Circulating programmed death-1 as a marker for sustained high hepatitis b viral load and risk of hepatocellular carcinoma e95870

Hsiang Yun Cheng; Pei Jen Kang; Ya Hui Chuang; Ya Hui Wang; Meng Chin Jan; Chih Feng Wu; Chih Lin Lin; Chun Jen Liu; Yun Fan Liaw; Shi Ming Lin; Pei Jer Chen; Shou Dong Lee; Ming Whei Yu

doi:10.1371/journal.pone.0095870

Circulating programmed death-1 as a marker for sustained high hepatitis b viral load and risk of hepatocellular carcinoma e95870

Hsiang Yun Cheng, Pei Jen Kang, Ya Hui Chuang, Ya Hui Wang, Meng Chin Jan, Chih Feng Wu, Chih Lin Lin, Chun Jen Liu, Yun Fan Liaw, Shi Ming Lin, Pei Jer Chen, Shou Dong Lee, Ming Whei Yu

School of Medicine

Research output: Contribution to journal › Journal Article › peer-review

67 Scopus citations

Abstract

Objective: Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk.

Methods: In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989-1992) through 2010, we determined sPD-1 levels in baseline plasma with enzymelinked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newlydiagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study.

Results: Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75-3.03], 2.15 [1.12-4.13], and 2.29 [1.20-4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval58.76-45.41]).

Conclusions: Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.

Original language	English
Article number	e95870
Journal	PLoS ONE
Volume	9
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0095870
State	Published - 26 11 2014

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Publisher Copyright:
©heng et al.

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Cheng, H. Y., Kang, P. J., Chuang, Y. H., Wang, Y. H., Jan, M. C., Wu, C. F., Lin, C. L., Liu, C. J., Liaw, Y. F., Lin, S. M., Chen, P. J., Lee, S. D., & Yu, M. W. (2014). Circulating programmed death-1 as a marker for sustained high hepatitis b viral load and risk of hepatocellular carcinoma e95870. PLoS ONE, 9(11), Article e95870. https://doi.org/10.1371/journal.pone.0095870

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title = "Circulating programmed death-1 as a marker for sustained high hepatitis b viral load and risk of hepatocellular carcinoma e95870",

abstract = "Objective: Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk.Methods: In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989-1992) through 2010, we determined sPD-1 levels in baseline plasma with enzymelinked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newlydiagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study.Results: Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75-3.03], 2.15 [1.12-4.13], and 2.29 [1.20-4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval58.76-45.41]).Conclusions: Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.",

author = "Cheng, {Hsiang Yun} and Kang, {Pei Jen} and Chuang, {Ya Hui} and Wang, {Ya Hui} and Jan, {Meng Chin} and Wu, {Chih Feng} and Lin, {Chih Lin} and Liu, {Chun Jen} and Liaw, {Yun Fan} and Lin, {Shi Ming} and Chen, {Pei Jer} and Lee, {Shou Dong} and Yu, {Ming Whei}",

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doi = "10.1371/journal.pone.0095870",

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T1 - Circulating programmed death-1 as a marker for sustained high hepatitis b viral load and risk of hepatocellular carcinoma e95870

AU - Cheng, Hsiang Yun

AU - Kang, Pei Jen

AU - Chuang, Ya Hui

AU - Wang, Ya Hui

AU - Jan, Meng Chin

AU - Wu, Chih Feng

AU - Lin, Chih Lin

AU - Liu, Chun Jen

AU - Liaw, Yun Fan

AU - Lin, Shi Ming

AU - Chen, Pei Jer

AU - Lee, Shou Dong

AU - Yu, Ming Whei

PY - 2014/11/26

Y1 - 2014/11/26

N2 - Objective: Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk.Methods: In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989-1992) through 2010, we determined sPD-1 levels in baseline plasma with enzymelinked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newlydiagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study.Results: Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75-3.03], 2.15 [1.12-4.13], and 2.29 [1.20-4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval58.76-45.41]).Conclusions: Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.

AB - Objective: Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk.Methods: In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989-1992) through 2010, we determined sPD-1 levels in baseline plasma with enzymelinked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newlydiagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study.Results: Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75-3.03], 2.15 [1.12-4.13], and 2.29 [1.20-4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval58.76-45.41]).Conclusions: Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.

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Circulating programmed death-1 as a marker for sustained high hepatitis b viral load and risk of hepatocellular carcinoma e95870

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