A Practical Model Evaluating Antiviral Cytokines by Natural Killer Cells in Treatment Naïve Patients with Chronic Hepatitis B Virus Infection

Xiaoyan Li, Yurong Gu, Xiaobo Guo, Lin Gu, Liang Zhou, Xiaojuan Wu, Xueqin Wang, Zania Stamataki, Yuehua Huang
2017 Scientific Reports  
Natural killer (NK) cells play a major role in anti-viral immunity as first line defense during hepatitis B infection, particularly in untreated patients whose T cells functions are profoundly impaired. Cytokine interferon (IFN)-γ and tumor necrosis factor (TNF)-α produced by NK cells are important anti-viral factors. However, there is lack of a quantifiable model to evaluate cytokine responses by NK cells. In this study, almost half of the patients (47.9%) beyond treatment criteria had high
more » ... okine activity, although it was lower than those recommended for antiviral therapy (78.2%). Moreover, we developed a model that low levels of HBsAg, HBcAb, and albumin and high fibrosis values predicted strong antiviral cytokine production by NK cells. Based on the cut-off score (0.361) obtained from the multivariable model, patients with 67%, 8%, 92%, and 74% in immune-active (IA), immune-tolerant (IT), immune-inactive (IC), and grey zone (GZ), respectively, showed active antiviral cytokines produced by NK cells. These results suggest that those who possess activated cytokine responses beyond the current treatment criteria may have potential implications for the timing of antiviral therapy to achieve better virus control. Despite the availability of a prophylactic vaccine, chronic hepatitis B (CHB) affects nearly 350 million people worldwide 1 . For those affected, lifelong infection carries the risk of developing cirrhosis, hepatocellular carcinoma (HCC), and liver failure. Efforts to understand the immunopathogenesis of CHB focus on the intricate relationship between the virus and the host. The natural course of this relationship progresses predictably through the following four recognized sequential phases: immune tolerant (IT); immune active (IA); inactive carrier (IC); and hepatitis B e antigen (HBeAg)-negative immune reactivation 2 . Although this phase-focused view of CHB allows for the design of rational therapeutic practices, the distinctions among the phases of infection are not absolute 3 . Current treatment guidelines recommend the presence of active liver inflammation on histology or elevated serum levels of alanine aminotransferase (ALT) of more than 2 upper limit of normal (ULN) level plus elevated HBV DNA above 2000 IU/mL (HBeAg negative) or 20,000 IU/mL (HBeAg positive) as criteria for initiating antiviral therapy 4 . However, an area of ongoing debate in CHB is the management of certain subgroups of patients beyond this treatment threshold, including patients with ALT < 2 x ULN, those in the immune-tolerant stage, patients with intermittently elevated ALT that can escape typical clinical surveillance, and those in the so-called Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 Scientific RepoRts | 7: 5866 |
doi:10.1038/s41598-017-06192-1 pmid:28725030 pmcid:PMC5517634 fatcat:c2fipg2ijnbovhdalfufm2ax4u