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In-depth genomic analyses identified novel letermovir resistance-associated substitutions in the cytomegalovirus UL56 and UL89 gene products.
Komatsu, Takashi E; Hodowanec, Aimee C; Colberg-Poley, Anamaris M; Pikis, Andreas; Singer, Mary E; O'Rear, Julian J; Donaldson, Eric F.
Afiliación
  • Komatsu TE; Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, USA. Electronic address: takashi.komatsu@fda.hhs.gov.
  • Hodowanec AC; Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, USA. Electronic address: aimee.hodowanec@fda.hhs.gov.
  • Colberg-Poley AM; Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, USA.
  • Pikis A; Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, USA.
  • Singer ME; Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, USA.
  • O'Rear JJ; Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, USA.
  • Donaldson EF; Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, USA. Electronic address: eric.donaldson@fda.hhs.gov.
Antiviral Res ; 169: 104549, 2019 09.
Article en En | MEDLINE | ID: mdl-31279814
Letermovir is a human cytomegalovirus (HCMV) terminase inhibitor recently approved in the United States for prophylaxis of HCMV infection or disease in adult HCMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant. In the registrational trial, the rate of clinically significant HCMV infection, defined as the development of HCMV DNAemia leading to preemptive antiviral therapy or the diagnosis of HCMV end-organ disease, through 24 weeks post-transplant, was significantly lower among subjects who received letermovir prophylaxis through 14 weeks post-transplant compared to those who received placebo. We performed independent analyses of the HCMV nucleotide sequencing data generated by next-generation sequencing from this phase 3 registrational trial of letermovir to identify viral genetic characteristics associated with virologic failure during and following letermovir prophylaxis. The pUL56 substitutions V236M, E237G, and C325W, identified at previously known resistance-associated positions, were detected in the virus of subjects who were treated with letermovir and failed letermovir prophylaxis. Several additional substitutions were detected in pUL56 and pUL89, and further characterization is needed to determine if any of these substitutions are clinically relevant. The analyses reported herein were conducted to confirm sponsor-reported drug-resistance pathways, to assess the frequency of resistance, and to better understand the risk of prophylaxis failures and treatment-emergent drug resistance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Proteínas Estructurales Virales / Genómica / Citomegalovirus / Farmacorresistencia Viral Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Antiviral Res Año: 2019 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Virales / Proteínas Estructurales Virales / Genómica / Citomegalovirus / Farmacorresistencia Viral Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Antiviral Res Año: 2019 Tipo del documento: Article Pais de publicación: Países Bajos