Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2014; 20(28): 9486-9496
Published online Jul 28, 2014. doi: 10.3748/wjg.v20.i28.9486
Viral infection parameters not nucleoside analogue itself correlates with host immunity in nucleoside analogue therapy for chronic hepatitis B
Cheng-Zhong Li, Jing-Jing Hu, Jian-Ya Xue, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Hao Xu, Xue-Song Liang
Cheng-Zhong Li, Jian-Ya Xue, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Hao Xu, Xue-Song Liang, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Jing-Jing Hu, Central Laboratory, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Author contributions: Li CZ and Hu JJ contributed equally to this work; Li CZ collected all human materials and helped draft the manuscript; Hu JJ performed most of the experiments; Xue JY, Yin W, Liu YY, Fan WH and Xu H were responsible for enrolling and following the patients; Liang XS conceived the study, participated in the study design, performed statistical analysis and drafted the manuscript; all authors have read and approved the final manuscript.
Supported by The Shanghai Natural Science Fund, No. 09ZR1400500; the National Natural Science Foundation of China, No. 30972600; the GuangHui Fund of Hepatitis Prevention Fund Committee China, No. GHZ20100204; and the Shanghai Health Bureau Fund, No. 2012092
Correspondence to: Xue-Song Liang, Associate Professor, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. liangxuesong2000@163.com
Telephone: +86-21-31161902 Fax: +86-21-65518368
Received: December 4, 2013
Revised: February 8, 2014
Accepted: April 1, 2014
Published online: July 28, 2014
Processing time: 234 Days and 2.9 Hours
Abstract

AIM: To determine the relationship between host immunity and the characteristics of viral infection or nucleoside analogues (NAs) themselves in patients with chronic hepatitis B (CHB) receiving NA therapy.

METHODS: Fifty-two hepatitis B envelope antigen (HBeAg) positive CHB patients were enrolled and divided equally into two groups. One group received telbivudine (LDT, 600 mg/d), and the other group received lamivudine (LAM, 100 mg/d). Clinical, virological and immunological parameters were assessed at the baseline and at 4, 12, 24, 36 and 48 wk.

RESULTS: Both groups achieved significant hepatitis B virus (HBV) replication inhibition and alanine aminotransferase normalization at 48 wk. At the baseline, compared to healthy controls, CHB patients had a lower circulating CD8 T cell frequency (29.44% ± 11.55% vs 37.17% ± 7.30%, P = 0.03) and higher frequencies of programmed death 1 positive CD8 T cells (PD-1+ CD8 T) (16.48% ± 10.82% vs 7.02% ± 3.62%, P = 0.0001) and CD4+ CD25+ FoxP3+ T regulatory cells (Tregs) (23.64% ± 9.38% vs 13.60% ± 6.06%, P = 0.001). On therapy, at the beginning 24 wk with the levels of hepatitis B virus deoxyribonucleic acid (HBV DNA) and HBeAg declining, the frequencies of PD-1+ CD8 T cells and Treg cells gradually and significantly declined at 12 and 24 wk in both therapy groups. At treatment week 4, patients treated with LDT had a lower frequency of PD-1+ CD8 T cells compared to patients treated with LAM (10.08% ± 6.83% vs 20.51% ± 20.96%, P = 0.02). The frequency of PD-1+ CD8 T cells in all of the CHB patients was significantly correlated with both the HBV DNA level (r = 0.45, P = 0.01) and HBeAg level (r = 0.47, P = 0.01) at treatment week 24, but the frequency of Treg cells was only significantly correlated with the HBeAg level (r = 0.44,P = 0.02). Furthermore, the ability of CD8 T cells to secrete pro-inflammatory cytokines was partially restored after 24 wk of therapy.

CONCLUSION: NA-mediated HBV suppression could down-regulate the production of negative regulators of host immunity during the first 24 wk of therapy and could partially restore the ability of CD8 T cells to secrete pro-inflammatory cytokines. This immune modulating response may be correlated with the levels of both HBV DNA and HBeAg.

Keywords: Chronic hepatitis B; Nucleoside analogues; Immune modulation; Programmed death-1; CD4+ CD25+ FoxP3+ T regulatory cells

Core tip: We compared the host immunity of hepatitis B envelope antigen (HBeAg)-positive patients treated with telbivudine (LDT) to those treated with lamivudine (LAM) and longitudinally investigated the relationship between two important negative immune modulating factors and viral infection parameters in HBeAg-positive chronic hepatitis B (CHB) patients that were treated with the nucleoside analogues (NAs) LDT and LAM. NA-mediated inhibition of hepatitis B virus replication could cause the downregulation of PD-1+ CD8 T cells and Treg cells during the first 24 wk of therapy and could also partially restore the ability of CD8 T cells to secrete pro-inflammatory cytokines. The immune modulating effect associated with NA treatment in CHB patients was correlated with the levels of both HBV DNA and HBeAg.