Hepatocellular Carcinoma Pattern after the Era of Direct-Acting Antiviral Agents: Does it Differ?

INTRODUCTION

Hepatocellular carcinoma (HCC) is a globally frequent tumor, accounting for 90% of primary hepatic tumors and ranking as the second leading cause of cancer-related mortality worldwide [1]. In countries with a high hepatitis C virus (HCV) burden, HCV contributes to over 70% of chronic liver disease morbidity and mortality [2].

Liver cirrhosis, often caused by chronic viral hepatitis, is a major risk factor for HCC, with an annual incidence of about three to eight percent in HCV-infected cirrhotic patients [1]. In Egypt, HCC represents the fourth most common cancer, with HCV being the leading risk factor for its development [3].

The utilization of direct-acting antiviral agents (DAAs) in the treatment of HCV showed that higher sustained virologic response (SVR) rates than the previously used interferon-based regimens could be achieved with fewer adverse events [4, 5]. Nevertheless, the risk of HCC has not been eliminated, particularly in patients with advanced fibrosis [6].

Clinical observations on patients receiving DAAs resulted in a debate over the impact of DAAs on hepatocellular carcinoma development [4]. This research aimed to compare tumor characteristics among patients with de novo HCV-induced HCC following DAAs and patients who developed de novo HCC without prior DAA treatment.

PATIENTS AND METHODS

The current retrospective observational study was carried out on HCV patients with de novo hepatocellular carcinoma presented to the HCC clinic at our university hospital between January 2019 and January 2020. Patients with HCC due to other causes rather than HCV and patients who received previous treatment for HCC were excluded.

The total number of hepatocellular carcinoma cases who visited the hepatocellular carcinoma clinic was 382 cases; of which 196 patients had de novo HCC fulfilling the inclusion criteria were enrolled in the study and separated into two groups. Group (A): included 79 chronic hepatitis C virus patients who developed hepatocellular carcinoma following achieving SVR after DAA treatment according to National Committee for Control of Viral Hepatitis (NCCVH) guidelines [7]. Group (B): included 117 untreated chronic hepatitis C virus patients who developed HCC not preceded by any antiviral drugs because most of these patients were accidentally discovered to have HCV at the time of diagnosis of HCC, and some patients were known to have chronic HCV, but they refused to receive DAA treatment.

Diagnosis of HCC was confirmed by abdominal triphasic CT scan and/or Dynamic Magnetic Resonance Imaging with heavy T2 diffusion showing hepatic focal lesion (HFL) with criteria of hepatocellular carcinoma in the form of enhancement in the early arterial phase and washout in portal-venous and delayed phases compared to the rest of the liver [8].

The two studied groups were compared together in terms of the recorded demographic data, clinical findings, laboratory data, radiological findings detected by abdominal triphasic CT scan and/or Dynamic MRI, Child-Pugh Classification, Eastern Cooperative Oncology Group (ECOG) Performance status, and The Barcelona-Clinic Liver Cancer (BCLC) staging system.

Statistical methods:

The collected data was processed using SPSS 23, with analysis tailored to each parameter type.

Descriptive statistics: Mean, SD, and range for parametric information; Median and IQR for non-parametric data. Frequency and percentage for categorical information.

Analytical statistics: Student T-test for comparing two group means; Mann-Whitney U test for non-parametric variables; Chi-Square and Fisher’s exact tests for qualitative variable relationships.

A P-value of ≤ 0.05 was considered statistically significant.

RESULTS

This retrospective study involved 196 de novo hepatocellular carcinoma patients meeting the inclusion criteria and divided into two groups. Group A included 79 patients who developed hepatocellular carcinoma following achieving SVR after DAA treatment according to NCCVH guidelines [7], while group B included 117 untreated chronic HCV patients who developed HCC without prior antiviral therapy.

Demographic characteristics, clinical presentation, and laboratory characteristics of the enrolled patients are illustrated in Tables 1, 2, and 3. A statistically insignificant variance was detected among group A and group B according to age, sex, residence, smoking, diabetes mellitus, or hypertension.

Regarding the clinical presentation shown in Table 2, abdominal pain, lower limb edema, and hepatic encephalopathy were significantly more common in group A. Non-significant variances were found among the two groups as regards their laboratory investigations, except for total bilirubin (P<0.001) and INR (P<0.005), which were significantly higher in group A, while AST was significantly lower in group A (P<0.001) (Table 3).

Radiological findings detected by Triphasic CT were reported in Table 4 showing non-significant variance among the two studied groups except for abdominal lymphadenopathy which was significantly higher in group A (P=0.005). Although a statistically insignificant variance was reported among the two studied groups as regards the presence of malignant portal vein thrombosis (PVT) and tumor extension, patients of group A still showed higher rates of malignant PVT and tumor extension (27.8% and 26.6%, respectively) compared to patients of group B (13.7% and 16.2%, respectively). Only two patients in group B had extrahepatic tumor metastasis to lung.

Table 5 shows liver condition according to different scoring systems. According to BCLC staging: in group A, 26.5% of patients were stage C and 6.3% were stage D, while in group B, 12.8 percent of patients were stage C and 1.7 percent were stage D showing significant differences among both groups regarding BCLC staging (P=0.002). Other parameters such as FIB-4 score, ECOG performance status, and Child-Pugh class showed no statistically significant variance among both groups.

Table (1): Comparative analysis between Group A and Group B regarding demographic characteristics (n=196)

^Independent t-test. #Chi square test.

 Table (2): Comparative analysis between Group A and Group B regarding clinical presentation (n=196)

#Chi square test. §Fisher’s Exact test. *Significant

 Table (3): Comparative analysis between group A and group B regarding important laboratory findings (n=196)

*Significant

ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio; AFP, α-fetoprotein

 Table (4): Comparative analysis between Group A and Group B regarding important radiological findings by Triphasic CT

          *Significant

HCC, hepatocellular carcinoma, PVT; portal vein thrombosis, IHBR; intrahepatic biliary radical dilation

 Table (5): Comparative analysis between Group A and Group B regarding different scoring systems (n=196)

   *Significant

Fib4; Fibrosis 4 index, ECOG: Eastern Cooperative Oncology Group, BCLC; Barcelona Clinic Liver Cancer

 DISCUSSION