Yuen Man-Fung, Wong Danny Ka-Ho, Schluep Thomas, Lai Ching-Lung, Ferrari Carlo, Locarnini Stephen, Lo Regina Cheuk-Lam, Gish Robert G, Hamilton James, Wooddell Christine I, Mak Lung Yi, Given Bruce D
Department of Medicine, The University of Hong Kong, Hong Kong, China
Department of Medicine, The University of Hong Kong, Hong Kong, China.
Gut. 2022 Apr;71(4):789-797. doi: 10.1136/gutjnl-2020-323445. Epub 2021 Mar 12.
We examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520.
The present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4-9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured.
All patients had 28.9-30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of -1.7 and -3.5 log IU/mL >30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with 10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL.
MD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable.
NCT02065336.
我们研究了慢性乙型肝炎病毒（HBV）患者在多次剂量（MD）ARC-520治疗期间及治疗结束后的血清学、病毒学（血清和肝脏中）及组织学特征。
本1b期研究是我们之前研究中接受单剂量ARC-520患者的多剂量、开放标签扩展队列。8名患者接受了4 - 9次每4周一次的MD ARC-520和恩替卡韦治疗。对6名患者进行了肝活检。检测了肝内和血清中的HBV DNA、HBV RNA及病毒抗原。
所有患者在最后一次MD治疗后均有28.9 - 30.4个月的随访。3例乙肝e抗原（HBeAg）阳性患者的乙肝表面抗原（HBsAg）、HBeAg、乙肝核心相关抗原及HBV RNA均显著降低，其中2例发生HBeAg血清学转换。另有1例实现HBsAg血清学转换（抗-HBs水平为25.1 IU/L），其余2例在MD治疗30多个月后HBsAg降低了-1.7和-3.5 log IU/mL。在5例HBeAg阴性患者中，4例在MD治疗结束29个月后HBsAg有适度降低，1例实现HBsAg血清学转换（抗-HBs水平为152.5 IU/L）且肝脏HBsAg染色阴性。该患者在HBsAg血清学转换12个月后成功停用恩替卡韦。3例患者在HBsAg降低之前出现了与时间相关的丙氨酸氨基转移酶升高，提示免疫激活。6例活检患者的HBcAg染色均为阴性。2例肝细胞HBsAg阳性染色率为10%的患者，其血清HBsAg水平相应较低，分别为1.5和11.5 IU/mL。
MD ARC-520治疗实现了病毒抗原和HBV RNA的持续且显著降低。HBsAg血清清除是可以实现的。
NCT02065336。
