Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by 64%-156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non-alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non-alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non-alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology-specific pathways and/or at more general aetiology-agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non-alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non-alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patients.

中文翻译：

---

未来非酒精性脂肪性肝炎肝硬化临床试验的结果和潜在替代标志物

非酒精性脂肪性肝炎已成为主要的公共卫生问题，预计到 2030 年非酒精性脂肪性肝炎肝硬化的负担将增加 64%-156%。非酒精性脂肪性肝炎的治疗。在本文中，我们回顾了非酒精性脂肪性肝炎肝硬化患者药物开发的主要挑战，并描述了对肝硬化临床和病理生理学细微差别的理解进展带来的机遇。非酒精性脂肪性肝炎肝硬化的治疗方案设计将根据特定的肝硬化亚期（代偿期与失代偿期）和特定的治疗机制基础而有所不同，旨在改善特定病因的途径和/或更一般的病因不可知过程。为了为临床试验和非酒精性脂肪性肝炎肝硬化个体患者选择适当的估计值和治疗策略，了解对整个潜在结果范围的概率期望（植根于每个特定亚阶段的不同机制驱动因素）至关重要。最后，我们总结了非酒精性脂肪性肝炎肝硬化临床试验设计中的主要缺陷和不确定性，并讨论了在这些患者的试验和实践中使用的潜在生物标志物。根植于每个特定亚阶段的不同机制驱动因素，对于为临床试验和非酒精性脂肪性肝炎肝硬化个体患者选择足够的估计和治疗策略至关重要。最后，我们总结了非酒精性脂肪性肝炎肝硬化临床试验设计中的主要缺陷和不确定性，并讨论了在这些患者的试验和实践中使用的潜在生物标志物。根植于每个特定亚阶段的不同机制驱动因素，对于为临床试验和非酒精性脂肪性肝炎肝硬化个体患者选择足够的估计和治疗策略至关重要。最后，我们总结了非酒精性脂肪性肝炎肝硬化临床试验设计中的主要缺陷和不确定性，并讨论了在这些患者的试验和实践中使用的潜在生物标志物。