Development and Validation of a PIVKA-II-Based Model for HCC Risk Stratification in Patients With HCV-Related Cirrhosis Successfully Treated With DAA

Abstract

Background and aims: Patients with hepatitis C virus (HCV)-related cirrhosis with sustained virological response (SVR) to direct-acting antivirals (DAA) remain at risk of developing hepatocellular carcinoma (HCC). Recently, serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) has shown promising results as an HCC-predictive biomarker. We aimed to develop and validate a PIVKA-II-based model for HCC risk stratification in cirrhotic patients with SVR to DAA.

Methods: A total of 1220 consecutive patients (Turin, n = 531; Pisa, n = 335; Milan, n = 354) with HCV-related cirrhosis treated with DAA were included in the study. Patients were retrospectively allocated to the training cohort (Turin+Pisa; median follow-up [FU] 39, 22-55 months; incident HCC: 93 [10.7%]) and validation cohort (Milan; median FU 49.0, 35.0-52.0 months; incident HCC: 19 [5.4%]). Serum PIVKA-II levels were measured using the LumipulseG system (Fujirebio, Japan) at SVR12 (Turin and Pisa cohorts) or the end of treatment (Milan cohort).

Results: Using Cox regression analysis, a model including PIVKA-II combined with age, sex, ALT, AST, γGT, platelet count, albumin and total bilirubin was derived from the training cohort (C-index = 0.72). In the validation cohort, the model showed a C-index of 0.71 with an area under the curve of 0.84 for identifying patients who developed HCC during the first 12 months of FU. When patients were grouped into three risk categories, the cumulative incidence of HCC was 2.7%, 4.0% and 14.3% in the low-, medium- and high-risk groups, respectively (p < 0.001). Notably, no HCC occurred within 3 years of FU in the low-risk group.

Conclusions: Our PIVKA-II-based model showed satisfactory accuracy for HCC risk stratification and may represent a valuable tool for implementing risk-based surveillance protocols in patients with HCV-related cirrhosis with SVR to DAA.

Keywords: DAA; HCC; biomarkers; hepatitis C; non‐invasive tests.

FIGURE 1

Flow chart of patients' enrolment in the training (Turin + Pisa) and validation cohorts (Milan). Patients of the Milan validation cohort were retrieved from Degasperi et al. [9] Patients HCC‐free at last visit/US examination but with FU < 6 months from SVR12 (training cohort) or EOT (validation cohort) were defined as lost to FU. DAA, direct‐acting antivirals; EOT, end‐of‐treatment; FU, follow‐up; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PIVKA‐II, protein induced by vitamin K absence or antagonist II; SVR, sustained virologic response.

FIGURE 2

Overtime stability of PIVKA‐II in serum according to storage temperature. All samples were stored at −20°C from baseline to day 0 for a mean of 20 ± 6 days. Red lines indicate the sample at high serum PIVKA‐II concentration (baseline: 2642 mAU/mL), green lines indicate the sample at intermediate serum PIVKA‐II concentration (baseline: 237 mAU/mL), and blue lines indicate the sample at low serum PIVKA‐II concentration (baseline: 50 mAU/mL). Solid lines indicate aliquots stored at +4°C from day 0 to day 14, while dashed lines indicate aliquots stored at room temperature from day 0 to day 14. PIVKA‐II, protein induced by vitamin K absence or antagonist II; rt., room temperature.

FIGURE 3

Dynamic AUC of non‐invasive scores and PIVKA‐II‐based model for HCC detection in the overall (A), training (Turin + Pisa) (B) and validation cohorts (Milan) (C). Depicted data refer to the AUC ± SE at each time point. AFP, α‐fetoprotein; aMAP, age–male–ALBI–platelets score; APRI, AST to platelets ratio index; AUC, area under the curve; FIB‐4, fibrosis 4 index; PIVKA‐II, protein induced by vitamin K absence or antagonist II; SE, standard error; THRI, Toronto HCC Risk Index.

FIGURE 4

Patients' stratification according to PIVKA‐II‐based model risk categories in the training (A) and validation cohorts (B). HCC, hepatocellular carcinoma; PIVKA‐II, protein induced by vitamin K absence or antagonist II.