Introduction

Hepatitis C virus (HCV) infection continues to be the main cause of hepatocellular carcinoma (HCC) globally [1]. Although advances in antiviral therapy have markedly increased rates of sustained virologic response (SVR), patients with HCV-related HCC continue to experience substantial mortality due to tumor progression, liver dysfunction, and competing comorbidities [2].

The achievement of SVR has been consistently associated with decreased occurrence of HCC in individuals with chronic HCV infection [3].

However, the survival benefit of SVR once HCC has already developed is less clearly defined. Observational studies have yielded inconsistent results, with some demonstrating improved overall survival following viral eradication, while others report attenuated or nonsignificant effects [4-7]. These discrepancies may be attributable to differences in tumor stage, treatment intent, antiviral regimen, and timing of SVR relative to HCC therapy.

In particular, heterogeneity in clinical context – such as inclusion of patients receiving only curative HCC treatment vs. mixed populations encompassing palliative or advanced disease – may substantially influence observed mortality outcomes. Additionally, the transition from interferon-based therapy to direct-acting antivirals (DAAs) has raised questions regarding whether survival benefits are driven by viral clearance itself or by antiviral class-specific effects.

Therefore, we conducted a systematic review and meta-analysis to quantify the association between SVR and all-cause mortality in patients with HCV-related HCC, with prespecified subgroup analyses to explore clinically relevant sources of heterogeneity.

Material and methods

Search strategy

This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed in PubMed and Google Scholar from inception to November 30^th, 2025. Keywords and MeSH terms combining “hepatitis C”, “hepatocellular carcinoma”, “sustained virologic response”, “mortality”, and “survival” were used, as shown in Table 1. Relevant articles’ reference lists were manually screened to identify further eligible studies.

Eligibility criteria

Studies were eligible if they included adult patients with HCV-related HCC and compared outcomes between patients achieving SVR and those who did not achieve SVR or were untreated. Eligible studies had to report adjusted hazard ratios (HRs) for all-cause mortality and utilize an observational cohort design. Studies lacking adjusted estimates, comparator groups, or sufficient data for effect size extraction were excluded.

Data extraction

Two reviewers independently extracted data on study characteristics; author, year, country, patient population, follow-up year, HCC clinical context, antiviral regimen, SVR timing, the number of patient in SVR group/non-SVR group/no treatment group, sample size, and HR. Discrepancies were resolved by consensus.

Risk of bias assessment

The methodological quality was evaluated using the Newcastle-Ottawa Scale (NOS), which assesses selection, comparability, and outcome domains.

Statistical analysis

Adjusted HRs were chosen over unadjusted HRs whenever available and were pooled using random-
effects models to account for between-study heterogeneity. Statistical heterogeneity was assessed using the I² statistic and τ². Prespecified subgroup analyses were conducted according to: 1. HCC context (curative-only vs. mixed populations), 2. SVR timing (pre-HCC vs. post-HCC vs. mixed), 3. Antiviral regimen (interferon-based vs. DAA-based therapy vs. mixed). Subgroup differences were evaluated using χ² tests for interaction. All analyses were performed using standard RevMan 5.4.

Results

Study selection

A total of 26 observational studies were included in the qualitative synthesis, and 25 observational studies were included in the quantitative synthesis after full-text review, as shown in Figure 1. A total of 11,315 patients were included in the meta-analysis, including 6,270 patients who achieved SVR, 2,777 non-SVR patients, and 2,268 untreated patients. Patients were derived from studies involving 3,642 curative HCC populations and 7,673 patients were from studies including mixed-stage cohorts. In terms of antiviral therapy, 2,028 patients were from interferon-based studies, 8,415 from direct-acting antiviral (DAA) studies, and 872 from studies with mixed antiviral studies.

Study characteristics

The included studies were published between 2006 and 2025 and originated predominantly from Asia, Europe, and North America. Most studies employed retrospective cohort designs and reported multivariable-adjusted HRs for mortality. Study populations varied with respect to HCC treatment intent and antiviral regimen, relative to HCC management, as shown in Table 2.

Risk of bias

Based on NOS, study quality ranged from 7 to 9 (Table 3). Eight studies achieved the maximum score of 9, nine studies scored 8, and nine studies scored 7, indicating overall high methodological quality across included cohorts. No study was rated as low quality (NOS < 7).

Primary outcome: all-cause mortality

In all studies analyzed, the attainment of SVR correlated with a substantial decrease in all-cause mortality relative to non-SVR, yielding a pooled HR of 0.37 (95% confidence interval [CI]: 0.30-0.47) (Fig. 2). Significant variability among studies was noted (I² = 78%, τ² = 0.21).

Subgroup analysis according to HCC clinical context

Figure 3 presents a subgroup analysis of overall survival according to HCC clinical context, comparing studies involving curative populations with those including mixed-stage cohorts. In both subgroups, SVR was associated with a significantly reduced risk of mortality, with identical pooled hazard ratios of 0.37, although the confidence intervals differed slightly between groups (curative: 95% CI: 0.27-0.50, mixed: 95% CI: 0.25-0.54). The overlapping confidence intervals and the absence of a statistically significant subgroup difference (p = 0.99) indicate that the effect of SVR is consistent regardless of HCC clinical context. Notably, substantial heterogeneity persisted within both subgroups (I² = 69% in curative and 83% in mixed populations), suggesting that variability in effect size is not explained by treatment setting alone. Overall, these findings support a robust and consistent survival benefit of SVR across different HCC populations.

Subgroup analysis according to SVR timing

The figure shows a subgroup analysis of overall survival according to the timing of SVR. SVR achieved before HCC diagnosis was associated with reduced mortality, with a pooled HR of 0.41 (95% CI: 0.31-0.53) and no observed heterogeneity (I² = 0%). Similarly, SVR achieved after HCC diagnosis demonstrated a significant survival benefit, with a pooled HR of 0.35 (95% CI: 0.25-0.49), although with substantial heterogeneity (I² = 80%). In studies with mixed timing, the pooled HR was 0.36 (95% CI: 0.24-0.56), also showing a significant reduction in mortality. The overall pooled estimate was 0.36 (95% CI: 0.29-0.46) (Fig. 4). Importantly, there was no statistically significant difference between subgroups (p = 0.75), indicating that the survival benefit of SVR is consistent regardless of timing, despite variability in heterogeneity across groups.

Subgroup analysis according to antiviral regimen

The figure presents a subgroup analysis of overall survival according to antiviral regimen. In interferon (IFN)-based studies, SVR was associated with reduced mortality, with a pooled HR of 0.39 (95% CI: 0.31-0.51) and minimal heterogeneity (I² = 1%). Similarly, in DAA studies, SVR remained associated with improved survival, with a pooled HR of 0.35 (95% CI: 0.24-0.51), although with substantial heterogeneity (I² = 84%). In studies including mixed antiviral regimens, the pooled hazard ratio was 0.48 (95% CI: 0.30-0.76), also indicating a significant survival benefit. The overall pooled estimate was 0.38 (95% CI: 0.30-0.47). Importantly, there was no statistically significant difference between subgroups (p = 0.59), suggesting that the survival benefit of SVR is consistent across antiviral treatment types despite variability in heterogeneity.

Discussion

This comprehensive review and meta-analysis of 26 observational studies suggests that achievement of a SVR is associated with a significant survival benefit in patients with HCV-related HCC. The pooled data demonstrated an approximately 63-67% relative reduction in all-cause mortality among patients achieving SVR, reinforcing the potential importance of viral eradication in modifying the historically poor prognosis associated with HCV-related HCC. The consistency of effect estimates across subgroup analyses based on HCC clinical context, SVR timing, and antiviral regimen further strengthens the biological plausibility and robustness of this association across diverse clinical settings.

The comparable mortality reduction observed across curative-intent and mixed HCC populations may be explained by the fact that SVR primarily modifies the underlying liver disease pathway rather than tumor stage alone. Viral eradication improves hepatic function, reduces chronic inflammation, and mitigates fibrosis progression, thereby influencing a major determinant of mortality in HCC regardless of tumor burden. As both tumor progression and liver failure contribute substantially to mortality, improvements in liver-related outcomes may translate into similar relative survival benefits across different disease stages, even when absolute risks differ. Although patients undergoing curative therapy may derive greater long-term clinical benefit due to lower tumor burden and preserved hepatic reserve, subgroup analyses demonstrated broadly comparable effect sizes and no significant subgroup interaction, suggesting that HCC clinical context does not meaningfully modify the overall treatment effect. Similarly, survival benefit was consistently observed regardless of whether SVR was achieved before or after HCC diagnosis, supporting the concept that viral eradication remains beneficial even after malignant transformation has occurred. In parallel, SVR was associated with improved survival across interferon-based, DAA, and mixed antiviral regimens. Although DAA-treated cohorts demonstrated numerically lower hazard ratios, overlapping confidence intervals and the absence of significant subgroup differences indicate that viral clearance itself, rather than the antiviral modality, is likely the principal driver of improved outcomes. Apparent subgroup differences therefore more likely reflect variations in patient selection, disease severity, and evolving treatment practices over time rather than intrinsic biological differences between antiviral therapies.

From a biological perspective, chronic HCV infection promotes hepatocarcinogenesis through persistent inflammation, fibrogenesis, oxidative stress, and immune-mediated hepatic injury, ultimately culminating in cirrhosis and malignant transformation [8, 9]. Viral eradication interrupts these processes, promotes hepatic regeneration, and may favorably modulate the tumor microenvironment by reducing pro-inflammatory and pro-oncogenic signaling pathways [10]. These mechanisms provide a strong rationale for the observed survival benefit beyond simple viral suppression alone. Our findings are consistent with previous studies demonstrating that SVR reduces liver-related morbidity and mortality and lowers the risk of HCC development. Morgan et al. reported that viral clearance reduces the risk of HCC occurrence by approximately 70%, highlighting its preventive potential [11]. More recent studies have extended these observations to patients with established HCC. Singal et al. demonstrated improved overall survival among patients with HCC who achieved SVR, particularly among those receiving curative treatment modalities [12]. In curative populations, lower tumor burden and preserved liver function may allow greater translation of viral eradication into long-term survival gains through delayed hepatic decompensation and reduced recurrence risk [13-15]. Conversely, in advanced disease, where tumor burden and hepatic insufficiency predominate, the relative contribution of SVR may be attenuated but remains clinically meaningful. The consistent benefit observed across antiviral regimens also supports the growing body of evidence demonstrating that DAA therapy does not adversely influence HCC outcomes and that the survival benefit observed after SVR is likely attributable to viral eradication itself rather than the antiviral platform used [16, 17].

Clinically, these findings support the integration of antiviral therapy as a fundamental component of HCC management. Achieving SVR should be prioritized in patients with HCV-related HCC, including those undergoing curative treatment, as viral eradication may improve hepatic reserve, reduce liver-related complications, and potentially facilitate eligibility for additional oncologic therapies. Early identification and treatment of HCV also remain essential strategies for reducing the overall burden of HCC and improving long-term outcomes.

Despite these consistent findings, heterogeneity remained substantial across several analyses, reflecting the inherent clinical complexity of HCV-related HCC populations. This variability is likely driven by overlapping differences in liver function, tumor burden, performance status, patient selection, timing of antiviral initiation, and variations in covariate adjustment across studies, many of which could not be fully captured in study-level subgroup analyses. Importantly, many clinically relevant variables were inconsistently reported across studies, limiting the ability to fully explain between-study variability. The covariates most commonly adjusted for across studies included age, sex, liver function parameters (e.g., Child-Pugh class, albumin, bilirubin), tumor-related factors (e.g., tumor size, number of nodules, vascular invasion, BCLC stage), treatment modality (e.g., resection, ablation, transarterial chemoembolization [TACE], systemic therapy), and performance status. Although most included studies reported adjusted hazard ratios, residual confounding remains possible given the differences in adjustment strategies and baseline characteristics between patients who achieved SVR and those who did not. Furthermore, this analysis was limited to all-cause mortality, because most studies did not consistently distinguish between liver-related and cancer-related death. Consequently, the relative contributions of hepatic versus oncologic mortality could not be determined, which may limit clinical interpretability. Nevertheless, the inclusion of a large and diverse patient population, the use of adjusted effect estimates where available, and the consistency of findings across multiple subgroup and sensitivity analyses strengthen the overall validity and generalizability of the present findings.

Conclusions

Achievement of SVR is associated with a significant reduction in mortality among patients with hepatitis C-related HCC.

Disclosures

This research received no external funding.

Institutional review board statement: Not applicable.

The authors declare no conflict of interest.

References