|
 
- 现金
- 17064 元
- 精华
- 12
- 帖子
- 9399
- 注册时间
- 2007-6-26
- 最后登录
- 2017-11-25
|
Program abstract
Background and Aims: Functional cure in chronic hepatitis B requires HBV DNA negativity, HBsAg loss and anti-HBs seroconversion. ARC-520 RNAi drug therapy targets cccDNA derived mRNA, including the full-length HBsAg transcript. Using a 19plex anti-HBs panel to map HBsAg epitopes, we have developed a predictive algorithm of an HBsAg clearance profile in patients undergoing HBsAg loss during tenofovir therapy, defined as reduced recognition at loop 1 and loop 2 HBsAg "a" determinant epitopes. Complimentary to this, we have developed assays to detect co-existing complexed anti-HBs (with HBsAg), and analysed the ARC-520 cohorts with the aim of evaluating the impact of RNAi therapy on HBsAg loss, the identification of an HBsAg clearance profile and the development of co-existing anti-HBs.
Methods: Analysis of HBsAg clearance profiles and concomitant anti-HBs was performed for 40 ARC-520 study HBeAg-negative (n=32) and HBeAg-positive (n=8) patients (under code: 30 ARC-520; 10 placebo), from pre-treatment to day 85, and then compared to the quantitative HBsAg responses. All were entecavir suppressed prior to (mean 5 years) and during ARC-520 therapy.
Results: ARC-520 therapy resulted in a dose response maximum decline in HBsAg of 0.3 log IU/ml observed at 1 mg/kg vs 0.5 log at 4 mg/kg in the HBeAg-negative patients (n=24), and 0.7 log at 4mg/kg in HBeAg-positive (n=6) patients. Analysis of the treated group identified that an HBsAg clearance profile preceded and/or coincided with HBsAg decline. A significant association between HBsAg clearance profile development and ARC-520 treatment emerged at week1 (11/30, p=0.038), and strengthened at week2 (12/30, p-value 0.019) and week3 (16/30, p= 0.003). A late HBsAg response at week6 was associated with development of an HBsAg clearance profile (14/30, p= 0.007). Clearance profiles were not observed in the placebo group. Complexed anti-HBs development coincided with HBsAg decline and HBsAg clearance profile detection.
Conclusions: Development of the HBsAg clearance profile was predictive of HBsAg decline due to ARC-520 therapy, with an increasing significant association from week1-3 coinciding with or preceding the HBsAg decline, and the detection of complexed anti-HBs, reflective of recovery of the anti-HBs response. Further longitudinal and multiple dose studies will assess the magnitude and persistence of HBsAg loss on ARC-520 therapy, in the context of the predictive potential of HBsAg clearance profile and anti-HBs response. |
|
发表于 2016-4-27 07:38
