Efficacy and Long-Term Outcomes of Direct-Acting Antivirals in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Abstract

Background/Aims

The role of direct-acting antivirals (DAAs) in patients with hepatocellular carcinoma (HCC) remains uncertain due to conflicting data on virologic efficacy and long-term outcomes.

Methods

This meta-analysis investigated studies reporting the sustained virologic response (SVR), recurrence, and overall survival in patients with HCC treated with DAAs.

Results

Eighty-eight studies were included, comprising 8,839 patients with HCC who were treated with DAAs. The pooled SVR rate in patients with HCC was 89% (95% confidence interval [CI], 87% to 91%). However, the SVR varied significantly depending on tumor viability; patients with non-viable HCC had the highest SVR (91%), followed by those with mixed (88%) and viable HCC (84%). The SVR was significantly lower in the HCC group than in the non-HCC group (risk ratio [RR], 0.95; 95% CI, 0.92 to 0.98). In 28 studies reporting on recurrence outcomes, patients with HCC who were treated with DAAs had a 40% lower recurrence risk than non-DAA-treated patients (RR, 0.60; 95% CI, 0.49 to 0.75). Pooled analyses of adjusted estimates showed that DAA treatment was independently associated with reduced recurrence (hazard ratio [HR], 0.47; 95% CI, 0.32 to 0.70) and all-cause mortality (HR, 0.40; 95% CI, 0.31 to 0.51). An SVR was linked to an improved prognosis, with lower recurrence (HR, 0.43; 95% CI, 0.31 to 0.61) and mortality (HR, 0.41; 95% CI, 0.14 to 1.24) risks.

Conclusions

DAAs are effective in patients with HCC. Despite slightly lower SVR rates than in patients without HCC, the overall benefits support the use of antiviral therapy in patients with HCC.

INTRODUCTION

Chronic infection with hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC).^1,2 Recently, the advent of direct-acting antivirals (DAAs) has revolutionized HCV management, achieving sustained virologic response (SVR) rates >95% in most patient populations.³ However, the benefits of DAA treatment in patients with HCC remain controversial.⁴

Several studies have reported that patients with HCC may experience lower SVR rates following DAA therapy, possibly due to underlying immune dysregulation, tumor-related immune evasion, or altered hepatic microenvironments.^5,6 Some researchers suggest that DAA treatment may be associated with higher rates of HCC recurrence, raising concerns regarding its safety and efficacy in this subgroup.⁷ Conversely, HCV eradication via DAAs reduced hepatic inflammation, improved liver function, and enhanced overall survival, even in patients with HCC.^8,9 These conflicting findings have led to a lack of consensus regarding optimal HCV management in the setting of HCC.

This uncertainty has important implications in clinical practice. In patients who have undergone curative treatments for HCC, clinicians are often faced with the dilemma of whether antiviral therapy should be initiated, especially in light of inconclusive data regarding its effect on recurrence and survival. Given this uncertainty, clinical policies regarding the reimbursement and implementation of DAA therapy in patients with HCC vary across countries. For instance, in South Korea, access to DAAs is limited or even denied for patients with active HCC, reflecting concerns regarding its cost-effectiveness and treatment benefits in this population. Nevertheless, it is biologically plausible that successful eradication of HCV could provide long-term benefits by reducing hepatic injury, halting fibrosis progression, and possibly decreasing the risk of de novo HCC or recurrence in curatively treated patients. In this context, a systematic evaluation of existing data is needed to better understand the potential advantages and limitations of DAA therapy in this unique population.

Thus, this study aimed to conduct a comprehensive meta-analysis to (1) assess whether patients with HCC achieve SVR rates comparable to those without HCC and (2) evaluate the long-term outcomes of DAA treatment in patients with HCC, including recurrence and overall survival.

MATERIALS AND METHODS

1. Study design and registration

This meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. The study protocol was prospectively registered in PROSPERO (CRD420251018868). This meta-analysis solely analyzed previously published data and did not include individual patient data. Therefore, institutional review board approval and informed consent were not required. This study was conducted in accordance with the principles of the Declaration of Helsinki.

2. Eligibility criteria

Randomized controlled trials, cohort studies (prospective or retrospective), and cross-sectional studies that evaluated the effects of DAA therapy in adult patients diagnosed with HCC were included. Eligible studies reported at least one of the following outcomes: SVR, HCC recurrence, overall survival, or other long-term clinical outcomes following DAA therapy. Studies were included regardless of the geographic region, HCV genotype, or DAA regimen. Both curative (e.g., resection, ablation, and liver transplantation) and palliative (e.g., transarterial chemoembolization and systemic therapy) treatment settings were eligible. Studies comparing patients with HCC to non-HCC controls were included if subgroup-specific outcomes were reported separately for patients with HCC.

We excluded studies that included only non-HCC populations and those that did not provide HCC-specific outcome data. Studies involving interferon-based regimens without the use of DAAs, pediatric populations, case reports, case series with <5 patients, review articles, editorials, and letters or conference abstracts that did not include original data were also excluded.

3. Outcomes of interest

The primary outcomes were (1) SVR rate in patients with HCC receiving DAA therapy and (2) long-term outcomes following treatment, such as HCC recurrence and overall survival. A secondary objective was to evaluate the effectiveness of DAA therapy by comparing SVR rates between HCV-infected patients with and without HCC. In addition, we assessed HCC prognosis, including recurrence and mortality, according to the DAA treatment status.

4. Literature search strategy

The literature was systematically searched using PubMed, EMBASE, the Cochrane Library, Web of Science, and KoreaMed. We imposed no restriction on the start date of the publications. All studies published through March 31, 2024, were considered eligible. The electronic databases were systematically searched on April 13, 2024 using a combination of keywords and MeSH terms related to “hepatocellular carcinoma,” “direct-acting antivirals,” “sustained virologic response,” and “HCV.” Full search strategies for each database are available in the Supplementary Materials. The search was independently performed by two investigators (J.J.Y. and S.K.H.) in collaboration with a professional librarian.

5. Study selection and data collection

Two reviewers (J.J.Y. and S.K.H.) independently screened the titles and abstracts, followed by a full text review to determine study eligibility. Disagreements were resolved through discussion or adjudication by a third reviewer (S.S.K.). Data—extracted using a standardized form—included study characteristics, patient demographics, treatment regimens, SVR rates, and relevant clinical outcomes.

6. Definition of HCC viability

HCC viability at the time of DAA initiation was classified based on the definitions reported in each original study. Viable HCC was defined as the presence of radiologically active tumor on contrast-enhanced imaging, typically characterized by arterial phase hyperenhancement with portal venous or delayed phase washout, consistent with commonly used response assessment frameworks such as the modified Response Evaluation Criteria in Solid Tumors (mRECIST) or European Association for the Study of the Liver (EASL) criteria. Non-viable HCC was defined as complete radiologic response following curative or locoregional treatment (e.g., resection, ablation, or transarterial chemoembolization), with no imaging evidence of residual viable tumor at the time of DAA initiation. When studies included patients with both viable and non-viable HCC and did not report outcomes separately for each subgroup, they were classified as mixed HCC studies. This classification was applied at the study level to reflect heterogeneity in tumor status within the study population.

7. Quality assessment and risk of bias

The risk of bias was assessed using the Cochrane Risk of Bias tool for randomized studies and the Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS) for observational studies. Two reviewers independently evaluated the risk of bias, and discrepancies were resolved by consensus. Funnel plots and Begg’s tests were used to assess potential publication bias. Forest plots for all subgroup analyses and publication bias assessments are provided in the Supplementary Materials.

8. Statistical analyses

A random-effects model using the DerSimonian and Laird method was employed to estimate the pooled SVR rates and clinical outcomes. Risk ratios (RRs) and hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated. When individual studies reported risk factors associated with clinical outcomes in the form of HRs or ORs, pooled estimates were calculated accordingly. Statistical heterogeneity across studies was evaluated using the I² statistic and Cochran’s Q test. Substantial heterogeneity was defined as I² >50%. Subgroup analyses were conducted based on HCC viability, study design, and study region. All analyses were performed using R software (version 4.3.1; R Foundation for Statistical Computing, Vienna, Austria) with “meta” and “metafor” packages.

RESULTS

1. Study selection

The literature search yielded 8,295 records. After removing 31 duplicates, 8,264 titles and abstracts were screened. Of these, 7,802 were excluded due to irrelevance or not meeting the inclusion criteria. The full-text of 462 articles was reviewed; 374 were excluded for the following reasons: wrong population (n=170), inappropriate study design (n=135), irrelevant intervention (n=39), non-relevant outcomes (n=19), wrong setting (n=9), and pediatric population (n=2). Thus, 88 studies met the eligibility criteria and were included in the final meta-analysis (Table 1).^9-96 A PRISMA flow diagram of the selection process is presented in Fig. 1.

Table 1.

Demographics and Characteristics of the Studies Included in This Systematic Review and Meta-Analysis

No.	Study	Year	Country	Study type	No. of DAA treatments	Age, yr	Male (%)	Viability of HCC
1	Sugiura et al.10	2018	Japan	Retrospective	79	72	61	Non-viable
2	Chan et al.11	2017	Canada	Retrospective	14	NA	NA	Non-viable
3	Yada et al.12	2018	Japan	Prospective	29	NA	NA	Non-viable
4	Emamaullee et al.13	2019	USA, Canada	Retrospective	30	NA	NA	Viable
5	Guarino et al.14	2020	Italy	Prospective	101	67.2	64.4	Non-viable
6	Curry et al.15	2015	USA	RCT	61	59	80	Viable
7	ANRS16	2016	France	Prospective	516	61	82	Non-viable
8	Conti et al.17	2016	Italy	Retrospective	59	63	60.2	Non-viable
9	Prenner et al.18	2017	USA	Retrospective	137	64	75	Mixed
10	Saberi et al.19	2017	USA	Retrospective	21	NA	NA	Viable
11	Beste et al.20	2017	USA	Retrospective	482	63	98.1	Mixed
11	Beste et al.20	2017	USA	Retrospective	142	62.7	97.2	Non-viable
12	Virlogeux et al.21	2017	France	Retrospective	23	58	87	Non-viable
13	Zanetto et al.22	2017	Italy	Retrospective	23	59	NA	Viable
14	Cabibbo et al.23	2017	Italy	Prospective	143	70.4	60.1	Non-viable
15	Kolly et al.24	2017	Europe, multiple	Retrospective	47	60	76.6	Non-viable
16	Pascasio et al.25	2017	Italy	Prospective	116	58	74	Viable
17	Yu et al.26	2017	Korea	Retrospective	16	NA	62.5	Mixed
18	Ikeda et al.27	2018	Japan	Retrospective	177	71	59.8	Non-viable
19	Warzyszyńska et al.28	2017	Poland	Retrospective	19	58.5	64	Non-viable
20	El Kassas et al.29	2017	Egypt	Prospective	53	56.7	66	Non-viable
21	Adhoute et al.30	2018	France	Retrospective	22	63	73	Non-viable
22	Huang et al.31	2018	USA	Retrospective	62	63	74.2	Mixed
23	Mashiba et al.32	2018	Taiwan	Prospective	368	73	56.5	Non-viable
24	Persico et al.33	2018	Italy	Prospective	161	NA	68.9	Non-viable
25	Toyoda et al.34	2018	Japan	Prospective	62	76	51.6	Non-viable
26	Hassany et al.35	2018	Egypt	Prospective	62	60.3	67.7	Non-viable
27	Revuelta-Herrero et al.36	2018	Spain	Prospective	3	65	33.3	Viable
28	Kinoshita et al.37	2019	Japan	Prospective	147	74.4	59	Non-viable
29	Nagaoki et al.38	2019	Japan	Retrospective	38	73	65.7	Non-viable
30	Degasperi et al.39	2019	Italy	Retrospective	60	72	62	Non-viable
31	Singal et al.40	2019	USA	Retrospective	304	62.4	70.4	Non-viable
32	Jain et al.41	2019	USA	Retrospective	27	60.1	85	Viable
33	Kogiso et al.42	2019	Japan	Retrospective	45	69	71	Non-viable
34	Nakano et al.43	2019	Japan	Prospective	459	74.9	58.6	Non-viable
35	Cabibbo et al.44	2019	Italy	Prospective	163	70.6	63.2	Non-viable
36	Zou et al.45	2019	USA	Retrospective	348	66.3	98.5	Non-viable
37	Huang et al.46	2019	Taiwan	Prospective	112	67.6	45.5	Mixed
38	Zavaglia et al.47	2019	Italy	Retrospective	31	65	NA	Non-viable
39	Preda et al.48	2019	Romania	Prospective	24	64	59	Non-viable
40	Iida et al.49	2019	Japan	Retrospective	19	74	52.6	Non-viable
41	Singal et al.50	2019	USA	Retrospective	383	62.1	72.1	Non-viable
42	Yen et al.51	2019	Taiwan	Retrospective	172	70.2	46.5	Non-viable
42	Yen et al.51	2019	Taiwan	Retrospective	23	65.9	60.9	Viable
43	Radhakrishnan et al.52	2019	USA	Prospective	157	63	72	Mixed
44	Okamura et al.53	2019	Japan	Retrospective	4	NA	NA	Viable
44	Okamura et al.53	2019	Japan	Retrospective	19	NA	NA	Non-viable
45	Kuo et al.54	2019	Taiwan	Retrospective	82	65.9	63.9	Non-viable
46	Kamp et al.55	2019	USA	Retrospective	123	61.7	80.5	Mixed
47	Chi et al.56	2021	Taiwan	Prospective	199	70.9	49.7	Non-viable
48	Ogawa et al.57	2020	Japan	Retrospective	436	71.8	53.2	Mixed
49	Teng et al.58	2020	Taiwan	Retrospective	50	66.8	54	Non-viable
50	Imai et al.59	2020	Japan	Retrospective	13	74.1	69.2	Non-viable
51	Gorgen et al.60	2020	America, Europe	Retrospective	121	61.1	75.2	Viable
52	Piñero et al.61	2020	Latin America	Retrospective	66	58	80.3	Mixed
53	Miuma et al.62	2020	Japan	Retrospective	17	74	52.4	Non-viable
54	Kwan et al.63	2021	Korea	Retrospective	24	72	62.5	Non-viable
55	Sangiovanni et al.64	2020	Italy	Prospective	124	73	69	Non-viable
56	Kamp et al.65	2020	USA	Retrospective	93	61.1	82.8	Viable
57	Lin et al.66	2020	Taiwan	Retrospective	60	69.6	51.7	Mixed
58	Tahata et al.67	2020	Japan	Retrospective	63	68	85.7	Mixed
59	Yeh et al.68	2020	Taiwan	Retrospective	5	67	64.2	NA
60	Ismail et al.69	2020	USA	Retrospective	68	62.2	74	Non-viable
61	Lim et al.70	2020	USA	Retrospective	34	60.2	82.4	Viable
62	Lithy et al.71	2020	Egypt	Prospective	60	57.8	80	Non-viable
63	Ochi et al.72	2021	Japan	Retrospective	56	71	55.3	Non-viable
64	Tse et al.73	2020	USA	Retrospective	99	61	79	Viable
65	Shao et al.74	2021	Taiwan	Retrospective	14	69.9	64.3	Viable
66	Kamal et al.75	2021	Egypt	Retrospective	52	NA	NA	Non-viable
67	Elbaz et al.76	2021	Egypt	Retrospective	523	53.8	49.9	Non-viable
68	Ohki et al.77	2020	Japan	Retrospective	47	75.0	66.0	Non-viable
69	Tanaka et al.78	2021	Japan	Retrospective	18	71.0	66.6	Non-viable
70	Turgeon et al.79	2021	USA	Retrospective	255	61.0	79.0	Viable
70	Turgeon et al.79	2021	USA	Retrospective	164	NA	NA	Non-viable
71	Ikenaga et al.80	2021	Japan	Retrospective	72	71.0	56.9	Non-viable
72	Nguyen et al.81	2021	USA	Retrospective	45	NA	NA	Non-viable
73	Chen et al.82	2021	Taiwan	Retrospective	78	69.5	70.5	Viable
74	Wu et al.83	2021	Taiwan	Retrospective	69	67.5	47.8	Non-viable
75	Tsai et al.84	2021	Taiwan	Retrospective	98	68.1	71.4	Viable
76	Chen et al.85	2022	Taiwan	Retrospective	48	65.2	54.2	Non-viable
77	Mashiba et al.86	2022	Japan	Retrospective	141	71.0	59.6	Non-viable
78	Kuromatsu et al.9	2022	Japan	Retrospective	70	71.0	58.5	Non-viable
79	Fukumoto et al.87	2022	Japan	Retrospective	137	76.0	56.0	NA
80	Tajiri et al.88	2022	Japan	Retrospective	53	75.8	50.9	Non-viable
81	Lee et al.89	2022	Taiwan	Retrospective	97	69.0	67.0	Mixed
82	Meunier et al.90	2022	France	Retrospective	104	54.5	84.6	Mixed
83	Ahn et al.91	2022	Korea	Retrospective	77	65.6	41.2	Non-viable
84	Cheng et al.92	2023	Taiwan	Retrospective	93	68.0	55.9	Non-viable
85	Kam et al.93	2023	USA	Retrospective	922	65.2	73.3	Mixed
86	Park et al.94	2024	USA	Retrospective	514	NA	NA	Mixed
87	Luan et al.95	2024	Taiwan	Retrospective	94	75.9	44.7	Non-viable
88	Munekage et al.96	2024	Japan	Retrospective	26	71.0	71.2	Mixed

DAA, direct-acting antivirals; HCC, hepatocellular carcinoma; RCT, randomized controlled trial; NA, not available.

Fig. 1.

Flowcharts of this study.

2. SVR in DAA-treated patients with HCC

Among 83 studies reporting SVR outcomes, data from 8,839 DAA-treated patients with HCC were analyzed. The pooled SVR rate was 89% (95% CI, 87% to 91%) (Fig. 2A). Subgroup analysis according to tumor viability showed notable differences: patients with non-viable HCC had the highest SVR rate at 91% (95% CI, 88% to 93%), followed by the mixed group at 88% (95% CI, 82% to 93%), and those with viable tumors had a lower SVR rate of 84% (95% CI, 77% to 89%) (Table 2).

Fig. 2.

Forest plot. (A) SVR rates after DAA therapy in patients with HCC. (B) SVR rates between the HCC and non-HCC groups. (C) Comparison of recurrence rates between patients with HCC treated with and without DAAs. SVR, sustained virologic response; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; CI, confidence interval; RR, risk ratio.

Table 2.

SVR Rates after DAA Therapy in Patients with HCC

Group	No. of studies	Total No. of patients	No. of SVR patients	SVR rate	95% CI	I2, %	p for heterogeneity
Total	83	8,839	7,544	0.89	0.87–0.91	88	<0.01
Viability of HCC
Viable	17	1,100	906	0.84	0.77–0.89	81	<0.01
Non-viable	50	5,656	4,903	0.91	0.88–0.93	88	<0.01
Mixed	14	1,941	1,628	0.88	0.82–0.93	91	<0.01
Study design
Prospective	20	2,661	2,333	0.89	0.85–0.93	89	<0.01
Retrospective	63	6,178	5,211	0.89	0.87–0.92	87	<0.01
Region
East	44	3,925	3,523	0.93	0.90–0.95	84	<0.01
West	39	4,914	4,021	0.85	0.82–0.88	86	<0.01

SVR, sustained virologic response; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; CI, confidence interval.

When analyzed according to the study design, both prospective and retrospective studies reported similar SVR rates (89%). A geographic subgroup analysis revealed that studies conducted in Eastern countries (primarily Japan, South Korea, and Taiwan) had higher pooled SVR rates (93%) than those conducted in Western countries (85%) (Table 2). Subgroup-specific forest plots and the results of the publication bias analyses are presented in Supplementary Fig. 1.

3. Comparison of SVR rates between patients with and without HCC

Seventeen studies directly compared SVR rates between patients with and without HCC undergoing DAA therapy (Supplementary Table 1). The pooled RR for SVR was 0.95 (95% CI, 0.92 to 0.98), suggesting a modest but significant reduction in SVR among HCC patients (Fig. 2B). The effect was more pronounced in the mixed and viable HCC groups, while the non-viable HCC group demonstrated near-equivalent SVR rates compared to non-HCC controls (RR, 0.98; 95% CI, 0.96 to 1.00). Subgroup-specific forest plots and the results of the publication bias analyses are presented in Supplementary Fig. 2.

4. HCC recurrence following DAA treatment

Twenty-eight studies assessed HCC recurrence after DAA therapy and compared the outcomes between DAA-treated and DAA-untreated patients with HCC (Table 3). The overall pooled RR for recurrence was 0.60 (95% CI, 0.49 to 0.75), indicating a significantly lower risk of tumor recurrence in those who received DAA therapy (Fig. 2C). Subgroup analysis revealed that the reduction in recurrence risk was most evident in patients with viable tumors (RR, 0.39; 95% CI, 0.18 to 0.87), followed by non-viable tumors (RR, 0.59; 95% CI, 0.46 to 0.76). Subgroup-specific forest plots and the results of the publication bias analyses are presented in Supplementary Fig. 3.

Table 3.

Comparison of Recurrence Rates between Patients with HCC Treated with DAAs and Those Not Treated with DAAs

Group	No. of studies	DAA HCC group*	Non-DAA HCC group*	RR (95% CI)	I2, %	p for heterogeneity
Total	28	738/2,503	1,867/3,744	0.60 (0.49–0.75)	86	<0.01
Viability of HCC
Viable	4	17/270	52/257	0.39 (0.18–0.87)	33	0.22
Non-viable	21	651/2,089	1,475/2,894	0.59 (0.46–0.76)	89	<0.01
Mixed	3	70/144	340/593	0.91 (0.76–1.09)	0	0.54
Study design
Prospective	5	129/816	173/604	0.67 (0.26–1.77)	96	<0.01
Retrospective	23	609/1,687	1,694/3,140	0.61 (0.50–0.74)	79	<0.01
Region
East	14	330/941	1,109/2,144	0.60 (0.43–0.82)	87	<0.01
West	14	408/1,562	758/1,600	0.60 (0.44–0.83)	87	<0.01

HCC, hepatocellular carcinoma; DAAs, direct-acting antivirals; RR, risk ratio; CI, confidence interval.

*Recurrence/total patients.

5. Pooled analysis of risk factors based on reported ORs and HRs: DAA failure, recurrence, and mortality

Subsequently, for studies that presented risk factors in the form of ORs or HRs, we performed meta-analyses to calculate the pooled ORs or HRs for each factor (Table 4). Patients with HCC had a significantly higher risk of DAA treatment failure, defined as non-SVR, than those without HCC. The pooled OR was 2.36 (95% CI, 1.71 to 3.26; I²=40.8%; p for heterogeneity=0.13).

Table 4.

Pooled Analysis of Risk Factors Based on Reported ORs and HRs: DAA Failure, Recurrence, and Mortality

Outcome	Factor	No. of studies	Pooled OR or HR	95% CI	I2, %	p for heterogeneity
DAA failure (non-SVR)	HCC (vs non-HCC)	6	2.36*	1.71–3.26	40.8	0.13
Recurrence	DAA (vs non-DAA)	19	0.47†	0.32–0.70	80.7	<0.01
	SVR (vs non-SVR)	12	0.43†	0.31–0.61	61.9	<0.01
	Time from complete response to DAA treatment	11	0.98†	0.94–1.01	66.5	<0.01
Mortality	DAA (vs non-DAA)	14	0.40†	0.30–0.54	70.4	<0.01
	SVR (vs non-SVR)	7	0.41†	0.14–1.24	93.9	<0.01

ORs, odds ratios; HRs, hazard ratios; DAA, direct-acting antiviral; CI, confidence interval; SVR, sustained virologic response; HCC, hepatocellular carcinoma.

*OR; ^†HR.

Regarding HCC recurrence, DAA treatment was associated with a significantly reduced risk compared to no DAA treatment (pooled HR, 0.47; 95% CI, 0.32 to 0.70; I²=80.7%; p<0.01). Similarly, achieving SVR was associated with a lower recurrence risk than not achieving SVR (HR, 0.43; 95% CI, 0.31 to 0.61; I²=61.9%; p<0.01). However, the timing of DAA initiation after complete response (CR) did not significantly affect recurrence risk (HR, 0.98; 95% CI, 0.94 to 1.01; I²=66.5%; p<0.01).

In terms of mortality, DAA treatment significantly reduced the risk of death compared to no DAA treatment (HR, 0.40; 95% CI, 0.30 to 0.54; I²=70.4%; p<0.01). Although SVR also appeared to be associated with reduced mortality, the result was statistically insignificant (HR, 0.41; 95% CI, 0.14 to 1.24; I²=93.9%; p<0.01), likely due to high heterogeneity among studies. Subgroup-specific forest plots and the results of the publication bias analyses are presented in Supplementary Fig. 4.

DISCUSSION

This meta-analysis demonstrated that DAA-treated patients with HCC achieved a high rate of SVR, although it was slightly lower than that in patients without HCC. Importantly, DAA therapy was associated with a meaningful reduction in both HCC recurrence and all-cause mortality, suggesting the long-term benefits of antiviral treatment in this population. These findings offer reassurance that DAA treatment remains effective and clinically valuable, even in the context of malignancy, which often complicates antiviral decision-making.

Several previous meta-analyses have examined the efficacy and safety of DAA therapy in this population, including studies by Ji et al.⁹⁷, He et al.,⁹⁸ and a more recent individual patient data meta-analysis published by Sapena et al.⁹⁹ Ji et al.⁹⁷ reported a noticeably lower SVR rate in patients with active HCC (73.1%) than in those without HCC (93.3%), raising concerns about impaired treatment response in this population. He et al.⁹⁸ also found lower SVR in patients with HCC and pointed out that outcomes were generally more favorable when tumor control had been achieved prior to starting antiviral therapy. Their study emphasized the potential impact of tumor biology and host immune dysfunction on the antiviral response. Conversely, an IPD meta-analysis by Sapena et al.,⁹⁹ focusing primarily on HCC recurrence, found that the risk remained substantial even after DAA treatment, with no clear difference compared to untreated controls. While these studies provide important insights, they are limited by narrow outcome definitions and a lack of subgroup analysis based on tumor status.

Compared to earlier reports, our review included a substantially larger and more recent body of literature, with 88 eligible studies encompassing nearly 9,000 patients. By introducing a viability-based classification of HCC (viable, non-viable, and mixed), we were able to analyze how tumor activity at the time of DAA initiation affects treatment outcomes, an aspect that has received limited attention in prior reviews. Moreover, our study evaluated not only SVR rates but also recurrence and mortality, offering a more comprehensive perspective on the clinical impact of DAA therapy in this complex patient population.

A key finding of our study is the slightly lower SVR rates observed in patients with HCC compared to those without HCC, particularly among patients with viable tumors. Although the pooled SVR rate in patients with HCC remained high overall, it was lowest in those with viable disease. Given the observational nature of the included studies, this finding should be interpreted as an association rather than a causal effect. The lower SVR rates in this subgroup may reflect factors such as a higher tumor burden or an altered hepatic microenvironment associated with active malignancy, rather than a direct impact of tumor viability itself.52,^100,101 Active tumors may be accompanied by local vascular changes, immune dysregulation, or altered intrahepatic drug distribution, which could potentially influence antiviral efficacy. Nonetheless, an SVR rate exceeding 80% even in the viable HCC group underscores the robustness of DAA therapy and supports its continued use in this population, particularly given the limited alternative options for viral eradication.

Additionally, the interval between achieving CR from HCC treatment and initiating DAA therapy did not significantly influence recurrence risk. This contradicts earlier concerns that early post-CR treatment might increase recurrence, possibly by altering immunosurveillance.^47,102,103 While some centers recommend delaying antiviral therapy for several months after curative HCC treatment,¹⁰⁴ our results do not support this. Instead, we suggest initiating DAA therapy once CR is confirmed, without concern for triggering early tumor recurrence. This has practical implications, particularly for patients with advanced liver fibrosis or decompensated cirrhosis, who may benefit from prompt viral clearance.

Additionally, DAA treatment was associated with lower risks of both recurrence (HR, 0.47) and mortality (HR, 0.40). These benefits appeared consistent across most viability subgroups, although somewhat attenuated in the mixed group, likely reflecting the heterogeneity in disease stage, treatment modality, and timing. The reduction in mortality is especially compelling, as it indicates that the benefits of HCV clearance extend beyond tumor-specific outcomes and may contribute to broader improvements in liver function, immune competence, and overall systemic health. Achieving SVR itself was also associated with a reduced risk of recurrence and death, reinforcing the central importance of viral eradication as a therapeutic goal in patients with HCC.

This study has several limitations that should be considered. Most of the included studies were observational, introducing the possibility of residual confounding despite statistical adjustment. Definitions of HCC viability and the timing of CR were not standardized across studies, which may have led to misclassifications. Additionally, there was variability in how outcomes, such as recurrence and mortality, were reported, and the follow-up durations were inconsistent. Furthermore, we were unable to access individual patient-level data, which limited the depth of subgroup analyses and prevented the evaluation of nuanced clinical factors such as liver function scores, tumor burden, or comorbidity profiles. Lastly, several pooled analyses demonstrated substantial heterogeneity, which is expected given the observational design and clinical complexity of patients with HCC. Potential sources of heterogeneity include differences in study design, geographic region, tumor viability at the time of DAA initiation, baseline liver function and disease severity, and the timing of antiviral therapy relative to HCC treatment. Indeed, our subgroup analyses showed variability in effect size across these factors. Nevertheless, despite heterogeneity in magnitude, the direction of the associations—particularly regarding reduced recurrence and mortality with DAA treatment—was largely consistent across studies. Therefore, the pooled estimates should be interpreted as reflecting average effects across heterogeneous real-world settings rather than uniform effects applicable to all patients.

Despite these limitations, our findings support the active use of DAA therapy in patients with HCC, particularly in those with well-controlled or curatively treated disease. Given the clear benefits—reduced recurrence and mortality, withholding antiviral therapy solely because of a history of HCC may not be justified. Furthermore, in patients receiving systemic chemotherapy for advanced HCC, active antiviral treatment should be considered to prevent deterioration of hepatic function caused by hepatitis C reactivation. Further studies are warranted to evaluate the impact of antiviral treatment on survival in patients with advanced HCC undergoing systemic chemotherapy. In clinical practice, the decision to initiate DAA therapy in patients with HCC is often complex, involving consideration of liver function, tumor status, and life expectancy. Our results suggest that when these factors are reasonably favorable, DAA therapy should be actively pursued.

In conclusion, this meta-analysis provides updated and comprehensive evidence that DAA therapy is effective and beneficial for patients with HCC. While the presence of viable tumors may modestly reduce the likelihood of SVR, the long-term benefits in terms of recurrence and mortality reduction support the broad application of DAA therapy in this patient population.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl260015.