Anti-HBV Therapy in Hepatocellular Carcinoma May Affect the Symptoms of SARS-CoV-2 Infection

Background: Anti-HBV therapy is an important therapy for improving the prognosis of patients with HCC, but the effect of long term Entecavir (ETV) treatment on SARS-CoV-2 infection is not clear.Methods: A total of 275 hepatocellular carcinoma (HCC) patients were included in the retrospective review. In the case of SARS-CoV-2 infection, the clinical symptom grading criteria were adopted from the ten edition of the Chinese treatment protocol for new coronavirus infection. COVID-19 (GSE213313) and anti-HBV therapy (GSE159413) datasets were obtained from the Gene Expression Omnibus (GEO) database. We then performed GO and KEGG analysis on the intersection genes. A total of 38 HCC patients were enrolled in the validation cohort, and changes in cytokines and lymphocyte subsets, including IL-2, IL-6, IL-8, IL-10, TNF-α, and TNF-β, were measured in the patients' serum samples.Results: Of the patients treated with NAs, 35 (64.8%) had moderate clinical signs, which was a higher proportion compared to the group that was not treated with NAs (F=10.432, p<0.005). There were 97 (43.9%) patients with mild symptoms in the no NA group, which was more significant than in the NA group. However, there were no significant differences between the two asymptomatic groups. 225 intersecting genes were primarily enriched in regulatory immune cells, including T and NK cells. And at the T cell level, anti-HBV treatment may have significantly affected T helper cell differentiation and activation. The stories of IL-2 were reduced in patients treated with ETV, whereas levels of IL-6, IL-8, IL-10, TNFα, and TNF-β were not significantly different. Lymphocyte subset analysis in both groups revealed reduced T-cell and NK-cell numbers in patients receiving ETV.Conclusion: Prolonged treatment with NAs reduced serum IL-2 levels in patients with HCC, suppressed T cell and NK cell numbers and may have exacerbated symptoms of SARS-CoV-2 infection.Funding: None.Declaration of Interest: The authors declare that they have no competing interests.Ethical Approval: This study involving human serum specimens was conducted in strict compliance with the Declaration of Helsinki, and patient informed consent was followed. Informed consent was obtained from patients for all patient serum specimens. The studies involving human participants were reviewed and approved by the Ethics Committee of the First Medical Center of Chinese PLA General Hospital (ethical approval no.: S2016-098-01).