Hepatocellular carcinoma (HCC) has long been recognized as a complication in people with chronic liver disease, particularly those with cirrhosis. Two gene therapies for haemophilia A and B recently approved in Europe and the US utilize adeno‐associated virus (AAV) vectors designed to target hepatocytes. A number of other AAV gene therapies are undergoing clinical investigation for both liver and extrahepatic diseases, many of which likely transduce hepatocytes as well. Although AAV vectors predominantly persist in episomal forms, concerns about insertional mutagenesis have arisen due to findings in pre‐clinical models and in a small subset of human HCC cases featuring wild‐type AAV integrations in proximity to potential oncogenes. Despite the absence of any causative link between AAV vector therapy and HCC in approved extrahepatic gene therapies or haemophilia gene therapy trials, the package inserts for the recently approved haemophilia gene therapies advise HCC screening in subsets of individuals with additional risk factors. In this review, we discuss HCC risk factors, compare various screening modalities, discuss optimal screening intervals, and consider when to initiate and possibly discontinue screening. At this early point in the evolution of gene therapy, we lack sufficient data to make evidence‐based recommendations on HCC screening. While AAV vectors may eventually be shown to be unassociated with risk of HCC, we presently favour a cautious approach that entails regular surveillance until such time as it is hopefully proven to be unnecessary.

中文翻译：

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肝癌基因治疗后监测——监测的程度和频率？

肝细胞癌（HCC）长期以来被认为是慢性肝病患者，特别是肝硬化患者的并发症。最近在欧洲和美国批准的两种针对血友病 A 和 B 的基因疗法利用旨在靶向肝细胞的腺相关病毒 (AAV) 载体。许多其他 AAV 基因疗法正在针对肝脏和肝外疾病进行临床研究，其中许多也可能转导肝细胞。尽管 AAV 载体主要以附加型形式存在，但由于临床前模型和一小部分人类 HCC 病例中的发现，其中野生型 AAV 与潜在癌基因整合，引起了对插入突变的担忧。尽管在批准的肝外基因治疗或血友病基因治疗试验中，AAV载体治疗与HCC之间不存在任何因果关系，但最近批准的血友病基因治疗的说明书建议对具有其他危险因素的个体亚群进行HCC筛查。在这篇综述中，我们讨论了 HCC 风险因素，比较了各种筛查方式，讨论了最佳筛查间隔，并考虑何时开始和可能停止筛查。在基因治疗发展的早期阶段，我们缺乏足够的数据来对 HCC 筛查提出基于证据的建议。虽然 AAV 载体最终可能被证明与 HCC 风险无关，但我们目前倾向于采取谨慎的方法，即定期监测，直到有希望证明没有必要为止。