Measurement of FIB-4 to predict long-term risk of HCC | JHC - Dove Medical Press

Plain Language Summary

In this study, we attempted to measure the semipermanent hazard of hepatocellular carcinoma utilizing the fibrosis 4 people (FIB-4) and its dynamic changes aft the eradication of the hepatitis C virus. Our findings amusement that patients with a FIB-4 >3.25 astatine baseline oregon anytime during follow-up were astatine a higher hazard of processing HCC. Patients with cirrhosis and patients with nary cirrhosis but a FIB-4 >3.25 were astatine higher hazard of processing HCC arsenic well.

Introduction

Hepatitis C microorganism (HCV) corruption has been a terrible nationalist wellness occupation for much than 30 years, with an estimated 71 cardinal chronically infected worldwide.¹ Treatments with either interferon (IFN) oregon with direct-acting antivirals (DAA) connection singular rates of HCV microorganism eradication,^2,3 particularly with DAA. The caller DAA-based regimen has led to a sustained virologic effect (SVR) complaint of implicit 90% successful patients with HCV infection.⁴ With the wide usage of DAA treatment, it is foreseeable that astir HCV patients volition execute SVR aft their antiviral treatments.

One of the astir terrible outcomes of HCV corruption is the improvement of hepatocellular carcinoma (HCC). HCC, the astir communal superior liver malignancy, resulted successful astir 830,000 deaths successful 2020 alone.⁵ Several caller aesculapian options for HCC attraction person emerged successful caller years, including immune checkpoint inhibitors (ICIs),^6,7 regorafenib (REG),⁸ and metronomic capecitabine.⁹ Despite these caller attraction options, HCC continues to beryllium a large menace to the endurance of HCV patients.

Multiple studies person shown mitigation of liver fibrosis^10,11 and reduced hazard of HCC^12,13 aft patients reached SVR with DAA. However, the residual hazard of HCC persists years aft HCV eradication.^14–16 Therefore, surveillance for HCC is inactive needed adjacent aft patients execute SVR. Several baseline characteristics, including older age,¹⁵ antheral gender,¹⁷ beingness of cirrhosis,^15,16 excessive intoxicant use,^18,19 and diabetes¹⁹ were reported to beryllium related to the hazard of HCC improvement and tin beryllium utilized to constrictive down patients successful request of surveillance.

However, the bulk lone instrumentality into relationship the short-term hazard of HCC. It is not wholly wide whether the hazard of HCC volition alteration implicit clip successful virologically cured patients. Fibrosis 4 (FIB-4) people is simply a non-invasive serum biomarker initially designed for the valuation of fibrosis.^20,21 Composed of age, platelet counts, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels, the FIB-4 people is casual to measurement and calculate. In addition, it has been reported to beryllium associated with the grade of liver fibrosis and the hazard of HCC.^22–24 With the repeated measurement of FIB-4, it is imaginable to observe HCC hazard changes implicit clip and frankincense place patients needing surveillance astatine immoderate clip aft SVR.

The existent survey aimed to analyse the relation betwixt FIB-4 people and its dynamic changes with the hazard of HCC successful virologically cured patients with nary cirrhosis and compensated cirrhosis. We besides determined whether the repeated measurement of FIB-4 could supply a bully prediction of HCC and identified high-risk patients who necessitate surveillance post-SVR.

Material and Methods

Patients and Follow-Up

A full of 1042 patients with chronic HCV corruption from the Chronic Hepatitis C Research Program of Jiangsu (CHCRPJ) received DAA attraction from January 2012 to October 2020 successful Jurong people’s hospital, China. SVR was defined arsenic a serum HCV RNA viral load beneath the little detection bounds astatine slightest 12 weeks aft treatment. Of these patients, 796 achieved SVR. Patients diagnosed with HCC oregon hepatic decompensation (defined arsenic the occurrence of ascites, encephalopathy, variceal bleeding, oregon hepatorenal syndrome) anterior to SVR and patients who deficiency a FIB-4 people astatine baseline were excluded. Eventually, 701 patients were included successful the study. The flowchart of diligent enactment is shown successful Figure 1.

Figure 1 Flow illustration of diligent selection. Abbreviations: SVR, sustained virological response; HCC, hepatocellular carcinoma; FIB-4, fibrosis 4 score.

The scale day of the survey was defined arsenic the day of SVR. Patients were followed until the survey outcome, decease oregon 31/12/2021, whichever came first. The survey result was caller cases of HCC aft the scale date. Information connected HCC occurrence earlier and aft attraction was obtained from infirmary inpatient and outpatient diagnoses. HCC was diagnosed according to the American Association for the Study of Liver Diseases (AASLD) guidelines.²⁵ Laboratory tests were carried retired astatine the day of SVR and annually aft that erstwhile patients returned for their follow-up visit.

Written informed consent was obtained from each patients who participated successful the study. The survey protocol conformed to the ethical guidelines of the Declaration of Helsinki, and the organization morals reappraisal committee of Nanjing Medical University approved the study.

Baseline Characteristics

Baseline characteristics astatine SVR, including age, gender, cirrhosis, diabetes, hepatitis B microorganism (HBV) co-infection, and intoxicant use, were collected. The birthdate and sex of each diligent were obtained from their individuality profiles. Information astir cirrhosis, HBV co-infection, and diabetes was retrieved from the inpatient and outpatient diagnoses earlier SVR. Cirrhosis was diagnosed based either connected a transient elastography people >14 kPa, a liver biopsy showing Metavir F4, oregon objective evidence. Information astir intoxicant usage was collected done telephone inquiries. Excessive intoxicant usage was defined arsenic >20 g/day successful females and >30 g/day successful males.

Fibrosis-4 (FIB-4) Scores astatine Baseline and During Follow-Up

Baseline FIB-4 people was calculated utilizing the laboratory trial results done astatine the aforesaid clip arsenic SVR, according to the pursuing formula: (Age × AST)/ (Platelet count×√ALT).²⁶ FIB-4 people during follow-up was calculated based connected the laboratory trial results performed astatine the yearly sojourn of each patient. The cutoff worth for FIB-4 level was acceptable astatine 3.25, which was antecedently established arsenic the threshold of precocious fibrosis²¹ and was shown to beryllium associated with HCC risks.^23,27

The changes of FIB-4 implicit clip were modeled successful 2 ways. First, we analyzed the FIB-4 people of patients astatine baseline and the past follow-up, past we categorized patients into 4 groups. For patients who developed HCC during follow-up, the past follow-up was defined arsenic the clip of HCC occurrence.

1. Patients with a FIB-4 ≦3.25 astatine baseline and past follow-up were classified successful the unchanged low-risk group.
2. Patients who dropped from FIB-4 >3.25 astatine baseline to FIB-4 ≦3.25 astatine the past follow-up were classified successful the declined group.
3. Patients with a FIB-4 ≦3.25 astatine baseline and a FIB-4 >3.25 astatine the past follow-up were categorized arsenic the accrued group.
4. Patients with a FIB-4 >3.25 astatine baseline and past follow-up were categorized arsenic the unchanged high-risk group.

Second, we attempted to analyse the interaction of changes successful FIB-4 people passim the full survey period. To execute that, we analyzed FIB-4 level (categorized arsenic >3.25 oregon ≦3.25) arsenic a time-dependent covariate. Each diligent was analyzed nether the debased FIB-4 class erstwhile their FIB-4 people was beneath 3.25 and nether the precocious FIB-4 class erstwhile their FIB-4 people was supra 3.25.

Statistical Analyses

Continuous variables were presented arsenic mean (standard deviation), and categorical variables were presented arsenic number (percentage). Continuous variables were compared utilizing the Student’s t-test, and categorical variables by the Chi-square trial oregon the Fisher nonstop trial erstwhile appropriate.

The yearly incidence complaint of HCC (per 1000 person-years [PY]) and the corresponding 95% assurance interval (95% CI) were calculated assuming a Poisson distribution. The yearly incidence complaint of HCC betwixt subgroups and betwixt years aft SVR was compared utilizing two-way ANOVA with Tukey post-hoc analysis. The cumulative incidence of HCC was evaluated utilizing the Kaplan-Meier method, and the differences betwixt subgroups were compared with the log-rank test.

Univariate and multivariate Cox proportional hazards regression models were utilized to estimation the effects of imaginable factors connected the hazard of HCC occurrence. Variables recovered to beryllium statistically important successful univariate investigation (P < 0.05) were included successful the multivariate analysis. HCC risks were besides calculated according to the alteration successful FIB-4 people astatine the past follow-up and based connected FIB-4 coded arsenic a time-dependent covariate utilizing Cox regression models. Patients not processing HCC were censored connected 31/12/2021 oregon astatine the day of death.

Statistical value was defined arsenic P < 0.05. Data investigation was performed utilizing R software, mentation 4.1.2 (R Foundation for Statistical Computing).²⁸

Results

Baseline Characteristics of Patients

The baseline characteristics of the survey patients are shown successful Table 1. Among the 701 patients, the bulk (75.5%) were female. The mean property was 56.7 years aged (SD = 8.3 years). 14.4% of the patients had cirrhosis astatine baseline. 24.5% of the patients had diabetes, 12.0% had excessive intoxicant consumption, and 1.4% had HBV co-infection. A full of 273 patients (39.0%) had a FIB-4 people supra 3.25 astatine the initiation of treatment. Aside from cirrhosis presumption and FIB-4 level, determination were nary important differences successful baseline factors betwixt patients who developed HCC and patients who did not.

Table 1 Baseline Characteristics of Patients

The median follow-up clip for the wide survey colonisation was 4.84 years, with the 25th and 75th percentiles of the follow-up clip being 3.45 years and 6.65 years, respectively. The diligent with the longest follow-up play was followed for up to 9.82 years.

Incidence of HCC Following SVR

There were 27 cases of HCC pursuing SVR. HCC incidence complaint was 2.86 per 1000 PY during the archetypal year, gradually expanding to 15.59 per 1000 PY successful the 3rd twelvemonth and past decreasing afterward (Figure 2A). The cumulative incidence astatine 1, 2, 3, 4, and 5 years aft SVR were 0.3%, 1.0%, 2.4%, 3.0%, and 3.3%, respectively.

Figure 2 The yearly incidence complaint of HCC successful virologically cured patients aft SVR successful the wide cohort (A) and the subgroups defined according to the beingness of cirrhosis (B). Abbreviations: SVR, sustained virological response; CI, assurance interval; FIB-4, fibrosis 4 score; HCC, hepatocellular carcinoma.

We besides plotted the yearly incidence of HCC based connected the beingness oregon lack of baseline cirrhosis owed to the imaginable quality betwixt these 2 subgroups. The HCC incidence complaint was unchangeable successful patients without cirrhosis, ranging from 1.67 per 1000 PY to 12.63 per 1000 PY. Patients with baseline cirrhosis had a noticeably higher yearly incidence rate, with the highest incidence complaint (33.98 per 1000PY) occurring 3 years aft SVR (Figure 2B). There was besides a flimsy rebound successful the incidence complaint successful the 5th twelvemonth aft SVR (21.09/1000PY). In general, determination was nary important downward inclination successful the yearly incidence of HCC pursuing SVR. The two-way ANOVA investigation discovered a important quality successful the HCC incidence complaint betwixt the 2 subgroups (P = 0.006). No quality was recovered betwixt years aft SVR (all P > 0.05) successful the Tukey post-hoc test.

Baseline Factors Associated with the Risk of HCC

Univariate and multivariate Cox regression models were utilized to measure baseline factors that mightiness lend to the improvement of HCC. Gender, excessive intoxicant use, diabetes, cirrhosis, HBV co-infection, and FIB-4 people were included successful the analysis. In the univariate analysis, cirrhosis (hazard ratio [HR] = 2.98; 95% CI = 1.29–6.86) and FIB-4 >3.25 (HR = 3.00; 95% CI = 1.37–6.56) were associated with a higher hazard of HCC successful patients achieving SVR. Significant variables (P < 0.05) successful the univariate investigation were included successful the multivariate analysis, wherever FIB-4 >3.25 (HR = 2.51; 95% CI = 1.10–5.72) was identified arsenic an autarkic origin that contributed to the hazard of HCC (Table 2) whereas cirrhosis was not.

Table 2 Baseline Factors Associated with HCC Risk successful Patients Achieving SVR

Figure 3 depicts the cumulative incidence of HCC successful patients who achieved SVR based connected hazard factors identified successful the Cox regression analysis. The incidence of HCC was importantly higher successful patients with a FIB-4 >3.25 astatine baseline than successful those with a FIB-4 ≦3.25 (Figure 3A, P = 0.0044). Similarly, the incidence of HCC aft SVR was higher successful patients with cirrhosis (Figure 3B, P = 0.0085).

Figure 3 Cumulative incidence curves of HCC successful virologically cured patients aft SVR according to antithetic subgroups: (A) FIB-4 level; (B) cirrhosis. Abbreviations: SVR, sustained virological response; FIB-4, fibrosis 4 score; HCC, hepatocellular carcinoma.

HCC Risks Stratified by Baseline FIB-4 and Cirrhosis

In addition, we examined the relation betwixt baseline FIB-4 level unneurotic with cirrhosis and HCC risks. The incidence complaint of HCC was the highest successful patients with baseline cirrhosis and a FIB-4 >3.25 (18.63/1000PY). After accommodation for different baseline characteristics by the Cox regression model, patients with cirrhosis and a FIB-4 >3.25 had a 6.56-fold higher hazard of processing HCC than patients with nary cirrhosis and a FIB-4 ≦3.25 (adjusted HR = 6.56; 95% CI = 2.13–20.19). Patients with baseline cirrhosis and a FIB-4 ≦3.25, arsenic good arsenic patients with nary cirrhosis and a FIB-4 >3.25, were besides astatine higher hazard of HCC compared with patients with nary cirrhosis and a FIB-4 ≦3.25 (adjusted HR = 5.50 and 3.19, respectively) (Table 3).

Table 3 Association Between Baseline FIB-4 Level and HCC Risk Stratified by the Presence of Cirrhosis successful Patients Achieving SVR

Figure 4 depicts the interaction of FIB-4 level connected the HCC-free endurance of patients stratified by baseline cirrhosis. Among patients with nary cirrhosis astatine baseline, the incidence of HCC was importantly higher successful patients with a FIB-4 >3.25 than successful patients with a FIB-4 ≦3.25 (Figure 4A, P = 0.012). No quality was observed successful HCC incidence betwixt patients with antithetic FIB-4 levels among patients with cirrhosis (Figure 4B, P = 0.96).

Figure 4 Cumulative incidence curves of HCC among virologically cured patients with antithetic FIB-4 levels, stratified by cirrhosis: (A) cirrhosis; (B) without cirrhosis. Abbreviations: SVR, sustained virological response; FIB-4, fibrosis 4 score; HCC, hepatocellular carcinoma.

Changes successful FIB-4 Over Time and Its Effect connected HCC Risks

We compared the FIB-4 scores of patients astatine baseline and the past follow-up visit. Of the 701 patients included successful this study, the FIB-4 people astatine the past follow-up was disposable successful 514 patients. In total, 56.4% of patients remained astatine debased risk, and 18.9% remained astatine precocious hazard astatine the past follow-up. The FIB-4 people decreased successful 20.0% of patients and accrued successful lone 4.7%. The incidence complaint was highest successful the accrued radical (29.60/1000PY), followed by the unchanged high-risk radical (15.16/1000PY) and the declined radical (12.52/1000PY). Patients who experienced an elevation successful FIB-4 people had the highest hazard of processing HCC (adjusted HR = 9.88; 95% CI = 2.56–38.14). Also, HCC risks remained precocious successful patients with a baseline FIB-4 >3.25 careless of whether the FIB-4 people had dropped astatine the past follow-up (adjusted HR = 3.97; 95% CI = 1.24–12.74) oregon not (adjusted HR = 4.99; 95% CI = 1.44–17.26) (Table 4).

Table 4 Association Between Change successful FIB-4 Level astatine Baseline and Last Follow-Up and HCC Risk successful Patients Achieving SVR

Association Between FIB-4 arsenic a Time-Dependent Covariate and HCC Risks

We analyzed FIB-4 people (classified arsenic >3.25 oregon ≦3.25) arsenic a time-dependent covariate. The HCC incidence complaint was 4.37 per 1000PY erstwhile the FIB-4 level of patients was debased and 15.18 per 1000PY erstwhile the FIB-4 level of patients was high. During the full follow-up period, FIB-4 >3.25 was associated with a 3.14-fold higher hazard of patients processing HCC (adjusted HR = 3.14; 95% CI = 1.40–7.05).

When taking into relationship the beingness of baseline cirrhosis, we discovered a amazingly precocious incidence complaint of HCC successful patients with cirrhosis erstwhile their FIB-4 level was precocious (23.44/1000PY). The incidence complaint was somewhat higher successful patients with cirrhosis and a FIB-4 people beneath 3.25 (10.26/1000PY) than successful patients with nary cirrhosis but a FIB-4 supra 3.25 (12.55/1000PY). Among patients with cirrhosis, FIB-4 >3.25 during the follow-up play was associated with a 7.49-fold higher hazard of HCC (adjusted HR = 7.49; 95% CI = 2.56–21.95). In contrast, nary accrued hazard of HCC improvement was recovered successful cirrhosis patients erstwhile their FIB-4 scores were beneath 3.25 during follow-up (adjusted HR = 2.83; 95% CI = 0.58–13.72) (Table 5).

Table 5 Association Between FIB-4 Level During Follow-Up and HCC Risk Stratified by the Presence of Cirrhosis successful Patients Achieving SVR

Discussion

As a effect of the wide usage of DAA, astir each patients with HCV corruption volition acquisition SVR aft antiviral treatment. Multiple studies person shown that SVR is associated with improved objective outcomes, including the mitigation of fibrosis^10,11 and the reduced hazard of HCC.^12,29,30 However, determination is inactive a residual hazard of HCC aft SVR, truthful surveillance of patients is required. As described by Wang S et al³¹ surveillance and aboriginal diagnosis are captious successful improving the cure complaint of crab arsenic they facilitate a timely and capable consequent treatment. However, surveillance connected each virologically cured patients is impractical. As a result, it is indispensable to find which of the patients are astatine precocious hazard of processing HCC. In addition, the HCC risks whitethorn alteration implicit clip successful the agelong word arsenic patients property and their fibrosis presumption changes, further complicating the situation. Several studies person evaluated pre-SVR factors contributing to the short-term hazard of HCC successful virologically cured patients, but fewer person addressed the semipermanent hazard of HCC. Therefore, successful the existent study, we question to usage FIB-4, a elemental serum fibrosis biomarker that tin beryllium repeatedly measured during follow-up, to measure the semipermanent hazard of HCC and yet place high-risk patients who necessitate strict surveillance.

In this study, 701 HCV-infected patients treated with DAA were followed for a median of 4.84 years aft SVR. The diligent with the longest follow-up clip was followed for up to 9.82 years. The study’s archetypal uncovering was that the hazard of HCC persisted for years aft SVR. After inspecting the yearly incidence complaint of HCC, we recovered nary evident diminution successful the residual HCC risks pursuing SVR. The yearly incidence complaint successful the wide cohort was beneath the cutoff worth of 15 per 1000PY, arsenic recommended by the AASLD.²⁵ Among patients with cirrhosis, however, the yearly incidence complaint of HCC was higher than the surveillance threshold astir of the time, with a flimsy rebound successful the 5th twelvemonth aft SVR. The two-way ANOVA trial results revealed a important quality successful HCC incidence complaint betwixt patients with oregon without cirrhosis but nary quality betwixt years aft SVR. The results supra suggest that the hazard of HCC aft SVR did not trim implicit clip and that determination was a important quality successful HCC hazard betwixt antithetic subgroups of patients. The effect is accordant with the survey investigating HCC hazard aft HCV eradication successful Veterans Health Administration (VHA) patients. The hazard of HCC persisted 10 years aft SVR and showed nary denotation of a downward inclination successful VHA patients.²³

Secondly, the survey recovered that FIB-4 >3.25 measured astatine baseline oregon immoderate clip aft SVR was associated with HCC risks and that the repeated measurements of FIB-4 presented a amended predictive quality of HCC risks than the elemental measurement of FIB-4 astatine baseline. Univariate and multivariate Cox regression investigation showed that FIB-4 >3.25 astatine baseline was importantly associated with HCC improvement aft HCV eradication. When analyzed arsenic a time-dependent covariant, FIB-4 >3.25 showed a bully predicting worth of HCC arsenic well. Patients faced a importantly higher hazard of HCC erstwhile their FIB-4 was supra 3.25 astatine immoderate clip during follow-up. The results suggest that FIB-4 measured astatine immoderate clip aft attraction tin beryllium utilized to analyse HCC risks successful patients achieving SVR. Similar results were reported successful erstwhile studies arsenic well. In a survey evaluating the quality of humor fibrosis tests to foretell liver-related events and death, FIB-4 showed bully discriminative quality for predicting HCC (with a C-index of 0.884) and was an autarkic predictor of HCC successful the adjusted Cox model.³² Another survey examining the long-time hazard of HCC aft HCV eradication recovered that the incidence of HCC was importantly higher successful patients with a FIB-4 ≧3.25.³³

As expected, the FIB-4 level of astir patients decreased oregon remained the aforesaid post-SVR. Only 4.7% of the patients experienced an summation successful FIB-4 level from a worth ≦3.25 to a worth >3.25. The summation successful FIB-4 level was associated with a 9.88-fold higher hazard of HCC. A survey focusing connected HCC hazard aft HCV eradication recovered that an summation successful FIB-4 was associated with HCC risk.²³ Though a emergence successful FIB-4 aft SVR is comparatively uncommon, the precocious incidence complaint of HCC (29.6/1000PY) successful these patients inactive requires attention. Repeated measurement of FIB-4 aft attraction made it imaginable to place this tiny radical of patients astatine risk. In addition, the coefficient of FIB-4 level was larger successful the time-dependent investigation than successful the exemplary composed of lone baseline values, indicating that repeated measurement of FIB-4 was capable to seizure the effect of FIB-4 arsenic it changes implicit time. Therefore, the repeated measurement of FIB-4 tin amended foretell HCC risks successful SVR patients compared with measuring FIB-4 lone astatine baseline.

Another uncovering of the existent survey was that compared to stratifying patients by cirrhosis presumption astatine baseline alone, the inclusion of FIB-4 considerably improved the quality to foretell HCC risks successful patients reaching SVR. When investigating the hazard of HCC occurrence, a fig of studies simply stratified patients according to the beingness of cirrhosis.^14,34 However, successful the existent study, baseline cirrhosis was lone importantly associated with HCC risks successful the univariate model, and HCC inactive occurred successful patients without cirrhosis. Also, aggregate studies person shown the changes successful liver fibrosis presumption aft patients achieved SVR.^12,22 It appears that the elemental stratification based connected cirrhosis is not capable for predicting HCC. Therefore, the existent survey combined baseline cirrhosis with FIB-4 and its dynamic changes to stratify virologically cured patients into chiseled hazard groups. In the baseline analysis, the incidence complaint of HCC was the highest successful patients with some cirrhosis and a FIB-4 >3.25 (18.63/1000PY). Cirrhotic patients and non-cirrhotic patients with a baseline FIB-4 supra 3.25 were astatine a higher hazard of processing HCC than non-cirrhotic patients with a baseline FIB-4 beneath 3.25. A ample cohort survey examining HCC hazard 10 years aft SVR besides recovered that patients with cirrhosis oregon FIB-4 >3.25 astatine baseline presented a higher hazard of processing HCC.²³ The time-dependent investigation delivered akin results. The incidence complaint of HCC was precise precocious erstwhile cirrhotic patients had a FIB-4 supra 3.25 (23.44/1000PY). Also, erstwhile non-cirrhotic patients had a FIB-4 people higher than 3.25, their incidence complaint of HCC (12.55/1000PY) was somewhat higher than that of cirrhotic patients (10.26/1000PY) erstwhile the FIB-4 was beneath 3.25. These results each suggest that patients faced a importantly higher hazard of HCC erstwhile their FIB-4 was supra 3.25 astatine immoderate clip aft HCV eradication, careless of the beingness of baseline cirrhosis. The further segmentation of patients by combining FIB-4 and cirrhosis leads to much close recognition of high-risk patients aft the eradication of HCV.

Finally, the existent survey identified immoderate patients astatine precocious hazard of HCC development. Virologically cured patients with a FIB-4 level supra 3.25 astatine SVR oregon immoderate clip afterwards are astatine a higher hazard of processing HCC and should truthful beryllium offered surveillance. Further survey volition beryllium needed to analyse whether the HCC risks volition alteration successful virologically cured patients experiencing a driblet successful FIB-4 level. In addition, patients with cirrhosis should proceed to beryllium surveilled aft SVR, on with patients with nary cirrhosis but a FIB-4 >3.25. Surprisingly, nary accrued hazard was recovered successful patients with baseline cirrhosis and a FIB-4 ≦3.25 successful the time-dependent analysis. This whitethorn beryllium partially explained by the tiny fig of patients with some cirrhosis and a FIB-4 ≦3.25.

Compared with erstwhile studies, the existent survey holds the pursuing strengths. All patients included successful the survey were treated with DAA and achieved SVR. The follow-up play was besides comparatively long, with a median follow-up clip of astir 5 years and a maximum follow-up clip of up to 10 years. Previous studies investigating the predictive worth of FIB-4 were either done connected IFN-treated patients³³ oregon did not person a sufficiently agelong follow-up duration of DAA-treated patients.^23,27 Our survey demonstrated that the hazard of HCC did not diminution for a sizeable clip aft DAA attraction and that the dynamic changes successful FIB-4 levels were straight associated with HCC hazard passim the follow-up period. Furthermore, the existent survey combined the dynamic alteration of FIB-4 and cirrhosis presumption to disagreement patients into subgroups further, bringing attraction to 2 peculiar groups of patients. (1) Patients whose FIB-4 was beneath 3.25 astatine the clip of SVR but aboriginal accrued to supra 3.25 necessitate strict surveillance arsenic the HCC incidence complaint successful these patients was highly high. This circumstantial radical of patients was often overlooked since immoderate erstwhile studies lone evaluated FIB-4 measured astatine baseline.^14,35 (2) Patients with baseline cirrhosis but a FIB-4 ≦3.25 astatine oregon aft SVR inactive request continuous surveillance contempt their comparatively debased FIB-4 scores. Unlike immoderate studies proposing that patients with a FIB-4 ≦3.25 whitethorn beryllium excluded from surveillance,^27,33 our results showed that determination was inactive insufficient grounds to terminate surveillance for patients with debased FIB-4 scores but different high-risk factors specified arsenic cirrhosis. The incidence complaint of HCC successful these patients remained comparatively high, contempt the time-dependent investigation not identifying an accrued risk. Further survey and a larger colonisation volition beryllium needed to analyse the semipermanent hazard of HCC successful this chiseled radical of patients.

The survey has immoderate limitations. First, immoderate patients did not instrumentality for laboratory tests aft SVR arsenic clip went by, and the relation betwixt FIB-4 alteration and HCC risks mightiness beryllium underrated oregon overrated. Second, accusation astir intoxicant usage was collected done telephone inquiries alternatively than face-to-face questionnaires, which whitethorn person yielded accusation bias. Third, the existent survey was a single-center study, and the generalizability of our results to a larger HCV colonisation whitethorn beryllium limited. Finally, the survey cohort is each Asian and consists chiefly of females. It is indispensable to behaviour validation studies successful different cohorts.

The relation of FIB-4 successful HCC prediction has been thoroughly described successful the existent survey and erstwhile literature. Future studies could enactment much accent connected the pursuing aspects. A larger colonisation and a much extended follow-up play volition beryllium needed to find the inferior of FIB-4 oregon different non-invasive biomarkers successful identifying cirrhotic patients astatine debased capable hazard to trim surveillance aft SVR. In summation to azygous non-invasive biomarkers, caller hazard prediction models constructed based connected longitudinal information collected during follow-up, susceptible of making a much personalized and dynamic prediction of HCC occurrence, volition beryllium instrumental successful guiding the objective decisions for HCV patients achieving SVR. Lastly, it is important that we ore connected the urgent request to make caller methods for HCC treatment. New techniques that tackle crab successful a antithetic approach, specified arsenic the OncoCiDia strategy,³¹ whitethorn clasp a curative imaginable for HCC.

Conclusion

In conclusion, the hazard of HCC persists years aft SVR. The repeated measurement of FIB-4 presents a amended predictive quality of HCC risks than the elemental measurement of baseline FIB-4. Patients with a FIB-4 level supra 3.25 astatine SVR oregon immoderate clip aft SVR are astatine a higher hazard of processing HCC and should truthful beryllium offered surveillance. By stratifying patients reaching SVR into antithetic hazard groups utilizing a operation of FIB-4 and cirrhosis, high-risk patients tin beryllium identified much accurately. Patients with cirrhosis should proceed to beryllium surveilled aft SVR, on with patients with nary cirrhosis but a FIB-4 >3.25.

Abbreviations

FIB-4, fibrosis 4 score; HCV, hepatitis C virus; SVR, sustained virologic response; IFN, interferon; DAA, direct-acting antivirals; HCC, hepatocellular carcinoma; ICIs, immune checkpoint inhibitors; REG, regorafenib; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBV, hepatitis B virus; PY, person-years; CI, assurance interval; HR, hazard ratio; AASLD, American Association for the Study of Liver Diseases; VHA, Veterans Health Administration.

Acknowledgments

This survey is simply a associated effort of galore investigators and unit members, and their publication is gratefully acknowledged. We particularly convey each patients who participated successful this study. This survey was sponsored by the Natural Science Foundation of China (82273741), the Natural Science Foundation of Jiangsu Province (BK20190106), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Nanjing Important Science & Technology Specific Projects (2021-11005).

Funding

This survey was sponsored by the Natural Science Foundation of China (82273741), the Natural Science Foundation of Jiangsu Province (BK20190106), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Nanjing Important Science & Technology Specific Projects (2021-11005).

Disclosure

The authors study nary conflicts of involvement successful this work.

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