Meissner Eric G, McLaughlin Mary, Matthews Lindsay, Gharib Ahmed M, Wood Bradford J, Levy Elliot, Sinkus Ralph, Virtaneva Kimmo, Sturdevant Dan, Martens Craig, Porcella Stephen F, Goodman Zachary D, Kanwar Bittoo, Myers Robert P, Subramanian Mani, Hadigan Colleen, Masur Henry, Kleiner David E, Heller Theo, Kottilil Shyam, Kovacs Joseph A, Morse Caryn G
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
Liver Int. 2016 Dec;36(12):1783-1792. doi: 10.1111/liv.13177. Epub 2016 Jul 6.
Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed.
The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease.
Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis.
Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-β3 and IL-10 pathways with treatment.
In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-β3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.
慢性肝损伤可导致纤维化，这种纤维化可能在数年内进展为终末期肝病。最有效的抗纤维化疗法是治疗潜在疾病，然而，若无法进行该治疗，则需要采取干预措施来逆转或减缓纤维化进程。
本研究旨在探讨西马珠单抗（一种针对赖氨酰氧化酶样2（LOXL2）酶的单克隆抗体）在丙型肝炎病毒（HCV）、人类免疫缺陷病毒（HIV）或HCV - HIV合并感染且患有晚期肝病的受试者中的安全性和耐受性。
18名晚期肝纤维化受试者每2周静脉注射700 mg西马珠单抗，共治疗22周。在筛查时和治疗结束时进行经颈静脉肝活检，以测量肝静脉压力梯度（HVPG）并对纤维化进行分期。
治疗耐受性良好，无因不良事件而停药的情况。治疗后，HVPG或肝活检纤维化评分未见显著变化。使用配对的治疗前和治疗后肝活检及血清样本进行的探索性转录和蛋白质谱分析表明，治疗后转化生长因子-β3（TGF-β3）和白细胞介素-10（IL-10）通路上调。
在这项开放标签的先导性临床试验中，西马珠单抗治疗在患有晚期肝病的HCV和HIV感染受试者中耐受性良好。西马珠单抗治疗期间对TGF-β3和IL-10通路的假定调节值得在未来试验中进一步研究。
