Age-male-albumin-bilirubin-platelet score stratifies hepatocellular carcinoma risk after sustained virological response in hepatitis C-related compensated advanced chronic liver disease

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) remains an important long-term complication after sustained virological response (SVR) in patients with hepatitis C virus (HCV)-related compensated advanced chronic liver disease (cACLD). Current guidelines generally recommend lifelong semiannual surveillance for patients with advanced fibrosis or cirrhosis; however, the residual risk of HCC after viral eradication is heterogeneous. We hypothesized that simple noninvasive scores could identify a very-low-risk subgroup suitable for individualized surveillance intensity.

AIM

To compare the performance of noninvasive scores for predicting HCC after SVR and to identify a very-low-risk subgroup.

METHODS

This single-center retrospective cohort study included 571 adults with HCV-related cACLD who achieved SVR at 12 weeks after treatment completion following interferon-free sofosbuvir-based direct-acting antiviral therapy between 2013 and 2023. The fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, albumin-bilirubin score, and age-male-albumin-bilirubin-platelet (aMAP) score were calculated. HCC risk was evaluated using Kaplan-Meier analysis, Cox proportional hazards regression, and time-dependent receiver operating characteristic curves at 1 year, 3 years, 5 years, and 8 years.

RESULTS

During a median follow-up of 4.59 years, 78 patients (13.7%) developed de novo HCC [annual incidence rate: 3.12%; 95% confidence interval (CI): 2.50-3.80]. Compared with those who did not develop HCC, patients who developed HCC had higher baseline liver stiffness, higher prevalence of diabetes mellitus and esophageal varices, lower platelet counts and albumin levels, and higher bilirubin levels. Among the evaluated scores, the aMAP score showed the highest discriminatory performance, with an 8-year area under the receiver operating characteristic curve of 0.74 (95%CI: 0.67-0.80). An exploratory aMAP threshold of < 55 identified 18.6% of patients with no observed HCC events, whereas patients with an aMAP score ≥ 60 had the highest annual HCC incidence of 6.42% per year.

CONCLUSION

The aMAP score effectively stratifies the risk of HCC after SVR and may support individualized surveillance intensity in patients with HCV-related cACLD. However, the exploratory aMAP threshold requires external validation.

Key Words: Hepatitis C virus; Compensated advanced chronic liver disease; Direct-acting antiviral therapy; Sustained virological response; Hepatocellular carcinoma; Age-male-albumin-bilirubin-platelet score; Risk stratification; Surveillance de-escalation

Core Tip: This retrospective cohort study evaluated the age-male-albumin-bilirubin-platelet (aMAP) score for predicting hepatocellular carcinoma (HCC) risk after sustained virological response in patients with hepatitis C virus-related compensated advanced chronic liver disease. Among 571 patients followed for a median of 4.59 years, 78 developed HCC. The aMAP score outperformed other noninvasive scoring systems, and an exploratory threshold of < 55 identified 18.6% of patients with no observed HCC events. These findings suggest that the aMAP score may support individualized surveillance intensity; however, the threshold requires external validation before routine clinical implementation.

INTRODUCTION

Chronic hepatitis C virus (HCV) infection remains a major global health concern, affecting an estimated 58 million individuals worldwide and causing approximately 290000 deaths annually, predominantly from cirrhosis and hepatocellular carcinoma (HCC)[1]. HCV-related cirrhosis contributes substantially to the global HCC burden, particularly in Western Europe, the Mediterranean/North Africa, Japan, and the Asia-Pacific region[2-5]. Cirrhosis and clinically significant portal hypertension together provide the biological basis for hepatocarcinogenesis[4].

The therapeutic landscape of HCV infection has been transformed by interferon-free, all-oral direct-acting antiviral (DAA) regimens. Historically, pegylated interferon plus ribavirin achieved only modest sustained virological response (SVR) rates and was limited by significant adverse effects[6]. In contrast, sofosbuvir-based DAA regimens routinely achieve SVR rates exceeding 95% across HCV genotypes, including in patients with advanced fibrosis or compensated cirrhosis, and are endorsed as first-line therapy by major liver societies[7,8]. Real-world studies from diverse settings have further confirmed their excellent efficacy and tolerability[9].

SVR is associated with improvements in liver histology and function. Prospective studies have demonstrated significant regression of fibrosis and lower incidence of HCC among patients with advanced fibrosis (stage F3) after DAA therapy[10]. Similarly, real-world cohorts have demonstrated significant reductions in liver stiffness after viral eradication, even in patients with cirrhosis[11]. Observational longitudinal studies—including the large European cohort by van der Meer et al[12]—have shown that viral eradication in patients with advanced fibrosis markedly reduces the risk of liver-related complications and mortality compared with individuals who fail to achieve SVR. Furthermore, large real-world studies of patients with advanced liver disease have demonstrated that achieving SVR with DAA therapy significantly lowers both all-cause and liver-related mortality[13].

Nevertheless, patients with advanced fibrosis or cirrhosis remain at risk of developing de novo HCC after achieving SVR. Multiple cohorts in the DAA era have consistently demonstrated that SVR reduces—but does not eliminate—HCC risk[14-20]. In a cohort of 636 patients with cirrhosis treated with DAAs, D’Ambrosio et al[14] reported a 5-year cumulative HCC incidence of 7.7%. Similarly, Caviglia et al[21] reported an HCC incidence of 9.9% over a median follow-up of approximately 45 months in 575 patients with HCV-related cirrhosis. Additional large observational studies have confirmed persistent HCC risk even after successful viral eradication[16-20].

Recognizing this persistent risk, major international guidelines—including those from the European Association for the Study of the Liver (EASL), American Association for the Study of Liver Diseases (AASLD), and Asian Pacific Association for the Study of the Liver (APASL)—recommend lifelong semiannual ultrasound-based HCC surveillance in patients with cirrhosis or compensated advanced chronic liver disease (cACLD), irrespective of SVR status[22-24]. However, this universal strategy is resource-intensive. Recent modeling studies suggest that surveillance may be cost-effective only when the annual HCC incidence exceeds specific thresholds, prompting intense interest in individualized, risk-stratified surveillance strategies[25].

Several widely available noninvasive indices have been proposed to refine HCC risk stratification, including the fibrosis-4 (FIB-4) index[26], aspartate aminotransferase-to-platelet ratio index (APRI)[27], albumin-bilirubin (ALBI) score[28,29], and the age-male-albumin-bilirubin-platelet (aMAP) score[30]. The aMAP model, which incorporates age, sex, ALBI score, and platelet count, was validated in 17374 patients across 11 international cohorts, including patients with HCV-related cirrhosis who achieved SVR, and stratifies patients into low-, intermediate-, and high-risk groups[30]. The ALBI score has also been identified as an independent predictor of de novo HCC after SVR in several studies[21,31].

Given the substantial burden of lifelong HCC surveillance, identifying a truly very-low-risk subgroup among patients who achieve SVR has become a priority. However, evidence supporting surveillance de-escalation in real-world populations with cACLD remains limited. Therefore, this study aimed to: (1) Determine the long-term incidence of de novo HCC in patients with HCV-related cACLD after SVR; (2) Compare the predictive performance of the FIB-4 index, APRI, ALBI score, and aMAP score over up to 8 years of follow-up; and (3) Evaluate whether these noninvasive scores can identify a very-low-risk subgroup that may support future surveillance de-escalation after external validation.

MATERIALS AND METHODS

Study design and population

This retrospective cohort study was conducted at Siriraj Hospital, a tertiary referral center in Thailand. Consecutive adult patients with HCV-related cACLD who initiated sofosbuvir-based DAA therapy between 2013 and 2023 were identified. Eligible patients had confirmed cACLD, defined by the Baveno VII consensus as histological stage F3/F4 fibrosis, vibration-controlled transient elastography (VCTE) ≥ 10 kPa, or clinical evidence of portal hypertension, and achieved SVR at 12 weeks after treatment completion (SVR12)[32]. This observational, longitudinal follow-up of real-world patients with HCV-related advanced fibrosis or cirrhosis after DAA therapy is consistent with previous studies evaluating HCC risk after SVR[14,15,18,19,21].

Ethical considerations

This study was approved by the Siriraj Institutional Review Board, Faculty of Medicine Siriraj Hospital, Mahidol University (Certificate of Approval No. Si 034/2024). The study was conducted in accordance with the principles of the Declaration of Helsinki. Owing to the retrospective nature of the study, the requirement for obtaining written informed consent was waived by the Institutional Review Board.

Study population, and inclusion and exclusion criteria

Eligible patients were required to meet all of the following criteria: Age ≥ 18 years; chronic HCV infection treated with DAA therapy with documented SVR12[7,8]; and evidence of advanced fibrosis or cirrhosis consistent with cACLD before DAA therapy, as defined by the Baveno VII consensus[32]. Briefly, patients were considered to have cACLD if they fulfilled at least one of the following criteria: Histological stage F3 or F4 fibrosis on liver biopsy; liver stiffness measurement by VCTE ≥ 10 kPa; radiological features consistent with cirrhosis or portal hypertension on ultrasonography, contrast-enhanced computed tomography, or contrast-enhanced magnetic resonance imaging; or clinical or endoscopic evidence of portal hypertension.

Radiological features were not used to diagnose histological stage F3 fibrosis but were used only to support the presence of cirrhosis or portal hypertension. Radiological features consistent with cirrhosis or portal hypertension included a nodular or irregular liver surface, morphological features of cirrhosis, splenomegaly, ascites, or portosystemic collaterals. Clinical or endoscopic evidence of portal hypertension included esophageal or gastric varices, portal hypertensive gastropathy, ascites, or other documented findings of portal hypertension. All patients were required to have a minimum follow-up of 12 months after achieving SVR.

Patients were excluded if they met any of the following criteria: (1) Incomplete or missing medical records precluding outcome assessment; (2) Known or suspected HCC before initiating DAA therapy; or (3) Failure to achieve SVR12.

Baseline data collection

Baseline demographic, clinical, and laboratory data were abstracted from electronic medical records. The collected variables included age, sex, metabolic comorbidities such as type 2 diabetes mellitus and dyslipidemia, prior HCV treatment history, routine laboratory parameters (complete blood count, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transferase, albumin, total bilirubin, and prothrombin time/international normalized ratio), and indicators of portal hypertension and hepatic functional reserve, including platelet count and the presence of esophageal varices. These variables—including markers of portal hypertension, thrombocytopenia, and impaired synthetic function—have been associated with subsequent liver-related events and de novo HCC in patients with HCV-related cirrhosis who achieved SVR[14,21,31,33].

Follow-up and HCC surveillance

After completion of DAA therapy, patients were followed in dedicated hepatology clinics with standardized laboratory monitoring and imaging-based HCC surveillance. Abdominal ultrasonography, with or without measurement of serum alpha-fetoprotein, was performed every 6 months in accordance with recommendations from the EASL, the AASLD, and the APASL for ongoing HCC surveillance in patients with cirrhosis or cACLD, even after achieving SVR[22-24].

Noninvasive scoring systems

Four noninvasive scoring systems were evaluated using laboratory data obtained at the SVR12 visit: APRI, FIB-4 index, ALBI, and aMAP score. The FIB-4 index[26] and APRI[27] have been widely validated for noninvasive fibrosis assessment in patients with chronic viral hepatitis, including chronic hepatitis B[34], whereas the ALBI score[28,29] and aMAP score[30] assess hepatic functional reserve and composite HCC risk, respectively. All scores were calculated using laboratory values obtained at the SVR12 visit.

Outcome and analysis

The primary outcome was the development of de novo HCC. The FIB-4 index, APRI, ALBI score, and aMAP score were calculated at SVR12. Kaplan-Meier survival analysis and time-dependent receiver operating characteristic curve analysis were performed to assess the predictive performance of these scoring systems for HCC at 1 year, 3 years, 5 years, and 8 years. The discriminatory performance of the aMAP score was evaluated using both the originally published cutoffs proposed by Fan et al[30] (< 50, 50 to < 60, and ≥ 60) and exploratory cohort-derived cutoff values identified in the present study (< 55, 55 to < 60, and ≥ 60). The exploratory cutoff of < 55 was selected because it represented the highest cutoff value that identified a subgroup with no observed de novo HCC during long-term follow-up while expanding the very-low-risk subgroup compared with the originally validated cutoff of < 50.

Statistical analysis

Baseline characteristics were summarized using descriptive statistics. Continuous variables were expressed as the mean ± SD for normally distributed data or as the median [interquartile range (IQR)] for nonnormally distributed data. Categorical variables were summarized as frequencies and percentages. Comparisons between the HCC and non-HCC groups were performed using the χ² or Fisher’s exact test for categorical variables and the Student’s t-test or Mann-Whitney U test for continuous variables, as appropriate.

Time-to-event analyses for the first occurrence of de novo HCC were performed using the Kaplan-Meier method, and differences in HCC-free survival were compared using the log-rank test. Cox proportional hazards regression analysis was performed to estimate hazard ratios and 95% confidence intervals (CIs) for the associations between baseline variables, including comorbidities, features of portal hypertension, hepatic synthetic function, and noninvasive scores, and the risk of HCC.

To evaluate the discriminatory performance of each noninvasive scoring system (APRI, FIB-4 index, ALBI, aMAP score), time-dependent receiver operating characteristic curves for HCC occurrence at 1 year, 3 years, 5 years, and 8 years of follow-up were generated, and the area under the curve (AUC) with 95%CIs was calculated. Patients were also stratified into aMAP-based risk categories using exploratory cohort-derived cutoff values (< 55, 55 to < 60, ≥ 60) and compared with the prespecified risk groups proposed by Fan et al[30] (< 50, 50 to < 60, ≥ 60). A two-sided P value < 0.05 was considered statistically significant.

All statistical analyses were performed using SPSS version 19 (IBM Corp., Armonk, NY, United States).

RESULTS

Patient selection and HCC incidence

Of 2971 patients with chronic HCV infection and evidence of advanced fibrosis or cirrhosis consistent with cACLD who were screened, 2179 were excluded because they did not receive interferon-free oral DAA therapy. The remaining 792 patients received oral DAA therapy. Before inclusion in the post-SVR outcome cohort, 204 patients were excluded: 203 who had inadequate long-term follow-up after DAA therapy owing to loss to follow-up or referral back to primary care or local hospitals, and 1 who did not achieve SVR12. Therefore, 588 patients achieved SVR12 and had adequate follow-up data for assessment of post-SVR HCC outcomes. Among these, 17 patients were excluded because of known or suspected HCC before initiation of DAA therapy. The final study population therefore comprised 571 patients (Figure 1).

Figure 1 Flowchart of patient selection. cACLD: Compensated advanced chronic liver disease; DAA: Direct-acting antiviral; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; SVR12: Sustained virological response at 12 weeks after treatment completion; SVR: Sustained virological response.

As Siriraj Hospital is a tertiary referral center, some patients were referred from other hospitals for specialist assessment and antiviral treatment and were subsequently referred back to primary care or local hospitals for long-term follow-up after completion of DAA therapy. Therefore, the large number of excluded patients was mainly attributable to non-receipt of oral DAA therapy and inadequate long-term post-treatment follow-up rather than missing baseline data.

The diagnostic criteria supporting cACLD in the final analytic cohort are summarized in Table 1. Among the 571 patients included in the final analysis, liver biopsy data were available for 62 patients (10.9%), including 19 (3.3%) with histological stage F3 fibrosis and 43 (7.5%) with histological stage F4 cirrhosis. VCTE ≥ 10 kPa was documented in 293 patients (51.3%). Radiological features consistent with cirrhosis or portal hypertension were present in 518 patients (90.7%), and clinical or endoscopic evidence of portal hypertension was present in 77 patients (13.5%). These criteria were not mutually exclusive.

Table 1 Diagnostic criteria supporting compensated advanced chronic liver disease in the final study cohort.

Diagnostic criterion supporting compensated advanced chronic liver disease	n (%)
Liver biopsy available	62 (10.9)
Histologic stage F3 fibrosis	19 (3.3)
Histologic stage F4 cirrhosis	43 (7.5)
Vibration-controlled transient elastography ≥ 10 kPa	293 (51.3)
Radiological features consistent with cirrhosis or portal hypertension	518 (90.7)
Clinical or endoscopic evidence of portal hypertension	77 (13.5)

Percentages were calculated using the final study cohort as the denominator (n = 571). Categories were not mutually exclusive and should not be summed. Histological stage F3 fibrosis and histological stage F4 cirrhosis were assigned only when liver biopsy data were available. Radiological features were used to support the presence of cirrhosis or portal hypertension and were not used to diagnose histological stage F3 fibrosis.

During a median follow-up of 4.59 years, 78 of the 571 patients (13.7%) developed de novo HCC. This corresponded to an annual incidence rate of 3.12% (95%CI: 2.50-3.80), indicating that a clinically significant risk of HCC persisted despite achieving SVR12 in this population with HCV-related cACLD.

Baseline characteristics

The sex distribution did not differ significantly between patients who developed HCC and those who did not (P = 0.177). Patients who developed HCC tended to be older on average than those who did not, although this difference did not reach statistical significance.

Metabolic and portal hypertension-related features differed between the two groups. Patients who subsequently developed HCC had a significantly higher prevalence of type 2 diabetes mellitus and esophageal varices (both P < 0.05). These clinical features are consistent with prior studies showing that portal hypertension, impaired hepatic reserve, and metabolic comorbidities are associated with an increased risk of HCC after SVR in patients with HCV-related cirrhosis[14,21,31,33]. Baseline VCTE (E, kPa) before DAA therapy was significantly higher in the HCC group than in the non-HCC group [median (IQR), 21.3 (15.7-35.3) kPa vs 15.1 (10.5-23.3) kPa; P < 0.001].

All patients in the cohort received one of three standard-of-care sofosbuvir-based DAA regimens commonly used in routine practice: Sofosbuvir 400 mg plus ledipasvir 90 mg [sofosbuvir (SOF)/ledipasvir (LDV)], sofosbuvir 400 mg plus velpatasvir 100 mg (SOF/velpatasvir), or sofosbuvir 400 mg plus daclatasvir 60 mg (SOF/daclatasvir). These interferon-free, all-oral regimens are consistent with current guideline recommendations for first-line treatment of chronic HCV infection[7,8].

At SVR12, all patients had undetectable HCV RNA levels. Laboratory parameters at SVR12 differed significantly between the two groups. Compared with patients who did not develop HCC, those who developed HCC had higher total bilirubin levels [median (IQR), 0.90 (0.54-1.47) mg/dL vs 0.71 (0.47-1.01) mg/dL; P = 0.028] and higher aspartate aminotransferase levels [34 (26-47) U/L vs 30 (23-40) U/L; P = 0.006]. Platelet counts were significantly lower in the HCC group [88 (68-150) × 10⁹/L vs 149 (96-195) × 10⁹/L; P < 0.001], and serum albumin levels were also significantly lower (3.77 ± 0.56 g/dL vs 4.08 ± 0.54 g/dL; P < 0.001). These findings, summarized in Table 2, are consistent with previous studies showing that thrombocytopenia, hyperbilirubinemia, hypoalbuminemia, and other surrogate markers of portal hypertension and impaired hepatic synthetic function are associated with an increased risk of subsequent HCC in patients with HCV-related cirrhosis who achieve SVR[14,21,31,33].

Table 2 Baseline characteristics, comorbidities, liver stiffness before direct-acting antiviral therapy, laboratory parameters at sustained virological response at 12 weeks after treatment completion, and noninvasive scoring systems, n (%)/median (interquartile range).

Characteristics	Overall	No HCC	De novo HCC	P value
Patients	571	493 (86.3)	78 (13.7)
Sex, male	267	225 (45.6)	42 (53.8)	0.177
Age (years), mean ± SD	59.75 ± 10.00	59.53 ± 10.24	61.18 ± 8.22	0.175
Comorbidities
T2DM	209	172 (34.9)	37 (47.4)	0.033
DLP	228	205 (41.6)	23 (29.5)	0.043
HT	315	270 (54.8)	45 (57.7)	0.629
Thalassemia	23	22 (4.5)	1 (1.3)	0.346
Esophageal varices without bleeding	87	67 (13.6)	20 (25.6)	0.006
Transient elastography
Baseline liver stiffness by VCTE (kPa)	15.8 (11.1-25.7)	15.1 (10.5-23.3)	21.3 (15.7-35.3)	< 0.001
SOF-based treatment	571 (100)	493 (86.3)	78 (13.7)	0.045
SOF/LDV	186 (32.6)	153 (31.0)	33 (42.3)
SOF/VEL	163 (28.5)	149 (30.2)	14 (17.9)
SOF/DAC	222 (38.9)	191 (38.7)	31 (39.7)
Laboratory parameters at SVR12
Total bilirubin (mg/dL)	0.71 (0.49-1.10)	0.71 (0.47-1.01)	0.90 (0.54-1.47)	0.028
Direct bilirubin (mg/dL)	0.31 (0.20-0.49)	0.28 (0.19-0.46)	0.37 (0.26-0.62)	0.046
AST (U/L)	30 (24-40)	30 (23-40)	34 (26-47)	0.006
ALT (U/L)	22 (16-31)	21 (16-31)	23.5 (17-31)	0.275
ALP (U/L)	91 (67.5-120.5)	91 (68-124)	85 (64-107)	0.193
GGT (U/L)	44.5 (27-92)	43 (27-92)	59 (59-59)	0.641
Platelet count (× 109/L)	140 (92-191)	149 (96-195)	88 (68-150)	< 0.001
Total protein (g/dL), mean ± SD	7.69 ± 0.74	7.71 ± 0.74	7.61 ± 0.71	0.393
Albumin (g/dL), mean ± SD	4.04 ± 0.56	4.08 ± 0.54	3.77 ± 0.56	< 0.001
Globulin (g/dL), mean ± SD	3.70 ± 0.71	3.68 ± 0.68	3.84 ± 0.85	0.170
Noninvasive scoring systems at SVR12
FIB-4	2.97 (1.81-4.97)	2.66 (1.76-4.51)	5.24 (2.79-7.46)	< 0.001
APRI	0.58 (0.35-1.08)	0.54 (0.34-0.96)	1.01 (0.51-1.65)	< 0.001
ALBI	-2.72 (-3.04 to -2.26)	-2.78 (-3.06 to -2.31)	-2.43 (-2.87 to -1.92)	0.001
aMAP	61.79 (56.59-66.22)	60.78 (55.45-65.31)	65.05 (62.29-68.57)	< 0.001

ALBI: Albumin-bilirubin score; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; aMAP: Age-male-albumin-bilirubin-platelet score; APRI: Aspartate aminotransferase-to-platelet ratio index; AST: Aspartate aminotransferase; DLP: Dyslipidemia; FIB-4: Fibrosis-4 index; GGT: Γ-Glutamyl transferase; HCC: Hepatocellular carcinoma; HT: Hypertension; IQR: Interquartile range; SD: Standard deviation; SOF: Sofosbuvir; DAC: Daclatasvir; LDV: Ledipasvir; VEL: Velpatasvir; SVR12: Sustained virological response at 12 weeks after treatment completion; T2DM: Type 2 diabetes mellitus; VCTE: Vibration-controlled transient elastography.

Each of the four noninvasive scoring systems—the FIB-4 index, APRI, ALBI, and aMAP score—calculated at SVR12 was significantly higher in the group that later developed HCC compared with the group that remained HCC-free. This finding is consistent with previous studies of patients with HCV-related cirrhosis who achieved SVR, in which these scoring systems were associated with the risk of de novo HCC during long-term follow-up[21,30,31].

When the discriminatory performance of the four noninvasive scoring systems was evaluated over time, the aMAP score demonstrated the highest predictive accuracy for overall HCC development, with an 8-year AUC of 0.74 (95%CI: 0.67-0.80). At earlier time points (1 year, 3 years, and 5 years), the aMAP score consistently achieved higher AUC values compared with FIB-4 index, APRI, and ALBI (Table 3, Figure 2). This pattern is consistent with the original multicohort validation of the aMAP score, which demonstrated strong discrimination for incident HCC across multiple etiologies of chronic liver disease and stable predictive performance across follow-up periods of up to 5 years[30].

Figure 2 Time-dependent receiver operating characteristic curves of four noninvasive scoring systems for predicting de novo hepatocellular carcinoma at 1-year, 3-year, 5-year, and 8-year follow-up. A: 1-year follow-up; B: 3-year follow-up; C: 5-year follow-up; D: 8-year follow-up. ALBI: Albumin-bilirubin score; aMAP: Age-male-albumin-bilirubin-platelet score; APRI: Aspartate aminotransferase-to-platelet ratio index; FIB-4: Fibrosis-4 index; ROC: Receiver operating characteristic; FU: Follow-up.

Table 3 Time-dependent diagnostic performance of four noninvasive scoring systems for predicting de novo hepatocellular carcinoma at 1-year, 3-year, 5-year, and 8-year follow-up.

Noninvasive scoring system at SVR12	1-year FU AUC (95%CI)	3-year FU AUC (95%CI)	5-year FU AUC (95%CI)	8-year FU AUC (95%CI)
FIB-4	0.64 (0.49-0.78)	0.69 (0.59-0.79)	0.69 (0.60-0.78)	0.69 (0.61-0.78)
APRI	0.61 (0.46-0.75)	0.67 (0.57-0.77)	0.65 (0.56-0.75)	0.66 (0.57-0.75)
ALBI	0.59 (0.44-0.73)	0.67 (0.58-0.76)	0.66 (0.57-0.74)	0.65 (0.56-0.74)
aMAP	0.74 (0.62-0.85)	0.76 (0.68-0.83)	0.74 (0.67-0.82)	0.74 (0.67-0.80)

ALBI: Albumin-bilirubin score; aMAP: Age-male-albumin-bilirubin-platelet score; APRI: Aspartate aminotransferase-to-platelet ratio index; AUC: Area under the curve; CI: Confidence interval; FIB-4: Fibrosis-4 index; FU: Follow-up; SVR12, sustained virological response at 12 weeks after treatment completion.

Patients were stratified according to exploratory cohort-derived aMAP cutoffs (< 55, 55 to < 60, and ≥ 60). Patients with an aMAP score < 55 experienced no HCC events during follow-up, whereas those with aMAP scores between 55 and < 60 and ≥ 60 had annual HCC incidence rates of 2.42 and 6.42 per 100 person-years, respectively (95%CI: 1.21-4.84 and 4.81-8.57, respectively) (Table 4). These patterns were corroborated by the Kaplan-Meier analysis, which demonstrated clear separation of cumulative HCC risk across the three strata, with the aMAP < 55 group maintaining a flat risk trajectory throughout follow-up (Figure 3A).

Figure 3 Kaplan-Meier curves. A: Kaplan-Meier curves of hepatocellular carcinoma risk according to empirically derived age-male-albumin-bilirubin-platelet (aMAP) score strata. Patients were stratified into low-, intermediate-, and high-risk groups using thresholds of < 55, 55 to < 60, and ≥ 60, respectively; B: Kaplan-Meier curves of hepatocellular carcinoma risk according to the originally validated aMAP score strata. Patients were stratified into low-, intermediate-, and high-risk groups using thresholds of < 50, 50 to < 60, and ≥ 60, respectively. aMAP: Age-male-albumin-bilirubin-platelet score.

Table 4 Exploratory age-male-albumin-bilirubin-platelet score strata for hepatocellular carcinoma risk.

Risk of developing de novo HCC	aMAP	Annual HCC incidence % (95%CI)	Proportion of the cohort, %
Low	< 55	0.0	18.55
Intermediate	55 to < 60	2.42 (1.21-4.84)	22.96
High	≥ 60	6.42 (4.81-8.57)	58.49

aMAP: Age-male-albumin-bilirubin-platelet score; HCC: Hepatocellular carcinoma.

To contextualize these findings, we additionally applied the originally validated aMAP thresholds proposed by Fan et al[30] (< 50, 50 to < 60, and ≥ 60). Consistent with the exploratory analysis, patients with an aMAP score < 50 also exhibited no observed HCC events, while those with aMAP scores of 50 to < 60 and ≥ 60 showed progressively higher HCC incidence rates (Table 5). The corresponding Kaplan-Meier curves demonstrated comparable stepwise risk stratification, supporting the robustness of the discriminatory performance of the aMAP score in this cohort of patients with cACLD (Figure 3B). Collectively, both the exploratory (< 55) and previously validated (< 50) cutoff values identified very-low-risk subgroups with no observed HCC events in this cohort.

Table 5 Risk stratification based on previously validated age-male-albumin-bilirubin-platelet score thresholds.

Risk of developing de novo HCC	aMAP score	Annual HCC incidence % (95%CI)	Proportion of the cohort, %
Low	< 50	0.0	6.60
Intermediate	50 to <60	1.58 (0.79-3.16)	34.91
High	≥ 60	6.42 (4.81-8.57)	58.49

aMAP: Age-male-albumin-bilirubin-platelet score; HCC: Hepatocellular carcinoma.

DISCUSSION

In this longitudinal cohort of patients with HCV-related cACLD, a clinically meaningful risk of HCC persisted despite achievement of SVR, with an annual incidence of 3.12%. Among the evaluated noninvasive scoring systems, the aMAP score demonstrated the highest discriminatory performance. Importantly, an exploratory cutoff of < 55 identified a very-low-risk subgroup comprising 18.6% of the cohort, in whom no HCC events were observed during long-term follow-up. This finding supports the potential role of the aMAP score as a risk-stratification and rule-out tool to support individualized surveillance strategies rather than as a definitive basis for discontinuing HCC surveillance.

While the FIB-4 index and APRI are widely used for fibrosis staging, their utility in predicting HCC after SVR appears limited compared with the aMAP score. In our analysis, the aMAP score consistently achieved the highest AUC values across all follow-up time points. This superior performance likely reflects the variables of the score. The aMAP score incorporates age and sex, which are nonmodifiable risk factors, together with the ALBI score, which reflects hepatic function, and platelet count, a surrogate marker of portal hypertension. After SVR, transaminase-based indices such as APRI and the FIB-4 index often decline rapidly as hepatic necroinflammation resolves, potentially underestimating the residual risk of HCC. In contrast, the aMAP score captures persistent physiological derangements—particularly hepatic synthetic dysfunction and portal hypertension—that drive hepatocarcinogenesis in patients with cirrhosis.

The originally validated aMAP score cutoff of < 50 proposed by Fan et al[30] also identified a subgroup with no observed HCC events in our cohort, although this group represented only 6.6% of the study population. In the exploratory cohort-based analysis, a cutoff value of < 55 was the highest cutoff that still identified a subgroup with no observed HCC events while expanding the very-low-risk subgroup to 18.6% of the cohort. This threshold should therefore be interpreted as hypothesis-generating and cohort-derived, not as a validated criterion for discontinuing HCC surveillance. Prospective multicenter external validation is required before it can be used to guide surveillance de-escalation in routine clinical practice.

The relatively high incidence of HCC observed in this cohort may partly reflect the advanced liver disease profile of patients treated and followed at a tertiary referral center. Compared with patients who did not develop HCC, those who developed HCC had higher baseline liver stiffness, lower platelet counts, lower serum albumin levels, higher bilirubin levels, and a higher prevalence of esophageal varices, indicating more advanced portal hypertension and impaired hepatic functional reserve. In addition, type 2 diabetes mellitus was common and was more prevalent among patients who subsequently developed HCC. These findings suggest that metabolic dysfunction may contribute to the residual risk of HCC after viral eradication.

Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are increasingly recognized as contributors to hepatocarcinogenesis, including in patients who achieve SVR for HCV infection. In patients with pre-existing advanced fibrosis or cirrhosis, metabolic risk factors such as diabetes mellitus, obesity, insulin resistance, and steatotic liver disease may sustain hepatic inflammation, fibrogenesis, and carcinogenic risk despite SVR. However, as systematic data on hepatic steatosis, body mass index, controlled attenuation parameter, and histologic steatohepatitis were not uniformly available, we could not directly quantify the independent contributions of metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis to the residual risk of HCC.

Current cost-effectiveness analyses suggest that HCC surveillance is cost-effective when the annual HCC incidence exceeds approximately 1.32%-1.5%[25]. The overall HCC incidence in our cohort (3.12% per year) strongly supports the current standard of surveillance in unselected patients with cACLD who achieve SVR. However, the marked risk stratification provided by the aMAP score suggests that a universal, one-size-fits-all surveillance strategy may be inefficient for some very-low-risk subgroups.

The aMAP score should also be interpreted as a dynamic risk stratification tool. As it incorporates serum albumin, bilirubin, and platelet count, the score may change over time as hepatic functional reserve, portal hypertension, fibrosis burden, or metabolic comorbidities evolve after SVR. Therefore, patients classified as being at very low risk should continue to undergo routine clinical assessment and laboratory monitoring, with periodic reassessment of the score rather than relying on a one-time permanent classification. As abdominal ultrasonography is inexpensive, widely available, noninvasive, and integrated into routine clinical practice, the findings of this study should not be interpreted as supporting the immediate universal discontinuation of ultrasound-based HCC surveillance. Instead, a more practical implication is that patients at very low risk may be considered for individualized surveillance intensity and may avoid unnecessary expensive cross-sectional imaging unless clinically, biochemically, or ultrasonographically indicated.

In our cohort, patients with an aMAP score ≥ 60 had an annual HCC incidence of 6.42%, supporting continued standard semiannual HCC surveillance and careful clinical follow-up in this high-risk subgroup. These findings may help optimize surveillance resource allocation by identifying patients who remain at high risk while generating a testable very-low-risk subgroup for future studies evaluating surveillance de-escalation.

Genomic-clinical risk models and biomarker-based approaches may provide additional risk discrimination, particularly in selected high-risk populations or in settings where genomic testing is readily available and affordable. However, such approaches may increase costs and may not be feasible in all healthcare systems. The aMAP score should therefore be viewed as a simple, low-cost, and complementary risk-stratification tool based on routinely available clinical and laboratory parameters rather than as a replacement for genomic-clinical models, advanced biomarkers, or guideline-recommended imaging-based HCC surveillance. Future studies should compare the aMAP score with genomic-clinical and biomarker-based models and evaluate their comparative cost-effectiveness across different healthcare settings.

Taken together, these findings support a practical risk-stratified framework rather than an immediate change in current guideline-recommended surveillance. Patients with higher aMAP scores, particularly those with scores ≥ 60, remain appropriate candidates for standard semiannual HCC surveillance and careful clinical follow-up. In contrast, patients with scores < 55 may represent a very-low-risk subgroup in whom future studies could evaluate less intensive surveillance strategies, periodic risk reassessment, and avoidance of unnecessary cross-sectional imaging. Thus, the main clinical contribution of this study is not to establish a criterion for discontinuing surveillance but to identify a reproducible low-risk subgroup that may inform individualized HCC surveillance intensity after external validation.

This study has several limitations. First, it was a single-center retrospective study conducted at a tertiary referral center, which may limit the generalizability of the findings and may have resulted in a cohort enriched with patients with more advanced liver disease. Second, although the absence of HCC events in the subgroup with an aMAP score < 55 is clinically encouraging, rare events cannot be excluded without validation in larger prospective multicenter cohorts. Third, the < 55 cutoff was exploratory and cohort-derived and should not be interpreted as a universally validated cutoff. Fourth, all patients received sofosbuvir-based regimens; therefore, the findings may not fully extrapolate to other DAA regimens, non-Asian populations, or populations with different etiological and metabolic risk profiles. Fifth, systematic data on hepatic steatosis, body mass index, controlled attenuation parameter, alcohol consumption, and histological evidence of steatohepatitis were not uniformly available. Therefore, the independent contributions of metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis could not be quantified. Finally, serial changes in the aMAP score were not evaluated, and future studies should investigate the value of dynamic risk reassessment over time.

CONCLUSION

The aMAP score assessed at SVR12 is a simple and readily available tool for stratifying HCC risk in patients with HCV-related cACLD. An exploratory threshold of < 55 identified a very-low-risk subgroup with no observed HCC events in this cohort and may support individualized HCC surveillance intensity or potential surveillance de-escalation strategies. However, prospective multicenter external validation is required before this threshold can be implemented in routine clinical practice.