Circulating soluble programmed death-1 levels may differentiate immune-tolerant phase from other phases and hepatocellular carcinoma from other clinical diseases in chronic hepatitis B virus infection.

Na Li,Yi Lv,Fang Li,Zhengwen Liu,Wenxuan Zhao,Zhihua Zhou,Chunyan Li,Jiao Sang,Qunying Han

doi:10.18632/oncotarget.17546

Abstract

Programmed death-1 (PD-1) is involved in the immune dysfunction of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study analyzed the association of circulating soluble PD-1 (sPD-1) levels with the phases and clinical diseases in chronic HBV infection. Serum sPD-1 levels were determined by enzyme linked immunosorbent assay in patients with different phases and liver diseases of chronic HBV infection. The sPD-1 levels in patients with chronic HBV infection were significantly elevated compared with HBV infection resolvers or healthy controls. According to phases, sPD-1 level in immune-tolerant phase (IT) was significantly lower than in other phases. Multivariate analysis showed that sPD-1 was an independent factor associated with IT. Area under the receiver operating characteristic (ROC) curves (AUC) showed that sPD-1 was significantly discriminative of IT from other phases with a cut-off of 1.535 ng/mL (AUC, 0.984; P<0.001). According to clinical diseases, sPD-1 level in HBV-related HCC was significantly higher than in other clinical diseases. Multivariate analysis showed that sPD-1 was an independent factor associated with HCC. The sPD-1 was significantly discriminative of HCC from other clinical diseases with a cut-off of 6.058 ng/mL (AUC, 0.962; P<0.001). The sPD-1 levels were significantly associated with HCC patients’ overall survival. HCC resection resulted in remarkable reduction in sPD-1 levels. These results demonstrate the involvement of sPD-1 in the disease course of chronic HBV infection and indicate the potential to apply sPD-1 as a biomarker for differentiating IT from other phases and HCC from other disease conditions in chronic HBV infection.

Highlights

Hepatitis B virus (HBV) infection is a major global health problem with at least two billion people having been infected and approximately 240 million people being chronically infected with the virus [1, 2]
The liver diseases including asymptomatic chronic hepatitis B virus (HBV) carrier status (ACS), chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) may develop in different phases during the natural history of chronic HBV infection the incidence and severity of each disease condition may vary with the phases [6]
The membrane bound Programmed death-1 (PD-1) has been demonstrated to be complicated in the dysfunction of T-cell immune response to chronic HBV infection and the associated liver diseases including HCC by many studies [8, 16,17,18,19,20, 22,23,24,25,26,27]

Summary

Introduction

Hepatitis B virus (HBV) infection is a major global health problem with at least two billion people having been infected and approximately 240 million people being chronically infected with the virus [1, 2]. IT is characterized by the active HBV replication with HBeAg positivity and high HBV DNA level in serum and the absence of abnormal biochemical liver function with no significant ongoing necroinflammatory disease of the liver; IR is characterized by the presence of HBeAg, high or fluctuating serum HBV DNA levels, persistent or intermittent elevation in serum aminotransferases, and active inflammation on liver biopsy; LR is characterized by absence of HBeAg, presence of anti-HBe, low or undetectable serum HBV DNA, persistently normal aminotransferase levels and mild inflammation and minimal fibrosis in the liver. The liver diseases including asymptomatic chronic HBV carrier status (ACS), chronic hepatitis (CH), liver cirrhosis (LC) and HCC may develop in different phases during the natural history of chronic HBV infection the incidence and severity of each disease condition may vary with the phases [6]

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Results

Conclusion