Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient

Abstract

Background 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. Case presentation 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. Conclusion 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.

Emergence and Persistence of Letermovir-Resistant Cytomegalovirus in a Patient With Primary Immunodeficiency

“…There are an increasing number of reports of acquired letermovir resistance. Among HSCT recipients, UL56 mutations V236M [1, 3], C325W [3], C325F [10], and C325Y [11, 12] are reported; in solid organ transplants patients, the C325Y [9, 13] and C325F [9] are reported. In this case, the UL56 mutation C325Y emerged after 17 weeks of letermovir prophylaxis.…”

Suppression of CMV Infection with Letermovir in a Kidney Transplant Patient

“…Unfortunately, pp65 antigenemia was also reported as an unreliable indicator of response to letermovir treatment in a case series of patients with drug-resistant CMV retinitis after solid organ transplantation [ 6 ] . Laboratory assays to distinguish between active viral particles and inactive leftovers are not yet available, but they will be important for the therapeutic use of letermovir, because development of resistance to letermovir due to mutations in the UL56 gene may occur and lead to treatment failure [ 7 ] . In our patient, we excluded all known resistance mutations by sequencing.…”

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

“…Notably, in the phase 3 prophylaxis study, 48 patients with detectable CMV viremia (viral load in all cases < 1000 copies/mL) prior to randomization received letermovir, thereby essentially receiving letermovir as preemptive therapy; of those, approximately 33% had clinically significant CMV infection by week 14 [22••, 39]. Additionally, concerns exist about the relatively low barrier to resistance in vitro, and emerging reports describe the development of resistance when used in the setting of active infection [40][41][42][43]. An ongoing clinical trial (NCT03728426) will evaluate the safety and efficacy of letermovir as salvage treatment of CMV infection or disease.…”