Determining the Optimal Hepatitis B Surface Antigen Level for Treatment Cessation of Nucleoside Analogue Therapy in Chronic Hepatitis B: a Prospective Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 124
- 试验地点
- 1
- 主要终点
- Off-treatment durability
研究概览
简要总结
Treatment cessation in chronic hepatitis B is associated with high rates of disease relapse. However patients who achieve the seroclearance of hepatitis B surface antigen (HBsAg) (<0.05 IU/mL) show good off-treatment durability after treatment cessation. Through the quantification of HBsAg, the study aims to investigate how low should quantitative HBsAg be before once can achieve successful disease control after treatment cessation.
详细描述
The treatment paradigm of chronic hepatitis B (CHB) has been transformed by the introduction of nucleoside analogue (NA) therapy. Long-term NA therapy can suppress viral replication, improve liver histology, and reduce the risk of liver-related complications and mortality. For the large majority of CHB patients, NAs need to be taken long-term, since the occurrence of hepatitis B surface antigen (HBsAg) seroclearance, the established treatment endpoint of CHB, is a rare event. Nonetheless, once HBsAg seroclearance is achieved, virologic suppression and improvement in clinical outcomes remain sustained in almost all patients even after treatment discontinuation.
So far, attempts to discontinue NA therapy before HBsAg seroclearance had yielded variable results. Concerning hepatitis B e antigen (HBeAg)-negative CHB, prior studies found rates of disease relapse to range from 45% to 66% after treatment cessation. A recent multicenter prospective study involving three Hong Kong institutes (including our center) and 184 patients found the 48-week cumulative rate of virologic relapse to be 91.4%. While variations in relapse rates could be explained by the difference in study design and definition of endpoints, an important factor which could play a role is the serum HBsAg level of recruited subjects.
The quantification of serum HBsAg has recently been advocated as a marker of disease monitoring for CHB [10]. Low levels of serum HBsAg are associated with good immune control of the hepatitis B virus (HBV), with serum HBsAg levels of 100-200 IU/mL being predictive of eventual HBsAg seroclearance in treatment-naïve CHB. Nonetheless , in the abovementioned multicenter prospective study, only 4.8% and 14.1% of study subjects had HBsAg levels <100 IU/mL or <200 IU/mL at the point of treatment cessation - which could explain the study's high rate of disease relapse. In contrast, in another study of retrospective nature which found a lower relapse rate of 66%, 27.6% of patients had HBsAg levels <200 IU/mL at treatment cessation.
Although HBsAg seroclearance is the established treatment endpoint of CHB, patients would still have low amounts of intrahepatic HBV DNA. Moreover, HBsAg seroclearance via a conventional assay (HBsAg <0.05 IU/mL) does not mean absence of serum HBsAg, but merely serum HBsAg at undetectable levels. Using more sensitive assays, detectable HBsAg can be found in 29.1% to 53.2% of such patients. So despite the continued presence of HBV, the off-treatment durability of HBsAg seroclearance would suggest for treatment cessation, viral replication and viral protein production do not need to be totally absent, but at sufficiently low amounts to permit successful host immune control.
Hence, a relevant clinical question would be:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years.
- •HBsAg-positive patients on entecavir or tenofovir therapy
- •Fulfill the European Association for the Study of the Liver of NA cessation:
- •HBeAg-positive at NA commencement: stable HBeAg seroconversion and undetectable HBV DNA and completed 12 months of consolidation therapy
- •HBeAg-negative: Virological suppression with undetectable HBV DNA (<10 IU/mL) for more than 3 years.
- •Normal levels of serum alanine aminotransferase (ALT) documented on two separate occasions 6 months apart.
- •Serum HBsAg between <200 IU/mL prior to NA cessation.
- •(At study commencement, in HBeAg-negative patients, we applied the APASL 2016 suggestion for at least 2 years with undetectable HBV DNA documented on three separate occasions 6 months apart. Upon publication of the EASL guidelines in 2017, we further scrutinized the inclusion criteria for HBeAg-negative patients to be viriological suppression with undetectable HBV DNA for more than 3 years. All recruited HBeAg-negative participants prior to the release of the EASL 2017 guidelines fulfilled the updated criteria).
排除标准
- •Concomitant liver diseases including chronic hepatitis C and D infection, Wilson's disease, autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis.
- •Significant alcohol intake (>30 grams per day).
- •Prior history of hepatocellular carcinoma (HCC) or any radiologic suspicion of HCC.
- •Decompensated liver disease (defined as Child's B or C cirrhosis), or presence of cirrhotic complications, including variceal disease, ascites, or history of hepatic encephalopathy.
- •Patient previously or currently on interferon therapy.
- •History of immunosuppressive therapy or organ transplantation.
- •Serious medical illness or malignancy.
- •Patient previously or currently prescribed interferon therapy.
- •Confirmed or radiologic suspicion of HCC.
- •Serious medical illness or malignancy. -
结局指标
主要结局
Off-treatment durability
时间窗: up to 48 weeks
HBV DNA \<2,000 IU/mL
次要结局
- HBsAg seroclearance (<0.05 IU/mL)(up to 48 weeks)
- HBV DNA <200 IU/mL(up to 48 weeks)
- HBV DNA <20 IU/mL(up to 48 weeks)
研究者
Wai-Kay Seto
Clinical Assistant Professor
The University of Hong Kong