在一项来特莫韦与缬更昔洛韦预防用药的3期试验中，肾移植受者的巨细胞病毒抗病毒耐药性
Cytomegalovirus Antiviral Resistance Among Kidney Transplant Recipients in a Phase 3 Trial of Letermovir vs Valganciclovir Prophylaxis.
作者信息
Strizki Julie M, Diamond Tracy L, Teal Valerie L, Gilbert Christopher L, Wang Weiwen, Stauffer Nicole, Haber Barbara A
机构信息
Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, USA.
出版信息
J Infect Dis. 2024 Dec 16;230(6):e1287-e1298. doi: 10.1093/infdis/jiae287.
BACKGROUND
In a phase 3 trial, letermovir was noninferior to valganciclovir for cytomegalovirus (CMV) disease prophylaxis in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive. Genotypic antiviral resistance and CMV glycoprotein B (gB) genotype are reported.
METHODS
Plasma samples with detectable CMV DNA were sequenced for the presence of known letermovir and valganciclovir resistance-associated amino acid substitutions (RASs) encoded by CMV gene regions (UL51, UL54, UL56, UL89, UL97) and prevalence of gB (UL55) genotypes (gB1-gB5).
RESULTS
Among participants, 84 of 292 (letermovir) and 93 of 297 (valganciclovir) had evaluable data for ≥1 gene target. Letermovir RASs were not detected in participants who received letermovir prophylaxis; however, 3 had valganciclovir RASs (pUL97). Twelve participants who received valganciclovir prophylaxis had valganciclovir RASs (pUL54, pUL97), and 1 who did not receive letermovir during the trial had letermovir RASs (pUL56). All but 1 participant responded to valganciclovir treatment irrespective of breakthrough CMV DNAemia or frequency of RASs. gB1 was the most frequent genotype across all participants and subgroups.
CONCLUSIONS
Letermovir RASs were not detected with letermovir prophylaxis, supporting a low risk for development of resistance in kidney transplant recipients who were CMV-seronegative and received kidneys from donors who were CMV-seropositive.
CLINICAL TRIALS REGISTRATION
ClinicalTrials.gov, NCT03443869; EudraCT, 2017-001055-30.
背景
在一项3期试验中，对于巨细胞病毒（CMV）血清学阴性且接受来自CMV血清学阳性供者肾脏的肾移植受者，来特莫韦在预防CMV疾病方面不劣于缬更昔洛韦。报告了基因型抗病毒耐药性和CMV糖蛋白B（gB）基因型。
方法
对检测到CMV DNA的血浆样本进行测序，以确定CMV基因区域（UL51、UL54、UL56、UL89、UL97）编码的已知来特莫韦和缬更昔洛韦耐药相关氨基酸替代（RASs）的存在情况以及gB（UL55）基因型（gB1 - gB5）的流行率。
结果
在参与者中，292例接受来特莫韦治疗者中有84例、297例接受缬更昔洛韦治疗者中有93例有≥1个基因靶点的可评估数据。接受来特莫韦预防的参与者中未检测到来特莫韦RASs；然而，有3例有缬更昔洛韦RASs（pUL97）。12例接受缬更昔洛韦预防的参与者有缬更昔洛韦RASs（pUL54、pUL97），1例在试验期间未接受来特莫韦治疗的参与者有来特莫韦RASs（pUL56）。除1例参与者外，所有参与者对缬更昔洛韦治疗均有反应，无论是否出现突破性CMV DNA血症或RASs频率如何。gB1是所有参与者和亚组中最常见的基因型。
结论
来特莫韦预防未检测到来特莫韦RASs，这支持了对于CMV血清学阴性且接受来自CMV血清学阳性供者肾脏的肾移植受者，耐药发生风险较低。
临床试验注册
ClinicalTrials.gov，NCT03443869；EudraCT，2017 - 001055 - 30。
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