several papers indicating that studies should consider ethanol consumption. HCV-related cirrhosis had a significantly lower decompensation rate than patients with HCV and alcohol consumption[165]. Moreover, primary liver cancer and alcohol were the most significant causes of death in HCV patients who achieved SVR, while high alcohol consumption was associated with an increased rate of HCC occurrence or recurrence after the achievement of SVR with DAAs treatment[5,27,28,166-168]. This observation was confirmed[169].

The role of diabetes and the metabolic syndrome

Obesity, diabetes, and metabolic syndrome are associated with increased morbidity and mortality in HCV infection[170]. These factors might influence the occurrence and recurrence rates of HCC development after SVR is achieved by IFN or DAAs treatment[5,69,171].

In two studies from Italy, diabetes was identified as a risk factor for the three-year probability of HCC occurrence or recurrence after DAAs[26,172]. Notably, the presence of obesity and metabolic syndrome has drawn more attention than those of earlier years[42,167,173]. Interestingly, increased glycation end-products were suggested as a causative factor of increased HCC incidence in diabetes[174], while a genetic component with somatic mutations in the tumor suppressor gene ACVR2A was also significantly associated with HCC[121].

A meta-analysis showed that diabetes significantly increased the risk of HCC occurrence in the entire group of HCV patients treated with DAAs; however, the risk was insignificant in patients achieving SVR[175]. The significance of non-alcoholic fatty liver disease (and alcohol) in developing HCC despite the achievement of SVR by DAAs has been suggested in reviews[130,176].

The role of HIV

The significance of HIV co-infection in HCC occurrence or recurrence is controversial. HIV co-infected patients were reported to have an earlier appearance and worse HCC outcomes[177]; however, those who achieved SVR after DAAs appeared to have a lower risk of HCC occurrence[178]. To add further confusion, no difference in the HCC incidence was reported in HIV co-infected patients[179].

The role of intravenous drug use

The role of intravenous drugs in developing HCC after HCV elimination by DAAs has not been extensively studied. However, it is essential to note that DAAs viral clearance does not protect from re-infection in intravenous drug users[117].

Concluding remarks

There is considerable discussion among researchers worldwide on several aspects of HCC management. There are two points of agreement on the question of DAAs and HCC, while one point is still debated. Agreement appears to exist on the surveillance issue and the time of DAAs introduction after the initial treatment of HCC. In contrast, the high risk of HCC occurrence or recurrence in cirrhotic patients who received DAAs remains open despite efforts to declare that the problem has been settled[117].

Screening for HCC development after DAAs viral cure

The need for careful monitoring for HCC occurrence or recurrence after DAAs is widely recognized. Studies indicate a substantial risk of death from HCC 5-10 years after DAAs eradication in patients with extensive fibrosis or cirrhosis[180,181]. Studies indicate that patients with[12,129] or without cirrhosis[68] should be followed up, as SVR obtained after DAAs reduces but does not abolish HCC occurrence or recurrence[22,36,68,179,182-184]. The risk is higher if SVR is not achieved[185].

Most reports recommend that patients after SVR achievement should be followed in a surveillance program[186-188].

All three major liver associations agree that cirrhotics should be indefinitely followed after SVR; however, there are differences in their recommendations for patients with advanced fibrosis without cirrhosis. The European and Asian associations recommend surveillance, but the American does not[189]. A large study on stage 3 fibrosis reported that most patients have a low risk of HCC after SVR; however, this was not the case for males over 55 years old[190].

Surveillance cost is a severe problem for most economies, particularly in the SARS-CoV-2 era, due to the large number of patients involved. To reduce the burden, investigators developed several prediction models[129,191,192], but none has been universally accepted.

Time of DAAs introduction after HCC treatment

The AGA Clinical Practice Update recommendation is that DAAS should be introduced after HCC curative therapy is completed and should be deferred for 4-6 months after HCC radical treatment[155]. However, most investigators agree that treatment with DAAS should be postponed for at least 6-12 months after successful treatment of HCC[11,157]. The theoretical justification for the delayed administration may be that the delay allows the immune surveillance to recover and that the verification of the treatment success is more accurate[157].

DAAs and HCC development

There have been two general opinions. The first is that the question has been solved once and for all in favor of DAAs[193]. Interestingly, some investigators changed their attitude toward their earlier observations[10,44] after reviewing new data[194]. Some investigators use strong expressions like “another nail in the coffin of the association of DAAs with HCC”[195] or claim that the story has ended[13] even though their comment was based on one study concluding that the effect of DAAs on HCC recurrence risk was inconclusive[12].

Three reviews, one by some authors[196] of the previous study[12], also agreed that the survival of HCC patients treated with DAAs is significantly improved[196-198]. However, the final issue remains unresolved, as many studies, including those that report no effect of DAAs in HCC development, found no difference in survival between treated and untreated patients [Tables 1 and 2]. The answer to this problem is critical. If survival is similar, it would be challenging to suggest further treatment after HCC cure and SVR, or as Sanduzzi-Zamparelli et al. point out, “until further information is available”[199].

The second opinion is that the matter has not been settled, and all available studies produce conflicting results[55,56,155,200,201].

The primary reason for such divergent views is the extreme heterogeneity of studies[131,202]. One of the problems is the presence of ribavirin in the IFN-treated groups. Ribavirin affects total DNA and RNA synthesis[203].This phenomenon may be further implicated in interpreting results, as in most studies, there is no discrimination between IFN + Rib and IFN monotherapy patients. Moreover, some papers included ribavirin in the DAAs treatment groups. Two examples come from Japan[71,168].

An observation demonstrated an interesting problem connected to the heterogeneity of studies. Retrospective studies underestimate HCC development compared to prospective studies[204]. Another reason that should be seriously considered is geographical variation[11,89].

The situation has been elegantly exemplified in a review of HCC recurrence after DAAs, where all results are available. HCC recurrence increased, decreased, or showed no difference[157]. A similar situation was demonstrated for the occurrence of HCC after DAAs[6,8,180,182].

Given the practically unresolved problems of heterogeneity, it should be stressed that all studies are based on statistical manipulations to incorporate as many confounding factors as possible. Although this is a perfectly accepted practice, it may produce precarious results. An example is revealed by a study of HCC after IFN treatment. In a multivariate analysis of risk factors, the use of illicit drugs appeared to offer strong protection against HCC development [subdistribution hazard ratio (SHR) = 0.27][205]. Moreover, patients with an SVR and viral cure have much higher overall mortality than viremic patients[205].

In another study, a misleading Forest plot line appeared in a DAAs meta-analysis of HCC occurrence. In the IFN occurrence Forest plot, the vertical line was placed correctly at 1 of the horizontal axis. In contrast, in the DAAs occurrence Forest plot, the line was not placed at 1. If one replaces the line at 1, it is evident that occurrence after DAAS is significantly increased[73].

What is the ideal study to resolve the problem?

A robust, correctly designed study is needed, including patients with comorbidities[197,206].

Such a study should be prospective, with patients carefully matched for alcohol consumption, the presence of metabolic syndrome, and diabetes, preferably after a liver biopsy. Most importantly, the selection of HCC patients for recurrence studies should be performed based on the current molecular classification of HCC and followed up for long intervals under careful surveillance. The control arms should be untreated patients (which is, by definition, unethical)[84].

Even if a study with these requirements were possible, the need for statistical adjustments would remain. Since this definitive study does not appear feasible, it is time for the debate to be halted, and the opposing attitudes should be reconciled, even though the final answer will be doubtful.

An essential observation of liver diseases was published two decades ago. The authors suggested that the 20-year survival of the scientific truth did not differ between randomized controlled trials and nonrandomized studies, while worse truth survival was observed in the meta-analyses! More importantly, the investigators found that conclusions based on suitable methodology and those based on poor methodology remained true for a similar period. This somewhat unorthodox view should be recalled when criticizing papers heavily based on statistical adjustments [207,208].

From the clinician’s point of view, it should be remembered that, when facing the individual patient, not all propensity score matches are applicable, and crude non-controlled observational data may be nearer to the clinical situation and should not be ignored. Unless a robust prognostic model is invented, all patients, even those with less extensive fibrosis, should be carefully monitored for the occurrence or recurrence of HCC after DAAs treatment.


Authors’ contributions

Designed the study and revised the final manuscript: Kouroumalis E

Performed data acquisition and wrote the first draft: Tsomidis I

Performed data analysis and interpretation and supervised the manuscript: Voumvouraki A

Availability of data and materials

Not applicable.

Financial support and sponsorship


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.


© The Author(s) 2023.


1. Salmon D, Mondelli MU, Maticic M, Arends JE. ESCMID Study Group for Viral Hepatitis. The benefits of hepatitis C virus cure: every rose has thorns. J Viral Hepat 2018;25:320-8.

2. Dang H, Yeo YH, Yasuda S, et al. Cure with interferon-free direct-acting antiviral is associated with increased survival in patients with hepatitis C virus-related hepatocellular carcinoma from both east and west. Hepatology 2020;71:1910-22.

3. Park H, Wang W, Henry L, Nelson DR. Impact of all-oral direct-acting antivirals on clinical and economic outcomes in patients with chronic hepatitis c in the united states. Hepatology 2019;69:1032-45.

4. 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.

5. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017;153:996-1005.e1.

6. Finkelmeier F, Dultz G, Peiffer KH, et al. Risk of de novo hepatocellular carcinoma after hcv treatment with direct-acting antivirals. Liver Cancer 2018;7:190-204.

7. Rutledge SM, Zheng H, Li DK, Chung RT. No evidence for higher rates of hepatocellular carcinoma after direct-acting antiviral treatment: a meta-analysis. Hepatoma Res 2019;5:31.

8. Semmler G, Binter T, Kozbial K, et al. Noninvasive risk stratification after HCV eradication in patients with advanced chronic liver Disease. Hepatology 2021;73:1275-89.

9. 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.

10. Rinaldi L, Di Francia R, Coppola N, et al. Hepatocellular carcinoma in hcv cirrhosis after viral clearance with direct acting antiviral therapy: preliminary evidence and posssible meanings. WCRJ 2016; 3:748.

11. Kassas M, Tawheed A, Eltabbakh M, Kaseb A. Hepatitis C antiviral therapy in patients with successfully treated hepatocellular carcinoma: dancing with wolves. J Hepatocell Carcinoma 2019;6:183-91.

12. 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.

13. Hernaez R, Thimme R. End of the story: direct-acting antiviral agents are not associated with recurrence of hepatocellular carcinoma. Gut 2022;71:454-6.

14. 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.

15. Kozbial K, Moser S, Schwarzer R, et al. Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment. J Hepatol 2016;65:856-8.

16. Ravi S, Axley P, Jones D, et al. Unusually high rates of hepatocellular carcinoma after treatment with direct-acting antiviral therapy for hepatitis C related cirrhosis. Gastroenterology 2017;152:911-2.

17. Cardoso H, Vale AM, Rodrigues S, et al. High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis. J Hepatol 2016;65:1070-1.

18. 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.

19. Calleja JL, Crespo J, Rincón D, et al. Spanish Group for the Study of the Use of Direct-acting Drugs Hepatitis C Collaborating Group. Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real-world cohort. J Hepatol 2017;66:1138-48.

20. Lashen SA, Shamseya MM, Madkour MA. Hepatocellular carcinoma occurrence/recurrence after direct-acting antivirals for hepatitis C in egyptian cohort: single-center experience. Dig Dis 2019;37:488-97.

21. Hassany SM, Hassan W, Abo-Alam H, et al. Direct-acting antiviral drugs and occurrence of hepatocellular carcinoma: unjust or oppressed. Infect Drug Resist 2020;13:1873-80.

22. 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.

23. Chan PPY, Levy MT, Shackel N, Davison SA, Prakoso E. Hepatocellular carcinoma incidence post direct-acting antivirals in hepatitis C-related advanced fibrosis/cirrhosis patients in Australia. Hepatobiliary Pancreat Dis Int 2020;19:541-6.

24. 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.

25. Kamal A, Elmoety AAA, Rostom YA, Shater MS, Lashen SA. Hepatocellular carcinoma recurrence after directly acting antivirals for chronic hepatitis C: a 2-year follow-up study. Clin Exp Hepatol 2021;7:66-73.

26. Degasperi E, D'Ambrosio R, Iavarone M, et al. Factors associated with increased risk of de novo or recurrent hepatocellular carcinoma in patients with cirrhosis treated with direct-acting antivirals for HCV infection. Clin Gastroenterol Hepatol 2019;17:1183-1191.e7.

27. Mariño Z, Darnell A, Lens S, et al. Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: Relevance of non-characterized nodules. J Hepatol 2019;70:874-84.

28. 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.

29. 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.

30. 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.

31. Yang JD, Aqel BA, Pungpapong S, Gores GJ, Roberts LR, Leise MD. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol 2016;65:859-60.

32. 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.

33. Fouad M, El Kassas M, Ahmed E, El Sheemy R. Tumor characteristics of hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C: Comparative analysis with antiviral therapy-naive patients. World J Hepatol 2021;13:1743-52.

34. Bielen R, Moreno C, Van Vlierberghe H, et al. The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C-infected patients treated with direct-acting antivirals with and without pegylated interferon: a belgian experience. J Viral Hepat 2017;24:976-81.

35. Fatima T, Mumtaz H, Khan MH, et al. Patterns of hepatocellular carcinoma after direct antiviral agents and pegylated-interferon therapy. Cureus 2020;12:e11565.

36. Nahon P, Layese R, Bourcier V, et al. ANRS CO12 CirVir Group. Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in Patients with cirrhosis included in surveillance programs. Gastroenterology 2018;155:1436-1450.e6.

37. Kwong AJ, Kim WR, Flemming JA. De novo hepatocellular carcinoma among liver transplant registrants in the direct acting antiviral era. Hepatology 2018;68:1288-97.

38. 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.

39. 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.

40. Teng W, Jeng WJ, Yang HI, et al. Interferon is superior to direct acting antiviral therapy in tertiary prevention of early recurrence of hepatocellular carcinoma. Cancers (Basel) 2019;12:23.

41. Karbeyaz F, Kissling S, Jaklin PJ, et al. Rates of hepatocellular carcinoma after start of treatment for chronic hepatitis C remain high with direct acting antivirals: analysis from a swiss liver transplant center. J Hepatocell Carcinoma 2021;8:565-74.

42. Ji D, Chen GF, Niu XX, 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.

43. Lithy RM, Elbaz T, H Abdelmaksoud A, et al. Survival and recurrence rates of hepatocellular carcinoma after treatment of chronic hepatitis C using direct acting antivirals. Eur J Gastroenterol Hepatol 2022;34:227-34.

44. Rinaldi L, Perrella A, Guarino M, et al. Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study. J Transl Med 2019;17:292.

45. Tayyab GUN, Rasool S, Nasir B, Rubi G, Abou-Samra AB, Butt AA. Hepatocellular carcinoma occurs frequently and early after treatment in HCV genotype 3 infected persons treated with DAA regimens. BMC Gastroenterol 2020;20:93.

46. Cheung MCM, Walker AJ, Hudson BE, et al. HCV Research UK. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol 2016;65:741-7.

47. collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts); Electronic address: 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.

48. Mettke F, Schlevogt B, Deterding K, et al. Interferon-free therapy of chronic hepatitis C with direct-acting antivirals does not change the short-term risk for de novo hepatocellular carcinoma in patients with liver cirrhosis. Aliment Pharmacol Ther 2018;47:516-25.

49. Carrat F, Fontaine H, Dorival C, et al. French ANRS CO22 Hepather cohort. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet 2019;393:1453-64.

50. Miuma S, Miyamoto J, Taura N, et al. Influence of interferon-free direct-acting antiviral therapy on primary hepatocellular carcinoma recurrence: a landmark time analysis and time-dependent extended cox proportional hazards model analysis. Intern Med 2020;59:901-7.

51. Kuromatsu R, Ide T, Okamura S, et al. Hepatitis C virus elimination using direct acting antivirals after the radical cure of hepatocellular carcinoma suppresses the recurrence of the cancer. Cancers (Basel) 2022;14:2295.

52. 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.

53. Lin WC, Lin YS, Chang CW, et al. Impact of direct-acting antiviral therapy for hepatitis C-related hepatocellular carcinoma. PLoS One 2020;15:e0233212.

54. Singal AG, Rich NE, Mehta N, 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.

55. Nault JC, Nahon P. Can we move on from the discussion of direct antiviral agents and risk of hepatocellular carcinoma recurrence? Gastroenterology 2019;156:1558-60.

56. Serviddio G, Villani R. The effect of direct-acting antivirals on hepatocellular carcinoma recurrence: still waiting for the turning point. Hepatobiliary Surg Nutr 2019;8:525-6.

57. Mun EJ, Green P, Berry K, Ioannou GN. No difference between direct-acting antivirals for hepatitis C in hepatocellular carcinoma risk. Eur J Gastroenterol Hepatol 2019;31:47-52.

58. Piñero F, Boin I, Chagas A, et al. Direct-acting antivirals and hepatocellular carcinoma: no evidence of higher wait-list progression or posttransplant recurrence. Liver Transpl 2020;26:640-50.

59. 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.

60. 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.

61. 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.

62. Ikenaga H, Uchida-Kobayashi S, Tamori A, et al. Direct-acting antivirals reduce the risk of tumour progression of hepatocellular carcinoma after curative treatment. J Viral Hepat 2022;29:52-9.

63. Chen YS, Huang KH, Wang PM, et al. The impact of direct-acting antiviral therapy on the risk of recurrence after curative resection in patients with hepatitis-C-virus-related early stage hepatocellular carcinoma. Medicina (Kaunas) 2022;58:259.

64. Romano A, Angeli P, Piovesan S, et al. Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: a prospective population study. J Hepatol 2018;69:345-52.

65. Calvaruso V, Cabibbo G, Cacciola I, et al. Rete Sicilia Selezione Terapia-HCV (RESIST-HCV). Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents. Gastroenterology 2018;155:411-421.e4.

66. Huang P, Liu M, Zang F, et al. The development of hepatocellular carcinoma in HCV-infected patients treated with DAA: a comprehensive analysis. Carcinogenesis 2018;39:1497-505.

67. Jain A, Miller D, Schreibman I, et al. Is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct-acting antiviral therapy? Hepatol Int 2019;13:190-8.

68. Toyoda H, Hiraoka A, Uojima H, et al. Characteristics and prognosis of de novo hepatocellular carcinoma after sustained virologic response. Hepatol Commun 2021;5:1290-9.

69. Mecci AJ, Kemos P, Leen C, et al. HCV Research UK. The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis. Aliment Pharmacol Ther 2019;50:204-14.

70. Toyoda H, Kumada T, Tada T, et al. The impact of HCV eradication by direct-acting antivirals on the transition of precancerous hepatic nodules to HCC: a prospective observational study. Liver Int 2019;39:448-54.

71. Minami T, Tateishi R, Nakagomi R, et al. The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma. J Hepatol 2016;65:1272-3.

72. 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.

73. 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.

74. Cammà C, Leandro G. Direct antiviral agents and risk of HCC: waiting for Godot. J Hepatol 2018;68:614-6.

75. Li DK, Ren Y, Fierer DS, et al. The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study. Hepatology 2018;67:2244-53.

76. 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.

77. Gorgen A, Galvin Z, Huang AC, et al. The impact of direct-acting antivirals on overall mortality and tumoral recurrence in patients with hepatocellular carcinoma listed for liver transplantation: an international multicenter study. Transplantation 2020;104:2087-96.

78. Janjua NZ, Wong S, Darvishian 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;27:781-93.

79. Imai K, Takai K, Hanai T, Suetsugu A, Shiraki M, Shimizu M. Sustained virological response by direct-acting antivirals reduces the recurrence risk of hepatitis C-related hepatocellular carcinoma after curative treatment. Mol Clin Oncol 2020;12:111-6.

80. 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.

81. Wu KC, Lee IC, Chi CT, et al. Comparable benefits of HCV eradication by direct acting antivirals and interferon-based therapy in patients with hepatocellular carcinoma undergoing surgical resection. Am J Cancer Res 2021;11:5526-42.

82. 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.

83. Ismail MS, Mohamed I, Polychronopoulou E, et al. Outcomes in the era of interferon-free direct-acting antiviral therapy after liver transplantation in patients with hepatitis C virus and hepatocellular carcinoma. J Hepatocell Carcinoma 2021;8:701-11.

84. Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol ;2017:25-32.

85. 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.

86. Innes H, Barclay ST, Hayes PC, et al. The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: Role of the treatment regimen. J Hepatol 2018;68:646-54.

87. Nagaoki Y, Imamura M, Nishida Y, et al. The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: comparison with interferon-based therapy. J Med Virol 2019;91:650-8.

88. Singer AW, Reddy KR, Telep LE, et al. Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study. Aliment Pharmacol Ther 2018;47:1278-87.

89. Frazzoni L, Sikandar U, Metelli F, et al. Hepatocellular carcinoma recurrence after hepatitis c virus therapy with direct-acting antivirals. a systematic review and meta-analysis. J Clin Med 2021;10:1694.

90. Sapena V, Rios J, Torres F, et al. Reply to: “Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: relevance of non-characterized nodules - a response”. J Hepatol 2019;71:447-8.

91. 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.

92. Tani J, Morishita A, Sakamoto T, et al. Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All Kagawa Liver Disease Group Study. Oncol Lett 2020;19:2205-12.

93. Hamoir C, Horsmans Y, Stärkel P, Dahlqvist G, Negrin Dastis S, Lanthier N. Risk of hepatocellular carcinoma and fibrosis evolution in hepatitis C patients with severe fibrosis or cirrhosis treated with direct acting antiviral agents. Acta Gastroenterol Belg 2021;84:25-32.

94. Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995;311:485.

95. Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol Hepatol 2007;22 Suppl 1:S108-11.

96. Zhao P, Malik S, Xing S. Epigenetic mechanisms involved in HCV-induced hepatocellular carcinoma (HCC). Front Oncol 2021;11:677926.

97. Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008;359:1995-2004.

98. Hoshida Y, Villanueva A, Sangiovanni A, et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 2013;144:1024-30.

99. Nakagawa S, Wei L, Song WM, et al. Precision Liver Cancer Prevention Consortium. Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition. Cancer Cell 2016;30:879-90.

100. Hayes CN, Zhang P, Zhang Y, Chayama K. Molecular mechanisms of hepatocarcinogenesis following sustained virological response in patients with chronic hepatitis C virus infection. Viruses 2018;10:531.

101. Goto K, Roca Suarez AA, Wrensch F, Baumert TF, Lupberger J. Hepatitis C virus and hepatocellular carcinoma: when the host loses its grip. Int J Mol Sci 2020;21:3057.

102. 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.

103. 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.

104. Owusu Sekyere S, Schlevogt B, Mettke F, et al. HCC Immune surveillance and antiviral therapy of hepatitis C virus infection. Liver Cancer 2019;8:41-65.

105. Wedemeyer H, Khera T, Strunz B, Björkström NK. Reversal of immunity after clearance of chronic HCV infection-all reset? Front Immunol 2020;11:571166.

106. Perez S, Kaspi A, Domovitz T, et al. Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet 2019;15:e1008181.

107. Hamdane N, Jühling F, Crouchet E, et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology 2019;156:2313-2329.e7.

108. Li MM, Tang YQ, Gong YF, et al. Development of an oncogenic dedifferentiation SOX signature with prognostic significance in hepatocellular carcinoma. BMC Cancer 2019;19:851.

109. Okamoto Y, Shinjo K, Shimizu Y, et al. Hepatitis virus infection affects DNA methylation in mice with humanized livers. Gastroenterology 2014;146:562-72.

110. Zheng Y, Hlady RA, Joyce BT, et al. DNA methylation of individual repetitive elements in hepatitis C virus infection-induced hepatocellular carcinoma. Clin Epigenetics 2019;11:145.

111. Ponziani FR, Putignani L, Paroni Sterbini F, et al. Influence of hepatitis C virus eradication with direct-acting antivirals on the gut microbiota in patients with cirrhosis. Aliment Pharmacol Ther 2018;48:1301-11.

112. Tovo PA, Garazzino S, Daprà V, et al. Chronic HCV infection is associated with overexpression of human endogenous retroviruses that persists after drug-induced viral clearance. Int J Mol Sci 2020;21:3980.

113. 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.

114. Butt AS, Sharif F, Abid S. Impact of direct acting antivirals on occurrence and recurrence of hepatocellular carcinoma: biologically plausible or an epiphenomenon? World J Hepatol 2018;10:267-76.

115. Takeda H, Takai A, Iguchi E, et al. Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus. Carcinogenesis 2021;42:672-84.

116. 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.

117. Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular carcinoma mechanisms associated with chronic HCV infection and the impact of direct-acting antiviral treatment. J Hepatocell Carcinoma 2020;7:45-76.

118. Aydin Y, Chatterjee A, Chandra PK, et al. Interferon-alpha-induced hepatitis C virus clearance restores p53 tumor suppressor more than direct-acting antivirals. Hepatol Commun 2017;1:256-69.

119. Aydin Y, Chedid M, Chava S, et al. Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture. Sci Rep 2017;7:9223.

120. Aydin Y, Kurt R, Song K, et al. Hepatic stress response in HCV infection promotes STAT3-mediated inhibition of HNF4A-miR-122 feedback loop in liver fibrosis and cancer progression. Cancers (Basel) 2019;11:1407.

121. Pinyol R, Torrecilla S, Wang H, et al. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2021;75:865-78.

122. 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.

123. 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.

124. Elmasry S, Wadhwa S, Bang BR, et al. Detection of occult hepatitis c virus infection in patients who achieved a sustained virologic response to direct-acting antiviral agents for recurrent infection after liver transplantation. Gastroenterology 2017;152:550-553.e8.

125. Yousif MM, Elsadek Fakhr A, Morad EA, et al. Prevalence of occult hepatitis C virus infection in patients who achieved sustained virologic response to direct-acting antiviral agents. Infez Med 2018;26:237-43.

126. Abd Alla MDA, Dawood RM, Rashed HAE, et al. Treatment of hepatitis C virus infection with direct-acting antivirals plus ribavirin eliminates viral RNA from peripheral blood mononuclear cells and reduces virologic relapse in diverse hepatic parenchymal changes. Arch Virol 2021;166:1071-81.

127. Matsuura K, Sawai H, Ikeo K, et al. Japanese genome-wide association study group for viral hepatitis. genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology 2017;152:1383-94.

128. Villani R, Vendemiale G, Serviddio G. Molecular mechanisms involved in HCC recurrence after direct-acting antiviral therapy. Int J Mol Sci 2018;20:49.

129. Rinaldi L, Nevola R, Franci G, et al. Risk of hepatocellular carcinoma after HCV clearance by direct-acting antivirals treatment predictive factors and role of epigenetics. Cancers (Basel) 2020;12:1351.

130. Oe N, Takeda H, Eso Y, Takai A, Marusawa H. Clinical and molecular basis of hepatocellular carcinoma after hepatitis C virus eradication. Pathogens 2022;11:430.

131. Guarino M, Sessa A, Cossiga V, Morando F, Caporaso N, Morisco F. Special Interest Group on “Hepatocellular carcinoma and new anti-HCV therapies” of the Italian Association for the Study of the Liver. Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: a few lights and many shadows. World J Gastroenterol 2018;24:2582-95.

132. Audureau E, Carrat F, Layese R, et al. ANRS CO12 CirVir group. Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status. J Hepatol 2020;73:1434-45.

133. D’Ambrosio R, Degasperi E, Lampertico P. Predicting hepatocellular carcinoma risk in patients with chronic HCV infection and a sustained virological response to direct-acting antivirals. J Hepatocell Carcinoma 2021;8:713-39.

134. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018;68:526-49.

135. Liu XN, Cui DN, Li YF, Liu YH, Liu G, Liu L. Multiple “Omics” data-based biomarker screening for hepatocellular carcinoma diagnosis. World J Gastroenterol 2019;25:4199-212.

136. Scheiner B, Pomej K, Kirstein MM, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol 2022;76:353-63.

137. Huo TI, Liao JI, Ho SY. Prognostic prediction for patients with hepatocellular carcinoma receiving immunotherapy: Are we there yet? J Hepatol 2022;76:987-8.

138. Khakoo SI. Immunotherapy for hepatocellular carcinoma: a “CRAFITY” approach to patient stratification. Hepatobiliary Surg Nutr 2022;11:327-9.

139. Thorsson V, Gibbs DL, Brown SD, et al. Cancer genome atlas research network. The immune landscape of cancer. Immunity 2018;48:812-830.e14.

140. Bidkhori G, Benfeitas R, Klevstig M, et al. Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes. Proc Natl Acad Sci U S A 2018;115:E11874-83.

141. Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol 2020;72:215-29.

142. Jiang Y, Sun A, Zhao Y, et al. Chinese Human Proteome Project (CNHPP) Consortium. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 2019;567:257-61.

143. Sun R, Xu Y, Zhang H, et al. Mechanistic modeling of gene regulation and metabolism identifies potential targets for hepatocellular carcinoma. Front Genet 2020;11:595242.

144. Krishnan MS, Rajan Kd A, Park J, et al. Genomic analysis of vascular invasion in HCC reveals molecular drivers and predictive biomarkers. Hepatology 2021;73:2342-60.

145. Dhanasekaran R, Nault JC, Roberts LR, Zucman-Rossi J. Genomic medicine and implications for hepatocellular carcinoma prevention and therapy. Gastroenterology 2019;156:492-509.

146. Wu Y, Liu Z, Xu X. Molecular subtyping of hepatocellular carcinoma: a step toward precision medicine. Cancer Commun (Lond) 2020;40:681-93.

147. Heinrich S, Craig AJ, Ma L, Heinrich B, Greten TF, Wang XW. Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis. J Hepatol 2021;74:700-15.

148. Dong X, Wang F, Liu C, et al. Single-cell analysis reveals the intra-tumor heterogeneity and identifies MLXIPL as a biomarker in the cellular trajectory of hepatocellular carcinoma. Cell Death Discov 2021;7:14.

149. Alvarez M, Benhammou JN, Darci-Maher N, et al. Human liver single nucleus and single cell RNA sequencing identify a hepatocellular carcinoma-associated cell-type affecting survival. Genome Med 2022;14:50.

150. Shimada S, Tanaka S. Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune oncology in hepatocellular carcinoma. Int J Clin Oncol 2022;27:1101-9.

151. Galle PR, Abou-Alfa GK. Decision making in systemic therapy of hepatocellular carcinoma: Should we pay attention to disease aetiology? J Hepatol 2021;75:763-4.

152. 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.

153. 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.

154. Tsai PC, Huang CF, Yu ML. Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: Issue of the interval between HCC treatment and antiviral therapy. J Hepatol 2017;66:464.

155. Singal AG, Lim JK, Kanwal F. AGA clinical practice update on interaction between oral direct-acting antivirals for chronic hepatitis C infection and hepatocellular carcinoma: expert review. Gastroenterology 2019;156:2149-57.

156. 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.

157. 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.

158. Wörns MA, Galle PR, Zeuzem S, Schirmacher P, Manns M, Vogel A. Drug treatment for chronic hepatitis C infection and cancer risk. Dtsch Arztebl Int 2017;114:597-602.

159. 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;48:127-37.

160. 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.

161. Kogiso T, Sagawa T, Kodama K, et al. Hepatocellular carcinoma after direct-acting antiviral drug treatment in patients with hepatitis C virus. JGH Open 2019;3:52-60.

162. Kuo MJ, Mo LR, Chen CL. Factors predicting long-term outcomes of early-stage hepatocellular carcinoma after primary curative treatment: the role of surgical or nonsurgical methods. BMC Cancer 2021;21:250.

163. Sanduzzi-Zamparelli M, Mariño Z, Lens S, et al. Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules. J Hepatol 2022;76:874-82.

164. Ramadori G, Bosio P, Moriconi F, Malik IA. Case report: 8 years after liver transplantation: de novo hepatocellular carcinoma 8 months after HCV clearance through IFN-free antiviral therapy. BMC Cancer 2018;18:257.

165. Samonakis DN, Koulentaki M, Coucoutsi C, et al. Clinical outcomes of compensated and decompensated cirrhosis: a long term study. World J Hepatol 2014;6:504-12.

166. Innes H, McDonald S, Hayes P, et al. Mortality in hepatitis C patients who achieve a sustained viral response compared to the general population. J Hepatol 2017;66:19-27.

167. Zayedi E, Makvandi M, Teimoori A, et al. Prevalence of hepatitis C virus among HIV-infected patients. Iran J Microbiol 2020;12:156-63.

168. Minami T, Tateishi R, Fujiwara N, et al. Impact of obesity and heavy alcohol consumption on hepatocellular carcinoma development after HCV eradication with antivirals. Liver Cancer 2021;10:309-19.

169. Semmler G, Meyer EL, Kozbial K, et al. HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease. J Hepatol 2022;76:812-21.

170. Kouroumalis E, Voumvouraki A. Hepatitis C virus: a critical approach to who really needs treatment. World J Hepatol 2022;14:1-44.

171. van der Meer AJ, Feld JJ, Hofer H, et al. Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication. J Hepatol 2017;66:485-93.

172. Degasperi E, Galmozzi E, Pelusi S, et al. Hepatic fat-genetic risk score predicts hepatocellular carcinoma in patients with cirrhotic HCV treated With DAAs. Hepatology 2020;72:1912-23.

173. D’Ambrosio R, Degasperi E, Anolli MP, et al. Incidence of liver- and non-liver-related outcomes in patients with HCV-cirrhosis after SVR. J Hepatol 2022;76:302-10.

174. Abdel-Razik A, Shabana W, El Nakib AM, et al. De novo hepatocellular carcinoma in hepatitis C-related cirrhosis: are advanced glycation end products a key driver? Front Cell Infect Microbiol 2021;11:662431.

175. Váncsa S, Németh D, Hegyi P, et al. Diabetes mellitus increases the risk of hepatocellular carcinoma after direct-acting antiviral therapy: systematic review and meta-analysis. Front Med (Lausanne) 2021;8:744512.

176. Luna-Cuadros MA, Chen HW, Hanif H, Ali MJ, Khan MM, Lau DT. Risk of hepatocellular carcinoma after hepatitis C virus cure. World J Gastroenterol 2022;28:96-107.

177. Salmon-Ceron D, Nahon P, Layese R, et al. ANRS CO12 CirVir and ANRS CO13 HEPAVIH study groups. Human immunodeficiency virus/hepatitis C virus (HCV) Co-infected patients with cirrhosis are no longer at higher risk for hepatocellular carcinoma or end-stage liver disease as compared to HCV mono-infected patients. Hepatology 2019;70:939-54.

178. Corma-Gómez A, Macías J, Lacalle-Remigio JR, et al. RIS-HEP13 and GEHEP 011 study groups. Human immunodeficiency virus (HIV) infection is associated with lower risk of hepatocellular carcinoma after sustained virological response to direct-acting antivirals in hepatitis c infected patients with advanced fibrosis. Clin Infect Dis 2021;73:e2109-16.

179. Quaranta MG, Ferrigno L, Monti M, et al. PITER Collaborating Group. Advanced liver disease outcomes after hepatitis C eradication by human immunodeficiency virus infection in PITER cohort. Hepatol Int 2020;14:362-72.

180. Ioannou GN, Beste LA, Green PK, 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.

181. Flisiak R, Zarębska-Michaluk D, Janczewska E, et al. Five-year follow-up of cured HCV patients under real-world interferon-free therapy. Cancers (Basel) 2021;13:3694.

182. Pons M, Rodríguez-Tajes S, Esteban JI, et al. Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals. J Hepatol 2020;72:472-80.

183. Piñero F, Mendizabal M, Ridruejo E, et al. LALREAN. Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma. Liver Int 2019;39:1033-43.

184. Singh S, Nautiyal A, Loke YK. Oral direct-acting antivirals and the incidence or recurrence of hepatocellular carcinoma: a systematic review and meta-analysis. Frontline Gastroenterol 2018;9:262-70.

185. Burlone ME, Fangazio S, Croce A, et al. Response rates to direct antiviral agents among hepatitis C virus infected patients who develop hepatocellular carcinoma following direct antiviral agents treatment. Hepatoma Res 2020;6:3.

186. Pazgan-simon M. Direct acting antivirals therapy and hepatocellular carcinoma risk in patients with hepatitis C virus. Hepatoma Res 2020;6:17.

187. Yang M, Ma R, Huang Y, Wei L. Impact of direct-acting antivirals on. Hepatoma Res 2020;6:31.

188. Yoo SH, Kwon JH. The interplay between direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C. Hepatoma Res 2020;6:9.

189. D'Ambrosio R, Ioannou GN. Hepatocellular carcinoma risk, outcomes, and screening after hepatitis C eradication. Hepatol Commun 2021;5:1465-8.

190. Sánchez-Azofra M, Fernández I, García-Buey ML, et al. Hepatocellular carcinoma risk in hepatitis C stage-3 fibrosis after sustained virological response with direct-acting antivirals. Liver Int 2021;41:2885-91.

191. Alonso López S, Manzano ML, Gea F, 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;72:1924-34.

192. Ioannou GN, Tang W, Beste LA, et al. Assessment of a deep learning model to predict hepatocellular carcinoma in patients with hepatitis C cirrhosis. JAMA Netw Open 2020;3:e2015626.

193. Muzica CM, Stanciu C, Huiban L, et al. Hepatocellular carcinoma after direct-acting antiviral hepatitis C virus therapy: a debate near the end. World J Gastroenterol 2020;26:6770-81.

194. Rinaldi B, Rosato V, Galiero R, Vetrano E, Fasano M, Rinaldi L. Editorial - direct-acting antivirals therapy in HCV patients with HCC: lights and shadow. Eur Rev Med Pharmacol Sci 2021;25:7622-5.

195. John BV. No association between direct-acting antivirals and hepatocellular carcinoma progression on the waiting list: time to put this controversy to rest? Liver Transpl 2020;26:621-3.

196. 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.

197. Dajti E, Ravaioli F, Festi D, Colecchia A. Clinical outcomes after treatment with direct-acting antivirals: not all concern hepatocellular carcinoma risk. Hepatobiliary Surg Nutr 2020;9:505-7.

198. Compagnoni S, Bruno EM, Madonia G, Cannizzaro M, Madonia S. Direct antiviral agents in hepatitis C virus related liver disease: don’t count the chickens before they're hatched. World J Gastroenterol 2021;27:2771-83.

199. Sanduzzi-Zamparelli M, Boix L, Leal C, Reig M. Hepatocellular carcinoma recurrence in HCV patients treated with direct antiviral agents. Viruses 2019;11:406.

200. Kassas M, Elbaz T, Salaheldin M, Abdelsalam L, Kaseb A, Esmat G. Impact of treating chronic hepatitis C infection with direct-acting antivirals on the risk of hepatocellular carcinoma: the debate continues - a mini-review. J Adv Res 2019;17:43-8.

201. Kamal A, Elsheaita A, Abdelnabi M. Association between direct-acting antiviral agents in hepatitis C virus treatment and hepatocellular carcinoma occurrence and recurrence: The endless debate. World J Clin Cases 2022;10:1764-74.

202. Lee CH, Kim IH. Direct-acting antiviral therapy and risk of hepatocellular carcinoma recurrence in patients with chronic hepatitis C. Gut Liver 2021;15:327-8.

203. Meier V, Bürger E, Mihm S, Saile B, Ramadori G. Ribavirin inhibits DNA, RNA, and protein synthesis in PHA-stimulated human peripheral blood mononuclear cells: possible explanation for therapeutic efficacy in patients with chronic HCV infection. J Med Virol 2003;69:50-8.

204. You MW, Kim KW, Shim JJ, Pyo J. Impact of liver-stiffness measurement on hepatocellular carcinoma development in chronic hepatitis C patients treated with direct-acting antivirals: a systematic review and time-to-event meta-analysis. J Gastroenterol Hepatol 2021;36:601-8.

205. Janjua NZ, Chong M, Kuo M, et al. Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada. J Hepatol 2017;66:504-13.

206. Rimassa L, Personeni N, Czauderna C, Foerster F, Galle P. Systemic treatment of HCC in special populations. J Hepatol 2021;74:931-43.

207. Poynard T, Munteanu M, Ratziu V, et al. Truth survival in clinical research: an evidence-based requiem? Ann Intern Med 2002;136:888-95.

208. Koretz RL, Poynard T. Truth is not determined by a majority vote. Gastroenterology 2003;124:1153-5.

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Kouroumalis E, Tsomidis I, Voumvouraki A. Hepatocellular carcinoma after treatment of hepatitis C with direct-acting antivirals: a critical re-appraisal. Hepatoma Res 2023;9:4.

AMA Style

Kouroumalis E, Tsomidis I, Voumvouraki A. Hepatocellular carcinoma after treatment of hepatitis C with direct-acting antivirals: a critical re-appraisal. Hepatoma Research. 2023; 9: 4.

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Elias Kouroumalis, Ioannis Tsomidis, Argyro Voumvouraki. 2023. "Hepatocellular carcinoma after treatment of hepatitis C with direct-acting antivirals: a critical re-appraisal" Hepatoma Research. 9: 4.

ACS Style

Kouroumalis, E.; Tsomidis I.; Voumvouraki A. Hepatocellular carcinoma after treatment of hepatitis C with direct-acting antivirals: a critical re-appraisal. Hepatoma. Res. 2023, 9, 4.

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