Soluble Programmed Cell Death-1 is a Novel Predictor of HBsAg Loss in Chronic Hepatitis B Patients When Long-Term Nucleos(t)ide Analog Treatment is Discontinued

Abstract

Purpose

The immunoinhibitory receptor, programmed death 1 (PD-1), plays a critical role in immune suppression during chronic viral infection. The significance of circulating soluble PD-1 (sPD-1) in patients with chronic hepatitis B who have discontinued long-term nucleos(t)ide analog (NA) treatment remains unknown.

Patients and Methods

A prospective cohort study was conducted using serial blood samples from chronic hepatitis B patients who discontinued long-term NA treatment. The current analysis included 115 non-cirrhotic patients with HBV DNA negative and HBsAg positive at the moment of NA discontinuation. Levels of sPD-1 were measured in all available samples using sandwich enzyme-linked immunoassay.

Results

Sixty-two patients experienced a clinical relapse and 14 occurred HBsAg loss, with 8-year cumulative rates of 56.6% and 23.4%, respectively. Time-dependent receiver operating characteristic curve analysis for sPD-1 derived 156 pg/mL, which is equivalent to the detectable threshold, as an optimal cut-off value for predicting 8-year clinical relapse. Patients with detectable sPD-1 at end of treatment (EOT) had a significant lower incidence of clinical relapse (48% vs 67%, hazard ratio [HR] 0.454, p = 0.006), but a remarkable higher probability of HBsAg loss (33.7% vs 2.4%, HR 9.17, p = 0.038), compared to those who with undetectable sPD-1, respectively.

Conclusion

EOT sPD-1 levels predicted clinical relapse and HBsAg loss after treatment discontinuation and may help to guide a finite NA treatment plan for patients with chronic hepatitis B virus infection.

Keywords:

• chronic hepatitis B
• discontinuation
• programmed cell death 1 protein
• nucleos(t)ide analogs

Abbreviations

HBV, hepatitis B virus; CHB, chronic hepatitis B; ALT, serum alanine aminotransferase; NA, nucleos(t)ide analogue; EOT, end-of-treatment; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; BcrAg, hepatitis B core-related antigen; cccDNA, intrahepatic covalently closed circular DNA;ULN, the upper limit of normal; LLOD, the lower limit of detection; ELISA, enzyme-linked immunoassay; SD, standard deviation; HR, hazard ratio; CI, confidence interval, IQR, interquartile range; ROC, receiver operating characteristic; SR, sustained response; CR, clinical relapse; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1, sPD-1, soluble programmed cell death 1.

Data Sharing Statement

Part of the data used during the study has been public available in ResMan (http://www.medresman.org.cn) and ChiCTR (http://www.chictr.org.cn/index.aspx), including age, values of ALT/AST, HBV DNA, HBsAg, HBsAb, HBeAg, HBeAb, HBcAb, AFP, ultrasonography, and liver stiffness.

Acknowledgments

The authors would like to thank all the patients included in this study, and the nurses who assisted in patient management and collection of serum samples.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Guichan Liao, Ziying Liu and Muye Xia share co-first authorship. Shaohang Cai, Xiaoyong Zhang and Jie Peng share co-senior authorship.

Disclosure

All authors have no competing interests to disclose.

Additional information

Funding

This study was supported by grants from the National Science Foundation of China (No.81971949, No.86878446), Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (No.LC2016PY003) and Clinical Research Program of Nanfang Hospital, Southern Medical University (No.2018CR026). The funding sources did not have any influence on the study design, data collection, analysis and interpretation of the data, writing of the manuscript, or decision to submit for publication.