INTRODUCTION

Hepatitis C virus (HCV), a hepatotropic RNA virus, is a major global cause of chronic liver disease. One of its most serious complications is hepatocellular carcinoma (HCC), which carries substantial rates of morbidity and mortality. The incidence of HCC among HCV-infected individuals is estimated at 1-3% over a 30-year period. In addition, cross-sectional and case-control studies have demonstrated that HCV infection has been associated with a 15- to 20-fold increased risk of HCC compared with HCV-negative individuals.¹ In a large United States prospective multicenter cohort of cirrhotic patients (median follow-up, 2.2 years), the overall annual incidence of HCC was 2.4% (95% confidence interval [CI], 1.8-3.1), with HCV-related cirrhosis showing the highest incidence at 3.02% (95% CI, 2.04-4.26).² Although the global prevalence of HCV is relatively lower in East Asian countries, including South Korea, than in Western populations, the clinical impact of HCV-related HCC remains significant due to the aging population and delayed diagnosis. According to a Korean nationwide cohort study of HCC cases from 2008 to 2018, HCV accounted for approximately 9.9% of all HCC etiologies, following hepatitis B virus, non-alcoholic fatty liver disease, and alcohol-related liver disease.³

Given the significant risk of HCC in patients with HCV-related cirrhosis, antiviral therapy has become a critical component for reducing liver-related morbidity and mortality. The advent of direct-acting antivirals (DAAs) has revolutionized the management of chronic HCV infection, offering high therapeutic efficacy with favorable safety profiles. However, the optimal timing and clinical appropriateness of initiating DAA therapy in patients with active HCC remain areas of ongoing debate. Notably, major international guidelines, including those from the American Gastroenterological Association (AGA), American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Korean Association for the Study of the Liver (KASL), offer differing recommendations on the use of DAA therapy in this complex patient population. The AASLD‑Infectious Diseases Society of America (IDSA) guidance does not provide a specific directive for patients with active HCC but acknowledges that the presence of HCC may be associated with reduced sustained virologic response (SVR) rates, thereby supporting individualized treatment decisions.⁴ The EASL similarly advises cautious timing and close monitoring when initiating antiviral therapy in this setting.^5,6 The AGA further underscores the potential for reduced treatment efficacy in the presence of active HCC and recommends deferring DAA therapy until curative oncologic treatment has been completed.⁷ In contrast, Korean data and practice patterns have tended to be more favorable toward integrating antiviral therapy after HCC treatment, although recent guidelines emphasize individualized decisions in this setting.^8,9

In light of these discrepancies, and with multiple cohort studies currently investigating the safety and efficacy of DAA therapy in patients with active HCC, this review aims to critically appraise the emerging evidence and offer an informed perspective on the potential role of antiviral therapy in this patient population.

INTERNATIONAL GUIDELINES ON DAA THERAPY IN HCV-RELATED ACTIVE HCC

The AGA clinical practice update (2019) advises caution when considering DAA therapy in patients with active HCC, due to consistently reported reductions in SVR rates in this population. While achieving SVR may theoretically improve liver function and broaden eligibility for HCC-directed treatments, these potential benefits must be weighed against the competing risks of HCC-related mortality and diminished virologic response. Based on these considerations, the AGA suggests deferring DAA therapy until after curative treatment, such as surgical resection or local ablation, in patients with early-stage HCC. For transplant candidates, antiviral timing should be individualized, taking into account regional wait times, donor organ availability, and liver function. In patients with advanced HCC, DAA therapy is generally not recommended unless life expectancy exceeds 2 years, as data on its benefit and cost-effectiveness remains lacking.⁷

In comparison, the AASLD-IDSA HCV guidance (2023) does not issue a specific recommendation to patients with active HCC, but acknowledges that malignancy may negatively impact SVR rates, citing several large studies that demonstrate reduced antiviral efficacy in this population.^10-12 Although DAA therapy is broadly supported in HCV-infected individuals, including those with compensated cirrhosis, the presence of active HCC introduces clinical uncertainty. Accordingly, the guidelines recommend that treatment decisions be individualized, incorporating tumor burden, hepatic reserve, and overall prognosis, in consultation with oncology and transplant teams.

The EASL recommendations (2018/2020 update) adopt a more structured approach, recommending that DAA therapy in patients with compensated cirrhosis and active or recently treated HCC be initiated only after completion of curative treatment (grade A1). For transplant candidates, pre-transplant antiviral therapy is advised in regions with long wait times to reduce dropout risk from tumor progression (grade B2). In those who have achieved complete response to HCC treatment, standard HCV treatment guidelines apply, but indefinite post-SVR surveillance is warranted due to recurrence risk (grade A1). For patients receiving palliative HCC therapy, DAA use may be considered based on clinical judgment and potential benefit (grade B2). These recommendations underscore the need to tailor antiviral treatment strategies with oncologic status, treatment intent, and broader clinical context, with particular emphasis on vigilant radiologic monitoring.^5,6

The KASL 2017 guidelines focused primarily on chronic hepatitis C treatment and did not provide specific recommendations for patients with active HCC.¹³ Subsequent Korean cohort studies, however, suggested that DAA therapy following curative HCC treatment was associated with reduced recurrence and liver-related mortality, supporting integration of antiviral therapy in this setting.⁸ In contrast, the 2022 KLCA-National Cancer Center (NCC) guidelines adopted a more cautious position, citing insufficient evidence to recommend routine preventive DAA therapy in patients with HCV-related HCC (evidence level C1) and instead emphasizing individualized decision-making and close monitoring.⁹ These recommendations are summarized in Table 1.

THE DAA PARADOX: WHY DOES VIRAL ERADICATION SEEM TO FUEL DE NOVO CANCER OR CANCER RECURRENCE?

Early clinical observations, most notably by Reig et al.¹⁴ and Conti et al.,¹⁵ reported unexpectedly high rates of HCC recurrence following DAA therapy in patients with HCV-related cirrhosis and prior HCC. These provocative findings fueled intense debate and prompted subsequent investigations into whether viral eradication might paradoxically accelerate tumor progression. However, later cohort studies and meta-analyses have not consistently reproduced the early reports, leaving uncertainty as to whether the observed associations reflected a true biological effect of DAAs or residual confounding.

One of the most frequently discussed hypotheses, highlighted by Nault and Colombo,¹⁶ is that the rapid and profound decline in viral load induced by DAAs may disrupt the delicate balance between pro-tumorigenic inflammation and anti-tumor immune surveillance. In this model, the abrupt clearance of HCV could transiently impair immune-mediated tumor control, thereby accelerating the outgrowth of subclinical HCC clones. This stands in contrast to interferon-based regimens, which exert slower antiviral effects accompanied by sustained immunomodulatory and antiproliferative properties. Importantly, this mechanism remains speculative: no robust preclinical studies have confirmed a direct oncogenic role for DAAs, and subsequent cohort studies and meta-analyses have failed to consistently confirm the early recurrence signals. Subsequent mechanistic studies provided preliminary biological correlates that could explain these clinical observations. Villani et al.¹⁷ reported that DAA therapy was associated with a rapid reduction in hepatic inflammation but a marked rise in circulating vascular endothelial growth factor levels, raising concern that enhanced angiogenesis might facilitate tumor growth. In parallel, Chu et al.¹⁸ demonstrated that on-treatment downregulation of the activating receptor natural killer group 2D (NKG2D) correlated with the early emergence of clinically evident HCC, suggesting that altered immune surveillance pathways may contribute to the risk of recurrence. Although both findings are hypothesis-generating and require further validation, they highlight potential biologic alterations accompanying abrupt viral clearance that may influence recurrence risk.

Regarding the mechanisms associated with reduced recurrence, DAA-induced viral eradication may improve the hepatic microenvironment through multiple biological pathways. Villani et al.¹⁹ demonstrated that DAAs rapidly reduce oxidative stress and restore systemic redox homeostasis, potentially mitigating carcinogenic drive. Sustained virologic response can also promote fibrosis regression and remodeling of liver architecture²⁰ and lead to measurable improvement in hepatic function.²¹ Furthermore, interferon-free DAA therapy has been shown to restore HCV-specific CD8⁺ T-cell function, reflecting partial recovery of immune surveillance.²²

To present the observations, Fig. 1 provides a schematic overview of the proposed mechanism by which DAAs may increase or decrease HCC recurrence risk.

THE PRACTICAL EFFECT OF DAA TREATMENT: A REPORT ON ACTIVE HCC OUTCOMES FROM VARIOUS RESEARCH CASES

Table 2 provides a comprehensive summary of research studies investigating the use of DAAs in patients with active HCC.^23-39 While DAAs have revolutionized the management of HCV infection, their role in patients with concurrent active HCC remains controversial due to conflicting evidence regarding oncologic outcomes. The following section synthesizes available data on overall survival (OS), recurrence-free survival, and recurrence rates to clarify the potential role of DAAs in the management of active HCC.

Across seven retrospective cohorts (aggregate n≈3,400), DAA exposure was generally associated with longer OS when integrated with locoregional or systemic HCC therapy in cohorts not centered on liver transplantation. For example, Kamp et al.³³ reported a median OS of 49.2 months in DAA-treated patients compared with 18.5 months in untreated patients, Shao et al.³⁶ observed 40.2 vs. 22.9 months, and Tsai et al.³⁹ noted a mean survival of 20.7 versus 12.5 months. In a surgical series, Okamura et al.³¹ found that preoperative DAA exposure significantly reduced mortality risk compared with non-SVR status (hazard ratio [HR]≈0.25), underscoring the importance of treatment timing. By contrast, in cohorts enriched for liver-transplant candidates or recipients, Emamaullee et al.²³ observed no significant difference in OS between DAA-treated and untreated patients, indicating no signal of increased mortality in this context. Similarly, Gorgen et al.³² noted that advantages apparent on crude rates did not persist after multivariable adjustment. The apparent survival advantage in unadjusted analyses diminished, and in some cases lost statistical significance, after adjustment for baseline differences in tumor burden, liver function, treatment timing, and transplant-related factors. When interferon-based antiviral therapy served as an active comparator, OS differences were likewise not evident.³⁸ Overall, the OS signal appears most favorable when DAAs are paired with active oncologic management outside of the transplantation cohort, while heterogeneity in tumor stage, timing of antiviral initiation, baseline hepatic reserve, and potential residual confounding factors such as immortal-time bias likely contribute to variability across studies.

Across six retrospective cohorts, findings on recurrence-free survival (RFS) with DAA therapy in patients with active HCC were mixed. In non-transplant surgical series, preoperative DAA exposure was associated with improved RFS compared with non- SVR status (HR≈0.49), highlighting the relevance of antiviral timing around curative procedures.³¹ By contrast, RFS differences were generally neutral in liver-transplant cohorts. Emamaullee et al.²³ and Jain et al.²⁹ reported no significant RFS advantage with DAAs, whereas Gorgen et al.³² observed higher crude RFS rates in pre-liver transplantation (LT) DAA recipients (to 93.4%) compared to interferon (to 84.8%) and antiviral-naïve patients (to 73.9%). However, this advantage did not persist after multivariable adjustment. Turgeon et al.³⁷ reported 5-year RFS of 93% in pre-LT patients, 100% in those receiving early post-LT DAAs (0-3 months), and 83% in those with late post-LT initiation (≥3 months), with late post-LT initiation associated with inferior RFS relative to early post-LT (Fig. 2). Lim et al.³⁴ were largely neutral overall but suggested increased recurrence risk in a subgroup analysis, again implicating selection and timing effects. Considered collectively, the available evidence suggests that any association between DAA therapy and prolonged RFS is most pronounced in cohorts not centered on liver transplantation and when DAAs are initiated around the time of curative HCC procedures. Notably, apparent benefits in unadjusted analyses often diminished or sometimes lost statistical significance after adjustment for baseline differences in tumor burden, hepatic reserve, antiviral-initiation timing, and transplant-related factors.

Across seven studies that directly evaluated tumor recurrence, the effect of DAA therapy in patients with active HCC was largely neutral. Emamaullee et al.,²³ Jain et al.,²⁹ and Zanetto et al.²⁶ all reported no significant differences in recurrence between DAA-treated and untreated patients. In a multicenter liver-transplant cohort, Gorgen et al.³² observed a lower hazard of recurrence in unadjusted analyses among DAA recipients (HR≈0.44 for pre-LT DAA vs. naïve; HR≈0.62 for post-LT DAA vs. naïve), but these associations did not remain significant after multivariable adjustment. Tse et al.³⁵ reported no significant difference, with a trend toward reduced risk (P≈0.07). Lim et al.³⁴ were neutral overall; in a multivariable analysis after liver transplantation, DAA use did not reach statistical significance for recurrence but showed a strong trend toward higher recurrence risk (HR, 5.17; 95% CI, 0.89-29.81; P=0.07). Outside transplant-centered settings, findings were inconsistent: Revuelta-Herrero et al.²⁸ reported no recurrences during follow-up in a small mixed locoregional/surgical cohort. Overall, current evidence does not demonstrate a reproducible increase in HCC recurrence with DAA therapy.

THE CRUCIAL QUESTION OF TIMING: WHEN TO INITIATE DAA THERAPY IN ACTIVE HCC

Across currently available major hepatitis and hepatocellular carcinoma guidelines, explicit month-based recommendations regarding the optimal timing of DAA initiation after curative HCC therapy are limited, aside from a few practice-oriented statements such as those from the AGA and the German Alliance for Liver Cancer. The AGA clinical practice update suggests that DAA therapy may be deferred for 4-6 months after curative HCC treatment to confirm oncologic stability, while reports summarizing the German Alliance for Liver Cancer recommendations describe initiation at 6-12 months after curative therapy.⁴⁰ These statements are therefore cited to provide pragmatic context alongside the largely retrospective evidence base.

Emerging data suggest that outcomes in active HCC may be influenced by the time when DAAs are started. However, in this dataset, only a few studies provide direct comparisons of treatment timing. Thus, findings are suggestive and require validation in prospective studies. For clarity, we categorize timing as pre-procedural, peri-procedural (around curative HCC procedures), pre-transplant, early post-transplant (0-3 months), and late post-transplant (≥3 months). Most studies are retrospective, with limited use of time-zero alignment, time-dependent exposure modeling, or landmark analyses; therefore, time-related bias and selection bias cannot be excluded. This study reviewed the evidence across curative-intent, transplant, and non-curative pathways.

In patients undergoing surgical resection for HCC, Okamura et al.³¹ reported that preoperative DAA exposure was associated with improved outcomes compared with a non-SVR reference group, RFS of HR=0.49 and lower mortality risk, with OS of HR=0.25. Although derived from observational data, these findings support the hypothesis that starting DAAs before or shortly after resection, when oncologic control is feasible, may be advantageous. Across several liver transplant cohorts, pre-LT DAA therapy did not appear to worsen post-transplant oncologic outcomes. Zanetto et al.,²⁶ Emamaullee et al.,²³ and Jain et al.²⁹ each reported no significant difference in post-LT recurrence rates between DAA-treated and untreated groups. In a multicenter analysis, Gorgen et al.³² observed higher crude RFS among pre-LT DAA recipients compared with interferon or antiviral-naïve comparators; however, these apparent benefits diminished after multivariable adjustment, highlighting sensitivity to baseline differences.

With respect to post-LT strategies, Turgeon et al.³⁷ reported a 5-year RFS of approximately 100% with early post-LT DAA initiation (0-3 months) compared with 83% in the late post-LT initiation (≥3 months) and demonstrated that late post-LT initiation was associated with inferior RFS (HR, 2.34) compared with the early post-LT initiation. By contrast, Tse et al.³⁵ observed no significant difference, with only a non-significant trend toward reduced recurrence risk (P=0.07). Lim et al.³⁴ was overall neutral, but multivariable analysis after LT reported a strong, yet non-significant trend toward higher recurrence risk with DAA use (HR, 5.17; 95% CI, 0.89-29.81; P=0.07). Taken together, the direction of effect appears to vary by timing window, with the most favorable signals emerging for pre-LT or early post-LT (0-3 months) initiation, acknowledging the limited number of direct comparative studies.

In non-curative settings, several studies have examined DAA initiation relative to transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and systemic chemotherapy. Revuelta-Herrero et al.²⁸ reported on patients who received DAAs long after locoregional or surgical treatments (e.g., TARE after nearly 2 years, resection after 1.5-1.6 years, or TACE after ≥5 years), showing that SVR could be achieved but without clear oncologic benefit, given the delayed initiation. By contrast, Shao et al.³⁶ evaluated DAA administration before or concurrent with TACE and found no evidence of increased HCC progression risk, suggesting that concomitant antiviral therapy may be feasible without compromising oncologic control. Similarly, Tsai et al.³⁹ observed that DAA treatment following systemic chemotherapy did not increase recurrence risk and even suggested possible survival advantages. Taken together, the available data, although limited and heterogeneous, consistently suggest that DAA therapy in non-curative contexts does not adversely affect tumor outcomes. These findings are summarized in Table 3.

NAVIGATING CLINICAL PRACTICE: DAA THERAPY FOR HCC IN THE REAL WORLD

The integration of DAAs into the management of HCV-related HCC remains a clinical challenge. While DAAs are firmly established as the standard of care for chronic HCV infection, their optimal use in patients with active or recently treated HCC is still uncertain. Evidence suggests that outcomes may vary according to tumor status, timing of antiviral initiation, hepatic reserve, and transplant eligibility. However, the absence of a universally accepted treatment framework creates ambiguity in clinical decision-making and underscores the need for individualized, multidisciplinary approaches.

In addition to treatment timing, the central question in real-world practice is identifying which patients are most likely to benefit from antiviral therapy. Not all individuals with active HCC should be approached uniformly; therapeutic decisions must consider tumor burden, hepatic reserve, transplant candidacy, and overall prognosis. Even after achieving SVR, patients with cirrhosis remain at ongoing risk of HCC. Accordingly, continued surveillance is strongly endorsed by international societies such as AASLD, EASL, and Asian Pacific Association for the Study of the Liver (APASL), which uniformly recommend biannual imaging in some cases of indefinite monitoring, particularly for those with prior HCC. These considerations highlight the necessity of multidisciplinary collaboration to balance antiviral efficacy with oncologic priorities.

Despite accumulating evidence, substantial gaps in investigation remain. Most available studies are retrospective and heterogeneous; prospective, time-anchored trials are lacking, and biomarkers to refine patient selection have yet to be validated. Large-scale registries and mechanistic studies will be essential to provide a more reliable framework for integrating DAAs into the management of HCV-related HCC.

CONCLUSION

Although DAA therapy is widely recommended for patients with chronic HCV infection, its application in those with active hepatocellular carcinoma remains a clinically unresolved domain. Major international guidelines, including those from the AGA, AASLD-IDSA, EASL, and KASL, do not offer consistent or definitive recommendations, deferring to individualized decisions or provide conditional recommendations without clear criteria for timing or patient selection. This absence of well-established evidence and explicit guidance underscores the need for further prospective studies and highlights the importance of multidisciplinary decision-making in this complex patient population.

Available evidence on oncologic impacts of DAA therapy in patients with active HCC remains heterogeneous. In non-transplant cohorts treated with surgical or systemic therapy, DAAs have often been associated with longer OS and, in some cases, improved RFS, particularly when treatment was initiated around curative procedures. By contrast, most studies of liver transplant candidates or recipients reported neutral effects on OS, RFS, and recurrence, with crude advantages frequently attenuated after adjustment for tumor burden, liver function, and treatment timing. Importantly, no study has shown a reproducible increase in HCC recurrence attributable to DAA therapy. Instead, variability in outcomes likely reflects differences in study design, patient selection, and timing of antiviral initiation.

The cumulative evidence reviewed suggests that the timing of DAA initiation in patients with active HCC should be individualized according to therapeutic intent and clinical context. For curative-intent candidates, such as those undergoing resection, peri-procedural initiation may optimize both viral clearance and oncologic outcomes, provided hepatic reserve permits. In transplant candidates, pre-LT initiation appears safe and potentially beneficial, while early post-LT initiation (within 3 months) has been consistently associated with more favorable RFS compared with later initiation. In non-curative settings, including TACE, TARE, and systemic chemotherapy, some available data indicate that concomitant or sequential DAA therapy does not exacerbate recurrence risk and may even confer survival advantages. Taken together, these findings suggest that DAAs can be safely integrated across the spectrum of HCC management, though the optimal initiation window remains to be defined. Until prospective time-anchored trials provide greater clarity, clinical decision- making should therefore incorporate multidisciplinary considerations, balancing tumor biology, hepatic function, organ allocation dynamics, and patient-specific priorities.

There are several notable limitations of existing studies that should be taken into account. Most available evidence on DAA therapy in patients with active HCC comes from retrospective, heterogeneous cohorts with relatively small sample sizes. Study populations vary considerably across tumor stage, baseline liver function, antiviral initiation timing, and oncologic treatments, which limits cross-study comparability. Furthermore, many analyses did not adequately account for time-related biases or residual confounding by indication, making it difficult to distinguish whether observed differences reflect treatment effects or underlying selection factors. In transplant-focused cohorts, outcome estimates were also influenced by center-specific listing practices, organ availability, and follow-up intensity. Finally, the absence of prospective, time-anchored trials and validated biomarkers of recurrence risk further constrains the ability to establish causal relationships or provide definitive clinical guidance.

In conclusion, DAA therapy can be integrated into the management of patients with HCV-related HCC without clear evidence of harm, but its optimal timing and patient selection remain unresolved. Clinical decisions should individualize based on tumor biology, hepatic reserve, and treatment intent, while maintaining vigilant post-SVR surveillance in patients with cirrhosis.

Article information

Conflicts of Interest

Jeong-Ju Yoo is an editorial board member of Journal of Liver Cancer and was not involved in the review process of this article. Otherwise, the authors have no conflicts of interests to declare.

Ethics Statement

The study protocol was approved by the Institutional Review Board.

Funding Statement

This work was supported by the Soonchunhyang University Research Fund (2025).

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions

Conceptualization: JJY

Investigation: SGK, YSK

Writing - original draft: SHJ

Writing - review & editing: JJY

Figure 1.

Proposed mechanisms linking DAA therapy to HCC recurrence. NK, natural killer; VEGF, vascular endothelial growth factor; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma.

Figure 2.

Five-year recurrence-free survival by timing of DAA initiation in liver transplant recipients. RFS, recurrence-free survival; LT, liver transplantation; DAA, direct-acting antiviral.

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