AASLD2020[720]可溶性免疫血清水平的变化 核苷（T）期间的检查

StephenW

720
CHANGES IN SERUM LEVELS OF SOLUBLE IMMUNE
CHECKPOINT PROTEINS DURING NUCLEOS(T)IDE OR
PEGINTERFERON-Α TREATMENT IN PATIENTS WITH
CHRONIC HBV INFECTION
Masaru Enomoto, Minh Phuong Dong, Hoang Hai, Le Thi
Thanh Thuy, Naoshi Odagiri, Kanako Yoshida, Kohei Kotani,
Hiroyuki Motoyama, Ritsuzo Kozuka, Atsushi Hagihara,
Hideki Fujii, Sawako Uchida, Akihiro Tamori and Norifumi
Kawada, Department of Hepatology, Osaka City University
Graduate School of Medicine
Background: Hepatitis B surface antigen (HBsAg)
seroclearance is the end-point of antiviral therapy for chronic
hepatitis B virus (HBV) infection At present, available
agents are nucleos(t)ide analog (NUC) and peginterferon-α
(PegIFNα) only, although many novel direct acting or
host targeting antiviral agents are currently under clinical
investigations An anti-PD-1 monoclonal antibody is one of the
candidates, because the exhaustion of HBV-specific CD8+ T
cells can be an explanation for the persistent HBV infection
The aims of this study were 1) to evaluate serum levels of
soluble immune checkpoint proteins and their changes in
patients with chronic hepatitis B during treatment with IFN or
NUC, and 2) to identify a soluble immune checkpoint protein
as a potential biomarker for prediction of treatment response
Methods: Thirty-two patients with chronic HBV infection were
included; 12 patients (33±7 years old; 9 men/3 women; HBsAg
4 1±0 6 log IU/mL; 8 HBeAg-pos ; HBV DNA 7 7±1 5 log IU/
mL) received PegIFNα monotherapy for 48 weeks, and 20
patients (46±13 years old; 12 men/8 women; HBsAg 3 9±0 6
log IU/mL; 10 HBeAg-pos ; HBV DNA 7 8±1 5 log IU/mL)
received NUC therapy with either entecavir (n=12) or tenofovir
(n=8) for ≥ 48 weeks. Response to treatment was defined
as 0 5 log decrease in HBsAg at week 48 Serum samples
were collected at baseline, 12, and 48 weeks of treatment
The concentration of 16 soluble checkpoint proteins, namely
sBTLA, sCD27, sCD28, sTIM-3, sHVEM, sCD40, sGITR,
sLAG-3, sTLR-2, sGITRL, sPD-1, sCTLA-4, sCD80, sCD86,
sPD-L1 and sICOS, were measured using multiplexed
fluorescent bead-based immunoassays. Results: The
patients in the IFN group were younger than those in the NUC
group (p=0 0009), but the other baseline characteristics of the
patients in the treatment groups were similar 1) Some soluble
protein levels, including sCD27, sGITR, sPD-1 and sCTLA-4,
decreased significantly at 12 and 48 weeks of NUC treatment,
but not during IFN In contrast, the levels of sGITR and sLAG-
3 changed significantly at 12 or 48 week of IFN treatment,
but not during NUC Interestingly, some proteins changed
inversely during IFN and NUC; sTIM-3 and sCD86 levels
significantly increased during IFN, whereas they decreased
during NUC treatment 2) The patients with response to NUC
(n=6) had significantly lower HBsAg (p=0.035) and HBV
DNA (p=0.026) levels and were significantly more likely to
have non-C genotypes (p=0 015) than those without (n=14)
However, there were no differences in serum soluble protein
levels between groups In contrast, the patients with response
to IFN (n=7) had significantly less increase in serum sCD86
levels at 12 weeks of treatment (p=0 048) than those without
(n=5) Conclusion: 1) Different levels of soluble immune
checkpoint proteins have been found between PegIFNtreated
and NUC-treated HBV patients 2) Changes in serum
sCD86 level at week 12 is a potential biomarker for prediction
of response to PegIFNα.

StephenW

720
可溶性免疫血清水平的变化
核苷（T）期间的检查点蛋白或
聚乙二醇干扰素-α治疗
慢性HBV感染
江本正（Masaru Enomoto），明富东（Minh Phuong Dong），黄海（Hoang Hai），勒锡（Le Thi）
Thanh Thuy，小田奈绪（Naoshi Odagiri），吉田加奈子（Kanako Yoshida），小谷晃平（Kohei Kotani），
本山弘之，小冢立三，Ha原淳
藤井秀树，内田泽子，田森明弘和中文典
大阪市立大学肝病学系川田
医学研究生院
背景：乙型肝炎表面抗原（HBsAg）
血清清除是慢性病毒抗病毒治疗的终点
乙型肝炎病毒（HBV）感染目前可用
药物是核苷酸（t）ide类似物（NUC）和聚乙二醇干扰素-α
（PegIFNα），尽管许多新颖的直接作用或
靶向抗病毒药物的宿主目前正在临床中
研究抗PD-1单克隆抗体是
候选人，因为用尽了HBV特异性CD8 + T
细胞可以解释HBV持续感染
这项研究的目的是1）评估血清水平
可溶性免疫检查点蛋白及其变化
IFN治疗期间患有慢性乙型肝炎的患者
NUC和2）识别可溶性免疫检查点蛋白
作为预测治疗反应的潜在生物标志物
方法：对32例慢性HBV感染患者进行了检查。
包括; 12名患者（33±7岁; 9名男性/ 3名女性; HBsAg
4 1±0 6 log IU / mL; 8 HBeAg-pos; HBV DNA 7 7±1 5 log IU /
mL）接受PegIFNα单药治疗48周，其中20周
患者（46±13岁； 12名男性/ 8名女性； HBsAg 3 9±0 6
log IU / mL; 10 HBeAg-pos; HBV DNA 7 8±1 5 log IU / mL）
接受恩替卡韦（n = 12）或替诺福韦的NUC治疗
（n = 8）≥48周。确定对治疗的反应
在第48周时血清HBsAg下降0 5 log
在基线，治疗12、48周时收集
16种可溶性检查点蛋白的浓度，即
sBTLA，sCD27，sCD28，sTIM-3，sHVEM，sCD40，sGITR，
sLAG-3，sTLR-2，sGITRL，sPD-1，sCTLA-4，sCD80，sCD86，
sPD-L1和sICOS，使用多重测量
基于荧光珠的免疫测定。结果：
IFN组的患者比NUC组的患者年轻
（p = 0 0009），但其他基线特征
治疗组中的患者相似1）一些可溶
蛋白质水平，包括sCD27，sGITR，sPD-1和sCTLA-4，
NUC治疗第12周和第48周显着下降，
而不是在IFN期间。相比之下，sGITR和sLAG-
在IFN治疗的第12或48周，有3例发生了明显变化，
但不是在NUC期间有趣的是，一些蛋白质改变了
在IFN和NUC期间相反； sTIM-3和sCD86水平
在IFN期间显着增加，而在IFN下降
NUC治疗期间2）对NUC有反应的患者
（n = 6）的HBsAg（p = 0.035）和HBV明显降低
DNA（p = 0.026）的水平，并且明显更可能
具有非C基因型（p = 0 015）而不具有非C基因型（n = 14）
但是，血清可溶性蛋白没有差异
组之间的水平相反，有反应的患者
干扰素（n = 7）的血清sCD86增加显着减少
治疗12周时的血脂水平（p = 0 048）
（n = 5）结论：1）不同水平的可溶性免疫
已在PegIFN治疗之间发现检查点蛋白
和NUC治疗的HBV患者2）血清变化
第12周的sCD86水平可能是预测的潜在生物标志物
对PegIFNα的反应。