An Increase in the Levels of Middle Surface Antigen Characterizes Patients Developing HBV-Driven Liver Cancer Despite Prolonged Virological Suppression.

Giuseppina Brancaccio,Vanessa Fini,Romina Salpini,Yasunori Oda,Arianna Battisti,Lorenzo Piermatteo,Marco Cantone,Matteo Surdo,Valentina Svicher,Giovanni Battista Gaeta,Luna Colagrossi,Francesca Ceccherini-Silberstein,Domenico Di Carlo,Carlo Federico Perno

doi:10.3390/microorganisms9040752

Abstract

Hepatitis B virus (HBV) contains three surface glycoproteins—Large-HBs (L-HBs), Middle-HBs (M-HBs), and Small-HBs (S-HBs), known to contribute to HBV-driven pro-oncogenic properties. Here, we examined the kinetics of HBs-isoforms in virologically-suppressed patients who developed or did not develop hepatocellular carcinoma (HCC). This study enrolled 30 chronically HBV-infected cirrhotic patients under fully-suppressive anti-HBV treatment. Among them, 13 patients developed HCC. Serum samples were collected at enrolment (T0) and at HCC diagnosis or at the last control for non-HCC patients (median (range) follow-up: 38 (12–48) months). Ad-hoc ELISAs were designed to quantify L-HBs, M-HBs and S-HBs (Beacle). At T0, median (IQR) levels of S-HBs, M-HBs and L-HBs were 3140 (457–6995), 220 (31–433) and 0.2 (0–1.7) ng/mL. No significant differences in the fraction of the three HBs-isoforms were noticed between patients who developed or did not develop HCC at T0. On treatment, S-HBs showed a >25% decline or remained stable in a similar proportion of HCC and non-HCC patients (58.3% of HCC- vs. 47.1% of non-HCC patients, p = 0.6; 25% of HCC vs. 29.4% of non-HCC, p = 0.8, respectively). Conversely, M-HBs showed a >25% increase in a higher proportion of HCC compared to non-HCC patients (50% vs. 11.8%, p = 0.02), in line with M-HBs pro-oncogenic role reported in in vitro studies. No difference in L-HBs kinetics was observed in HCC and non-HCC patients. In conclusion, an increase in M-HBs levels characterizes a significant fraction of HCC-patients while under prolonged HBV suppression and stable/reduced total-HBs. The role of M-HBs kinetics in identifying patients at higher HCC risk deserves further investigation.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide [1]
The clinical endpoint was the development of HCC; the diagnosis of HCC was confirmed by Magnetic Resonance Imaging (MRI) or Computed
Patients with Hepatitis Delta Virus (HDV) coinfection were younger than patients with Hepatitis B virus (HBV) mono-infection (median 58 years (39–73) vs. 66 (54–76); p < 0.05)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide [1]. In the last two decades, anti-HBV treatment with nucleos(t)ide analogues (NUCs) has resulted in remarkable improvements in the survival of patients with chronic hepatitis B and has determined a reduced incidence of HBV-related HCC [4,5,6]. These critical goals have been achieved by the capacity of the most recent NUCs to maintain long-term viral suppression in >90% of treated patients and, in turn, to reduce hepatic inflammation and to prevent or reverse liver fibrosis [7,8,9].

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