1. Background
Patients with chronic hepatitis B (CHB) infection significantly show an over-
expression of immune co-inhibitory molecules such as programmed cell
death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
on the HBV-specific T cells.[2] PD-1 and CTLA-4 are receptors in the CD28
family which provide inhibitory signals to T cells and cause the dysfunction in
antiviral effector T cells.[4]
Aim
To investigate whether soluble form of PD-1, CTLA-4 (sPD-1, sCTLA-4) and
PDL-1 can be additional predictors for the milestone transitions of CHB,
particularly hepatitis B surface antigen (HBsAg) seroclearance.
Methods
Four hundred CHB patients from the REVEAL-HBV cohort were enrolled in
this study. These patients were recruited from seven townships in Taiwan
between 1991 and 1992. Two hundred of them reached the stage of HBsAg
clearance during the follow-up while other two hundred participants were
controls without HBsAg clearance matched on gender, age, and serum ALT
levels. Baseline samples of these individuals were tested for sPD-1, sCTLA-
4 and PDL-1 levels using ELISA kits.
Results
The sPD-1 and sCTLA-4 levels were significant predictors for HBsAg
seroclearance but PDL-1 was not. Compared to participants with sPD-1
levels <280 pg/mL, the multivariate-adjusted odds ratio (95% CI) of HBsAg
non-clearance was 3.01 (1.75-5.17) and 6.18 (2.42-15.8) for those with sPD-
1 levels of 280 - 3999 and ≥4000 pg/mL, respectively. Compared to
participants with sCTLA-4 levels <1.4 ng/mL, the multivariate-adjusted odds
ratio of HBsAg non-clearance was 1.71 (0.85-3.43), 3.32 (1.71-6.45), and
5.79 (2.27-14.76) for those with sCTLA-4 levels of 1.5 - 3.9, 1.5 - 3.9, 4 -
15.9 and ≥16 ng/mL, respectively.
Conclusion
Patients with high levels of sPD-1 and sCTLA-4 in their circulation have a
higher risk in inhibiting HBsAg clearance. These two novel seromarkers can
potentially be used to improve the precision of clinical outcomes.
Po-Ting Ho 1, Wun-Sheng Luo 2, Dr. Hui-Han Hu 2, and Dr. Hwai-I Yang 2
1 Department of Biological Sciences, University of Alberta, Canada 2 Genomics Research Center, Academia Sinica, Taiwan
Abstract Natural History of CHB
Inhibitory Signaling Pathway
a
Q1
Q2
Q3
mean
b
c
Fig. 1 │ Box plots for each marker in HBsAg non-
clearance and clearance. a) Distributions of sPD-1
level for each group. b) Distributions of sCTLA-4 leve
l for each group. c) Distributions of PDL-1 level for
each group.
References
Chronicity of HBV infection
(HBsAg persistance)
Study design
1991 1992 2004
Baseline Follow-up
sPD-1, sCTLA-4, PDL-1 HBsAg clearance
1 Chen, C.J. and Yang, H.I. 2011. Natural history of chronic hepatitis B REVEALed. J. Gastroenterol. Hepatol., 26: 628-638.
2 Cho, H., Kang, H., Kim, C.W., Kim, H.Y., Jang, J.W., Yoon, S.K., and Lee, C.D. 2016. Phenotypic Characteristics of PD-1 and CTLA-4 Expression in Symptomatic Acute Hepatitis A. Gut Liver, 10(3): 288-294.
3 Freeman, G.J. 2008. Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek. PNAS, 105 (30): 10275-10276.
4 Iwai, Y., Terawaki, S., Ikegawa, M., Okazaki, T., and Honjo, T. 2003. PD-1 inhibits antiviral immunity at the effector phase in the liver. J. Exp. Med., 198 (1): 39-50.
Chen, C.J. and Yang, H.I. 2011. J. Gastroenterol. Hepatol., 26: 628-638 [1]
Freeman, G.J. 2008. PNAS, 105 (30): 10275-10276 [3]
Two Novel Seromarkers for Predicting the Progression of Chronic Hepatitis B: Soluble
Form of Programmed Cell Death 1 and Cytotoxic T Lymphocyte-associated Antigen 4
*p value for trend test. ƗData missing for 4 individuals. ǂData missing for 84 individuals.
Table 2 │ Univariate analysis of factors associated with HBsAg clearance in 400 participants
Table 3 │ Multivariate analysis of factors associated with HBsAg clearance in 400 participants
Table 1 │ Descriptive statistics of sPD-1, sCTLA-4, and PDL-1
(3)