Lynch Katie, Märtson Anne-Grete
Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, The Netherlands.
Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, The Netherlands.
Int J Antimicrob Agents. 2025 Sep;66(3):107537. doi: 10.1016/j.ijantimicag.2025.107537. Epub 2025 May 13.
Human cytomegalovirus (CMV) is a widespread pathogen which remains asymptomatic in healthy individuals. However, CMV disease can be life-threatening in immunocompromised individuals, particularly in transplant patients. This disease is routinely managed by antiviral agents, including (val)ganciclovir, foscarnet, cidofovir, letermovir, and maribavir. Subtherapeutic antiviral drug exposure is a common occurrence and can lead to drug-resistant CMV development, a key contributor to disease progression. Breakthrough CMV often results in graft loss, end-organ failure, or death. By optimizing intracellular exposure levels of antiviral therapies, it may be possible to improve patient outcomes. Therefore, this review aims to explore the relationship between antiviral exposure and the development of drug-resistant CMV.
A literature search was conducted in Pubmed database including keywords "cytomegalovirus", "resistance", "pharmacokinetics", "pharmacodynamics", "drug exposure", "ganciclovir", "foscarnet", "maribavir", "letermovir", "cidofovir".
There are several challenges to achieving optimal concentrations of current and novel CMV therapies. Narrow therapeutic indices and toxicity profiles of current CMV therapeutics contribute to their subtherapeutic exposure and, hence, suboptimal clinical outcomes. Alternately, novel antivirals such as letermovir and maribavir offer improved pharmacokinetic profiles. However, these agents are associated with rapid resistance development. Overall, a distinct gap exists in understanding the relationship between antiviral exposure and resistance development. As a result, current clinical markers used to predict clinical efficacy lack reliability. In future, resistance development in relation to drug exposure should be included as a clinical trial endpoint to gain understanding of exposure-resistance relationships.
With solid knowledge of exposure-resistance relationships, more predictive in vitro and in vivo markers of clinical efficacy can be identified. PK/PD targets that account for free EC50/EC90 and viral load should be defined to improve clinical outcomes and reduce the risk for emergence of R/R CMV.
人巨细胞病毒（CMV）是一种广泛传播的病原体，在健康个体中通常无症状。然而，CMV疾病在免疫功能低下的个体中可能危及生命，尤其是在移植患者中。这种疾病通常通过抗病毒药物进行治疗，包括（缬）更昔洛韦、膦甲酸钠、西多福韦、来特莫韦和马立巴韦。抗病毒药物暴露不足是常见现象，可导致耐药CMV的产生，这是疾病进展的一个关键因素。突破性CMV感染常导致移植物丢失、终末器官衰竭或死亡。通过优化抗病毒治疗的细胞内暴露水平，有可能改善患者预后。因此，本综述旨在探讨抗病毒药物暴露与耐药CMV产生之间的关系。
在PubMed数据库中进行文献检索，关键词包括“巨细胞病毒”、“耐药性”、“药代动力学”、“药效学”、“药物暴露”、“更昔洛韦”、“膦甲酸钠”、“马立巴韦”、“来特莫韦”、“西多福韦”。
实现当前和新型CMV治疗的最佳浓度存在若干挑战。当前CMV治疗药物狭窄的治疗指数和毒性特征导致其暴露不足，从而导致临床疗效欠佳。相比之下，来特莫韦和马立巴韦等新型抗病毒药物具有更好的药代动力学特征。然而，这些药物与耐药性的快速产生有关。总体而言，在理解抗病毒药物暴露与耐药性产生之间的关系方面存在明显差距。因此，目前用于预测临床疗效的临床标志物缺乏可靠性。未来，应将与药物暴露相关的耐药性产生纳入临床试验终点，以了解暴露-耐药关系。
有了对暴露-耐药关系的扎实了解，就可以确定更具预测性的体外和体内临床疗效标志物。应定义考虑游离EC50/EC90和病毒载量的药代动力学/药效学靶点，以改善临床结局并降低R/R CMV出现的风险。
