Diakonissenkrankenhaus und Paulinenhilfe gGmbH, Diakonie-Klinikum Stuttgart, Rosenbergstraße 38, 70176, Stuttgart, Germany.
Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
BMC Infect Dis. 2019 May 8;19(1):388. doi: 10.1186/s12879-019-4016-1.
The compound letermovir (LMV) has recently been approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. LMV inhibits CMV replication by binding to the viral terminase complex. However, first cases of clinical LMV resistance have been occurred. Here we report a fast breakthrough of resistant cytomegalovirus during secondary LMV prophylaxis in a hematopoietic-cell transplant recipient.
A 44-year-old male patient with acute myeloid leukemia (AML) experienced a CMV-reactivation within the first 4 weeks of allogeneic hematopoietic-cell transplantation. Administration of LMV was initiated at day + 34. Due to increasing viral loads, LMV treatment was discontinued after 8 days. The patient was then administered with valganciclovir (valGCV) until viral DNA was undetectable. Due to neutropenia, valGCV treatment was switched to LMV secondary prophylaxis. For 4 weeks, the patient maintain virologic suppression. Then, CMV viral loads increased with a fast kinetic. Genotypic testing of the viral polymerase UL54, the kinase UL97 as well as the viral terminase UL56 and UL89 revealed the mutation C325Y in UL56, which is associated with the high level LMV resistance.
It is known that Letermovir is approved for prophylactic purposes. However, it may be used for some patients with CMV infection who either have failed prior therapies or are unable to tolerate other anti-CMV compounds. Particularly, the administration of LMV should be avoided in patients with detectable viral loads. When this is not possible, viral load must be routinely monitored along with UL56 genotyping. Furthermore, LMV administration at high virus loads may foster the rapid selection of resistant CMV mutants.
复合制剂乐韦玛（LMV）最近已被批准用于预防异基因造血干细胞移植后 CMV 血清阳性的成人 CMV 感染和疾病。LMV 通过与病毒端酶复合物结合来抑制 CMV 复制。然而，已出现首例临床 LMV 耐药病例。在此，我们报告了一名造血细胞移植受者在进行 LMV 二级预防时，快速出现耐药 CMV 的情况。
一名 44 岁男性，患有急性髓系白血病（AML），在异基因造血细胞移植后的前 4 周内发生 CMV 激活。在第+34 天开始给予 LMV。由于病毒载量增加，在 8 天后停止 LMV 治疗。随后，患者给予缬更昔洛韦（valGCV）治疗，直至病毒 DNA 不可检测。由于中性粒细胞减少，将 valGCV 治疗转换为 LMV 二级预防。在接下来的 4 周内，患者的病毒学抑制得以维持。随后，CMV 病毒载量增加，呈快速动力学。对病毒聚合酶 UL54、激酶 UL97 以及病毒端酶 UL56 和 UL89 的基因分型检测显示 UL56 中的突变 C325Y，该突变与高水平的 LMV 耐药相关。
已知 Lermovir 被批准用于预防目的。然而，对于那些先前治疗失败或无法耐受其他抗 CMV 化合物的 CMV 感染患者，可能会使用它。特别是在存在可检测病毒载量的患者中应避免使用 LMV。如果无法避免，应常规监测病毒载量并进行 UL56 基因分型。此外，在高病毒载量时给予 LMV 可能会促进耐药 CMV 突变体的快速选择。
