Relative frequency of cytomegalovirus UL56 gene mutations detected in genotypic letermovir resistance testing

Chou, Sunwen; Kleiboeker, Steven B.

doi:10.1016/j.antiviral.2022.105422

Cited by 11 publications

(11 citation statements)

References 18 publications

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“…LMV-resistant CMV mutants arising in vivo, during LMV treatment, have been reported. [93][94][95][96][97][98][99][100][101]104 Data from the Phase II and III LMV prophylaxis clinical trials revealed that, overall, the emergence incidence of LMV resistance was very low. Genotyping results showed that two mutations in pUL56, V236M, and C325W, known to be associated with high LMV-resistance levels, were predominantly selected in vivo.…”

Section: Lmv Resistancementioning

confidence: 99%

“…Most of these mutations map within the highly conserved region (between codons 229 and 369) of the UL56 gene, and less frequently within UL89 and UL51 (Table 3). 88–92,102 Single mutations leading to LMV resistance were individually characterized by recombinant phenotyping, showing different degrees of resistance, ranging from <4 to >3000‐fold changes in EC 50 (Supporting Information: Table ) 88–93,95,98–100,103 . Of note, viral replicative fitness was preserved in most mutants, as demonstrated by viral growth curves 89–92 .…”

Section: Lmv Resistancementioning

confidence: 99%

“…LMV‐resistant CMV mutants arising in vivo, during LMV treatment, have been reported 93–101,104 . Data from the Phase II and III LMV prophylaxis clinical trials revealed that, overall, the emergence incidence of LMV resistance was very low.…”

Section: Lmv Resistancementioning

confidence: 99%

“…Furthermore, additional substitutions potentially associated with LMV resistance were detected both in genes UL56 ( n = 36) and UL89 ( n = 23), although their clinical significance remained undetermined. Chou and Kleiboeker 99 used Sanger sequencing to analyze a total of 1165 anonymized samples from patients seemingly displaying a lack of response to LMV. They found 12 known substitutions in pUL56 (N232Y, V231L, V236M, R246C, L257F, C325Y/F/W/R, R369S/G/T) along with 24 novel amino acid changes.…”

Section: Lmv Resistancementioning

confidence: 99%

See 3 more Smart Citations

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Solano

Giménez

Albert

et al. 2023

Journal of Medical Virology

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On November 7, 2017, the US Food and Drug Administration approved the use of letermovir (LMV) for prophylaxis of cytomegalovirus (CMV) infection in adult CMV‐seropositive allogeneic stem cell transplant recipients. After 6 years of use, a large body of real‐world experience has been accumulated that validates the Phase III clinical trial results, in which LMV was shown to significantly reduce the risk of clinically significant CMV infection—defined as CMV end‐organ disease or CMV DNAemia requiring pre‐emptive antiviral therapy (PET)—and increase survival up to Week 24 after treatment inception. Notwithstanding, several issues still need to be settled, thus further investigation is required. First, since viral DNA may accumulate as a result of LMV‐driven abortive CMV infection, what is the optimal viral load threshold in the blood that would prompt LMV prophylaxis interruption and PET inception? Should this be adapted to the patient's risk? Second, what is the impact of LMV prophylaxis on the reconstitution of functional CMV‐specific T‐cell responses? Would it be a wise approach to individually tailor the duration of LMV treatment according to the number of peripheral blood CMV‐specific T cells at the end of regular prophylaxis? Third, how frequently do LMV‐resistant strains arise while patients are on LMV prophylaxis and how could this be minimized? Here, we discuss the literature addressing these topics.

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Section: Lmv Resistancementioning

confidence: 99%

Section: Lmv Resistancementioning

confidence: 99%

Section: Lmv Resistancementioning

confidence: 99%

Section: Lmv Resistancementioning

confidence: 99%

See 2 more Smart Citations

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Solano

Giménez

Albert

et al. 2023

Journal of Medical Virology

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“…There is concern about the ease in which in vitro resistance develops for LTV. 6 Cohort studies are summarised in Table 1. [7][8][9][10][11][12] They show LTV is often effective in controlling viremia particularly when commenced at modest plasma viral loads, [7][8][9][10][11][12] though failure and relapse have been reported often with associated genetic resistance mutations.…”

Section: Introductionmentioning

confidence: 99%

Letermovir for pre‐emptive cytomegalovirus therapy after allogeneic hematopoietic cell transplantation

Kaur,

Purtill,

Cooney

et al. 2023

Transplant Infectious Dis

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BackgroundCytomegalovirus (CMV) is a common cause of morbidity after allogeneic haematopoietic cell transplantation (alloHCT). Pre‐emptive therapy (PET) with valganciclovir (VGC) is associated with haematological toxicity.MethodsWe included alloHCT patients from 2018 to 2021 where letermovir (LTV) was used for CMV PET because of cytopenias.ResultsTen patients were included. Six received VGC prior to LTV. VGC was commenced at median d42, given for median 40 days. LTV was commenced at median d90, given for median 54 days. At commencement of antiviral, CMV viral load was higher for VGC at 3.7 log10 IU/mL, compared to LTV at 2.9 log10 IU/mL. Viral load reduction occurred at 0.18 log10 IU/mL per week for VGC, compared to 0.17 log10 IU/mL per week for LTV. There was no clinically significant CMV viremia after stopping LTV. Cytopenias improved on LTV.ConclusionLTV was effective in controlling CMV viremia when it was given at a lower starting CMV viral load and later post alloHCT than VGC. Further study is required of LTV as upfront PET following alloHCT. image

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Prevalence of cytomegalovirus antiviral drug resistance in transplant recipients

Kleiboeker

2023

Antiviral Research

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Relative frequency of cytomegalovirus UL56 gene mutations detected in genotypic letermovir resistance testing

Cited by 11 publications

References 18 publications

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

Letermovir for pre‐emptive cytomegalovirus therapy after allogeneic hematopoietic cell transplantation

Prevalence of cytomegalovirus antiviral drug resistance in transplant recipients

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