长期核苷酸（t）模拟疗法可降低慢性乙型肝炎患者的HBV DNA整

StephenW

Long term nucleos(t)ide analogue therapy reduced the extent of HBV DNA integration in chronic hepatitis B patients

NUCs May Prevent HCC by Reducing HBV DNA Integration

AASLD The Liver Meeting Digital Experience, November 13-16, 2020

Mark Mascolini

Ongoing nucleos(t)ide analog (NUC) therapy “drastically reduced” HBV DNA integration into chromosomes of people with chronic hepatitis B virus (HBV) infection, according to a detailed 28-person analysis [1]. University of Hong Kong researchers suggested this anti-integration activity could explain why NUC therapy lowers the risk of hepatocellular carcinoma (HCC) in people with HBV.

Research links chromosomal integration of HBV DNA in people with chronic HBV infection to HCC development. This integration happens early in the course of chronic HBV. But because currently used anti-HBV NUCs rein in HBV replication, lower HBV DNA in blood and liver, and trim HCC risk, the Hong Kong team asked whether they might cut cancer risk by reducing HBV DNA integration.

To answer that que­­stion the researchers studied 28 people who took NUCs for chronic HBV infection. Everyone had a liver biopsy before NUC therapy began (baseline) and after 1 year of treatment. Five people (18%) had a third biopsy 10 years after HBV therapy began. The investigators used inverse PCR to detect HBV DNA integration in chromosomes and expressed extent of integration as hepatocyte clone size.

Twenty-one of the 28 participants were men and age averaged 40 years at baseline. Fourteen people were HBeAg-positive (indicating actively replicating HBV) and 14 were HBeAg-negative. Eleven people took lamivudine, 10 entecavir, and 7 telbivudine.

From baseline to treatment year 1, several median HBV measures dropped significantly: serum HBV DNA (6.36 to 1.3 log IU/mL, P = 0.009), HBcrAg (3.56 to 2.71 kU/mL, P = 0.016), intrahepatic total HBV DNA (185.3 to 3.87 copies/cell, P = 0.007), and intrahepatic cccDNA (4.21 to 0.70 copies/cell, P = 0.007). The last three measures continued to fall in the 5 people who had 10 years of follow-up. HBsAg did not drop significantly in the first year of treatment (3.49 to 3.30 log IU/mL) but continued drifting downward in the next 9 years (to 2.56 log IU/mL) (P = 0.247 for trend).

Before treatment began, all participants had detectable HBV DNA integration at a median hepatocyte clone size of 1.40 x 10(5). Integration could be detected randomly across the whole genome, in all chromosomes except Y. Initial hepatocyte clone size did not correlate with age, HBeAg status, or virologic parameters.

After 1 year of NUC therapy median hepatocyte clone size dropped by 42.5% to 6.72 x 10(4), a significant decline (P = 0.003). Three of 5 people with a biopsy 10 years after therapy began had no detectable HBV DNA integration into chromosomes. In these 3 study participants median hepatocyte clone size fell significantly from before NUC therapy to year 1 and to year 10 (4.54 x 10(4) to 2.62 x 10(4) to <1.00 x 10(2), P = 0.015). In the 5 people with 3 biopsies across 10 years, HBV DNA in the liver fell by 1.5 log (about 32-fold) after 1 year of NUC therapy and by 3.0 log (1000-fold) after 10 years.

Falling HBV measures in serum and the liver did not correlate significantly with declining hepatocyte clone size.

The researchers concluded that NUC therapy significantly lowered clone size of infected liver cells, and that long-term therapy “drastically reduced” HBV DNA integration. Why NUCs have these effects remains unclear. The investigators see a need for further study on how HBV DNA integration may differ by therapeutic agent or patient subgroup.

Reference
1. Chow N, Wong DKH, Mak LY, et al. Long term nucleos(t)ide analogue therapy reduced the extent of HBV DNA integration in chronic hepatitis B patients. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 22.

StephenW

长期核苷酸（t）模拟疗法可降低慢性乙型肝炎患者的HBV DNA整合程度

NUC可能通过减少HBV DNA整合来预防HCC

AASLD肝脏会议数字体验，2020年11月13日至16日

马克·马斯科利尼

一项详细的28人分析表明，正在进行的核苷类似物（NUC）治疗“大大减少”了HBV DNA在慢性乙型肝炎病毒（HBV）感染者染色体中的整合[1]。香港大学的研究人员认为，这种抗整合活性可以解释为什么NUC治疗可以降低HBV患者肝细胞癌（HCC）的风险。

研究将慢性HBV感染者的HBV DNA的染色体整合与HCC的发生联系起来。这种整合发生在慢性HBV的早期。但是，由于目前使用的抗HBV NUC抑制了HBV复制，降低了血液和肝脏中的HBV DNA并降低了HCC风险，因此香港研究小组询问他们是否可以通过减少HBV DNA整合来降低癌症风险。

为了回答这个问题，研究人员研究了因慢性HBV感染而服用NUC的28人。在开始NUC治疗之前（基线）和治疗1年后，每个人都进行了肝活检。 HBV治疗开始10年后，有5人（18％）进行了第三次活检。研究人员使用反向PCR来检测染色体中的HBV DNA整合，并以肝细胞克隆大小表示整合程度。

28名参与者中有21名是男性，基线时的平均年龄为40岁。 HBeAg阳性的人为14人（表明正在积极复制HBV），HBeAg阴性的人为14人。 11人服用了拉米夫定，10个恩替卡韦和7个替比夫定。

从基线到治疗第1年，一些HBV中位数测量值显着下降：血清HBV DNA（6.36至1.3 log IU / mL，P = 0.009），HBcrAg（3.56至2.71 kU / mL，P = 0.016），肝内总HBV DNA（ 185.3至3.87拷贝/细胞，P = 0.007）和肝内cccDNA（4.21至0.70拷贝/细胞，P = 0.007）。在进行了10年随访的5人中，最后三项措施继续下降。在治疗的第一年，HBsAg并未显着下降（3.49至3.30 log IU / mL），但在接下来的9年中继续下降（至2.56 log IU / mL）（趋势P = 0.247）。

在开始治疗之前，所有参与者的肝细胞克隆中位大小为1.40 x 10（5），均可检测到HBV DNA整合。整合可以在Y以外的所有染色体上的整个基因组中随机检测。初始肝细胞克隆大小与年龄，HBeAg状态或病毒学参数无关。

NUC治疗1年后，中位肝细胞克隆大小下降了42.5％，为6.72 x 10（4），显着下降（P = 0.003）。在开始治疗10年后进行活检的5个人中，有3个人没有可检测到的HBV DNA整合入染色体。在这3名研究参与者中，从NUC治疗前到第1年和第10年，中值肝细胞克隆大小均显着下降（4.54 x 10（4）到2.62 x 10（4）到<1.00 x 10（2），P = 0.015）。在10年中进行3次活检的5人中，NUC治疗1年后肝脏中的HBV DNA下降了1.5 log（约32倍），而10年后下降了3.0 log（约1000倍）。

血清和肝脏中HBV指标下降与肝细胞克隆大小下降没有明显关系。

研究人员得出结论，NUC治疗显着降低了受感染肝细胞的克隆大小，长期治疗“大大减少了” HBV DNA整合。为什么NUC具有这些作用仍不清楚。研究者认为有必要进一步研究HBV DNA整合可能因治疗剂或患者亚组而异。

参考
1. Chow N，Wong DKH，Mak LY等。长期核苷酸（t）模拟疗法可降低慢性乙型肝炎患者的HBV DNA整合程度。 AASLD肝脏会议数字体验，2020年11月13日至16日。摘要22。

lancas

只要不耐药，这也算一个好消息~~