Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospitalgrid.415193.b, Sydney, New South Wales, Australia.
School of Medical Sciences, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia.
Microbiol Spectr. 2022 Jun 29;10(3):e0268421. doi: 10.1128/spectrum.02684-21. Epub 2022 Jun 6.
Cytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir exposure, cytomegalovirus infection, and genotypic resistance markers during the first year posttransplant. Ganciclovir plasma concentrations were measured using mass spectrometry. Population pharmacokinetics was used to determine individual ganciclovir exposure and to evaluate the ability of manufacturer dosing guidelines to meet therapeutic target daily area under the curve (AUC) of 40 to 50 μg·h/mL. Full-length and were assessed using high-throughput sequencing in cytomegalovirus DNA-positive patient specimens. Valganciclovir doses administered to recipients with creatinine clearance of <40 mL/min were higher than specified by guidelines, and they were lower for recipients with creatinine clearance of ≥40 mL/min. The mean ganciclovir AUC was 33 ± 13 μg·h/mL, and 82% of subjects did not attain the therapeutic target. Pharmacokinetic simulations showed that the guidelines similarly could not attain the therapeutic target in 79% of individuals. Cytomegalovirus breakthrough occurred in 6% (3/50) of recipients, while 12% (6/50) developed late-onset infection. The mean AUCs of recipients with ( = 3) and without ( = 47) infection were not significantly different (0.528). However, one recipient with an AUC of 20 μg·h/mL acquired two ganciclovir resistance mutations. Current prophylaxis guidelines resulted in subtherapeutic ganciclovir exposure in several study recipients, including the emergence of resistance genotypes. This study examined the pharmacokinetics and viral genomic data from a prospective cohort of kidney transplant recipients undergoing valganciclovir prophylaxis for cytomegalovirus (CMV) prevention. We showed for the first time using high-throughput sequencing the detection of ganciclovir resistance mutations in breakthrough CMV infection during subtherapeutic plasma ganciclovir as indicated by the pharmacokinetic parameter daily area under the curve (AUC). In addition, we found that current valganciclovir dosing guidelines for CMV prophylaxis are predicted to attain therapeutic targets in only 21% of recipients, which is consistent with previous pharmacokinetic studies. The novel findings of resistance mutations during subtherapeutic ganciclovir exposure presented here can inform future studies investigating the dynamics of drug selection pressure and the emergence of resistance mutations .
巨细胞病毒感染在抗病毒预防期间发生在移植受者中，尽管根据肾功能制定了个体化方案。在 2016 年至 2019 年期间，评估了 50 名接受肾移植的患者，以评估伐昔洛韦给药、更昔洛韦暴露、巨细胞病毒感染和移植后第一年的基因型耐药标志物。使用质谱法测量更昔洛韦的血浆浓度。群体药代动力学用于确定个体更昔洛韦暴露，并评估制造商剂量指南在达到治疗目标每日 AUC（40 至 50μg·h/mL）方面的能力。使用高通量测序在巨细胞病毒 DNA 阳性患者标本中评估全长和。对于肌酐清除率<40 mL/min 的受者，给予的伐昔洛韦剂量高于指南规定的剂量，而对于肌酐清除率≥40 mL/min 的受者，给予的剂量较低。更昔洛韦 AUC 的平均值为 33±13μg·h/mL，82%的受试者未达到治疗目标。药代动力学模拟表明，在 79%的个体中，该指南同样无法达到治疗目标。6%（3/50）的受者发生了巨细胞病毒突破，12%（6/50）发生了迟发性感染。有（ = 3）和没有（ = 47）感染的受者的 AUC 平均值没有显着差异（0.528）。然而，一名 AUC 为 20μg·h/mL 的受者获得了两种更昔洛韦耐药突变。当前的预防指南导致了几项研究受者的更昔洛韦暴露低于治疗范围，包括耐药基因型的出现。 本研究使用高通量测序技术对接受缬更昔洛韦预防巨细胞病毒（CMV）预防的前瞻性肾移植受者队列的药代动力学和病毒基因组数据进行了检测。我们首次表明，在低于治疗范围的血浆更昔洛韦水平下，通过药代动力学参数（每日 AUC）检测到耐药突变的突破性 CMV 感染。此外，我们发现，当前的更昔洛韦预防 CMV 感染的剂量指南预计仅能使 21%的受者达到治疗目标，这与之前的药代动力学研究一致。本研究中首次发现的耐药突变，在低于治疗范围的更昔洛韦暴露下，可能会影响未来对药物选择压力和耐药突变出现的动态的研究。
