AASLD2020[22] 減少長期核苷（T）類比療法 慢性乙型肝炎病毒DNA

StephenW

22
LONG TERM NUCLEOS(T)IDE ANALOGUE THERAPY REDUCED
THE EXTENT OF HBV DNA INTEGRATION IN CHRONIC
HEPATITIS B PATIENTS
Ning Chow1, Danny Ka-Ho Wong1,2, Lung Yi Mak1,3, James
Fung1,2, Wai Kay Walter Seto1,2, Ching Lung Lai1,2 and Man
Fung Yuen1,2, (1)Medicine, The University of Hong Kong, (2)
State Key Laboratory of Liver Research, The University of
Hong Kong, (3)State Key Laboratory for Liver Research, The
University of Hong Kong
Background: Integration of HBV DNA into host chromosomes
is associated with the development of hepatocellular
carcinoma (HCC) in chronic hepatitis B (CHB) patients
Current anti-viral therapeutic agents, in the form of nucleos(t)
ide analogue (NUCs), suppress HBV replication and reduce
HCC risk We aimed to study the effect of long-term NUC
treatment on the extent of HBV DNA integration in CHB
patients Methods: 28 CHB patients who had received NUC
treatment were studied All had paired liver biopsies collected
before treatment (baseline) and one year after treatment Five
of them had a third liver biopsy at 10 years post treatment HBV
DNA integration was detected in the liver DNA using inverse
PCR The extent of HBV DNA integration was expressed as
hepatocyte clone size Results: Of the 28 patients (21 males
and 7 females; 14 HBeAg-positive and 14 HBeAg-negative;
mean age 40 years), 11 received lamivudine, 7 received
telbivudine, and 10 received entecavir At baseline, all had
detectable HBV DNA integration (median hepatocyte clone
size: 1 40×105) HBV DNA integration sites were found in
all chromosomes except chromosome Y, with integration at
chromosomes 1, 2, 6, 16 and 21 being more prevalent There
was no significant association between hepatocyte clone size
and patients’ age Baseline hepatocyte clone size in HBeAgpositive
and HBeAg-negative patients were comparable HBV
DNA integration was detectable one year after treatment, with
a median hepatocyte clone size decreased to 6 72 × 104 (P
= 0 003 compared with baseline) and a mean reduction of
42 5% Of the 5 patients with liver biopsy at year 10, 3 had
undetectable HBV DNA integration A trend of reduction in
hepatocyte clone size in these 5 patients was seen during
the course of NUC treatment (baseline vs 1 year vs 10 year
= 4 54×104 vs 2 62×104 vs <1 00×102, P = 0 015) At years
1 and 10, intrahepatic HBV DNA reduced by 1 5 and 3 0
logs respectively, and cccDNA reduced by 0 7 and 2 6 logs
respectively. There was no significant correlation between the
reduction in clone size and that of intrahepatic HBV DNA and
cccDNA Conclusion: One-year NUC treatment significantly
reduced the extent of HBV DNA integration, which was further
reduced upon 10 years of treatment This supports the notion
that long term NUC treatment reduces HCC risk through
the reduction of HBV DNA integration Further studies on
the cellular/virologic pathways and the degree of integration
reduction among different treatment agents and patient
subgroups are needed.

StephenW

22
減少長期核苷（T）類比療法
慢性乙型肝炎病毒DNA整合的程度
乙型肝炎患者
周寧1，黃家豪1,2，龍怡麥1,3，詹姆斯
Fung1,2，Wai Kay Walter Seto1,2，Ching Lung Lai1,2和Man
馮源1,2，（1）香港大學醫學，（2）
加州大學肝臟研究國家重點實驗室
香港（3）肝臟研究國家重點實驗室
香港大學
背景：HBV DNA整合入宿主染色體
與肝細胞的發展有關
慢性乙型肝炎（CHB）患者的癌症（HCC）
當前的抗病毒治療劑，以核仁形式存在
ide類似物（NUCs），抑制HBV複製並減少
肝癌風險我們旨在研究長期NUC的影響
CHB中HBV DNA整合程度的治療
患者方法：28名接受NUC的CHB患者
對治療進行了研究所有收集的肝活檢均已配對
治療前（基線）和治療後一年5
他們中的乙肝患者在治療10年後進行了第三次肝活檢
使用反向檢測肝臟DNA中的DNA整合
PCR HBV DNA整合的程度表示為
肝細胞克隆大小結果：28例患者中（21例男性）
7名女性； 14 HBeAg陽性和14 HBeAg陰性；
平均年齡40歲），接受拉米夫定11例，接受7例
替比夫定，10例接受恩替卡韋治療
可檢測的HBV DNA整合（肝細胞中位數克隆
大小：1 40×105）在
除Y染色體外的所有染色體，在
染色體1、2、6、16和21更普遍
與肝細胞克隆大小之間無明顯關聯
和患者年齡HBeAg陽性的基線肝細胞克隆大小
和HBeAg陰性患者可比HBV
治療一年後可檢測到DNA整合
中位數肝細胞克隆大小降至6 72×104（P
=與基線相比為0 003），平均減少了
42 5％在10年級的5名肝活檢患者中，有3名
無法檢測到的HBV DNA整合
這5例患者的肝細胞克隆大小在
NUC治療過程（基線vs 1年vs 10年
= 4 54×104對2 62×104對<1 00×102，P = 0 015）年
1和10，肝內HBV DNA減少1 5和3 0
分別減少log和cccDNA減少0 7和2 6個對數
分別。兩者之間無顯著相關性
減少克隆大小以及肝內HBV DNA和
cccDNA結論：一年的NUC治療顯著
降低了HBV DNA整合的程度，這進一步
經過10年的治療後減少
長期的NUC治療可通過以下方式降低HCC風險：
減少HBV DNA整合
細胞/病毒途徑和整合程度
不同治療藥物和患者之間的減少
子組是必需的。