Failure of Ganciclovir Treatment Associated With Selection of a Ganciclovir-Resistant Cytomegalovirus Strain in a Lung Transplant Recipient

Alain, Sophie; Honderlick, P.; Grenet, Dominique; Stern, M.; Vadam, C.; Pors, M. J. Sanson-Le; Mc, Mazeron

doi:10.1097/00007890-199705270-00031

Cited by 60 publications

(35 citation statements)

References 9 publications

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“…In the event of recurrent disease despite therapy, determination of the susceptibility of the isolated CMV strain to currently available antiviral drugs may be considered; the occurrence of resistant strains has been documented among organ transplant recipients (10,271,383).…”

Section: Ganciclovirmentioning

confidence: 99%

“…So far, in vitro ganciclovir resistance has not been common in solid-organ transplant recipients. Nevertheless, reports that ganciclovir resistance can be a clinically significant problem in this population are increasing (10,22,384). It is possible that the incidence of resistance will increase further with changes in the ways that primary prophylaxis and treatment for CMV are administered.…”

Section: Antiviral Resistancementioning

confidence: 99%

See 1 more Smart Citation

New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

Sia¹,

Patel²

2000

Clinical Microbiology Reviews

220

181

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Section: Ganciclovirmentioning

confidence: 99%

Section: Antiviral Resistancementioning

confidence: 99%

New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

Sia¹,

Patel²

2000

Clinical Microbiology Reviews

220

181

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“…A consequence of this antiviral drug therapy is the development of GCVresistant CMV strains, which have been well documented in human immunodeficiency virus-infected patients (3,20,21,24,36). More recently resistance has been increasingly detected in isolates from transplant recipients following extended prophylactic or preemptive therapy (1,2,9,16,17,19,23,25).The UL97 phosphotransferase (kinase), a virus-encoded product, activates GCV by monophosphorylation (32). Subsequent di-and triphosphorylation are carried out by cellular enzymes.…”

mentioning

confidence: 99%

Sequencing of Cytomegalovirus UL97 Gene for Genotypic Antiviral Resistance Testing

Lurain

Weinberg

Crumpacker

et al. 2001

Antimicrob Agents Chemother

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The widespread use of ganciclovir (GCV) to treat cytomegalovirus (CMV) infections in immunosuppressed patients has led to the development of drug resistance. Phenotypic assays for CMV drug resistance are presently too time-consuming to be therapeutically useful. To support the development of genotypic assays for GCV resistance, the complete sequences of the UL97 phosphotransferase genes in 28 phenotypically GCVsensitive CMV clinical isolates were determined. The gene was found to be highly conserved, with nucleotide sequence identity among strains ranging from 98.6 to 100% and amino acid sequence identity of >99%. Primers for a genotypic assay were designed to amplify codons 400 to 707, because all known UL97 mutations conferring drug resistance occur at three sites within this region. This part of the UL97 gene was amplified from over 50 clinical isolates, and two sequencing reactions for the coding strand were successfully used to identify GCV resistance mutations. This genotypic assay can be performed in 48 h using genomic DNA extracted from cell monolayers at very low levels of virus infectivity, thus rapidly providing therapeutically useful results.Ganciclovir (GCV), the most widely used antiviral drug for treatment of systemic cytomegalovirus (CMV) disease, has proven effective in significantly reducing the CMV viral load in transplant recipients and patients with AIDS. A consequence of this antiviral drug therapy is the development of GCVresistant CMV strains, which have been well documented in human immunodeficiency virus-infected patients (3,20,21,24,36). More recently resistance has been increasingly detected in isolates from transplant recipients following extended prophylactic or preemptive therapy (1,2,9,16,17,19,23,25).The UL97 phosphotransferase (kinase), a virus-encoded product, activates GCV by monophosphorylation (32). Subsequent di-and triphosphorylation are carried out by cellular enzymes. A second viral product, the DNA polymerase, incorporates GCV triphosphate into the viral genome, leading to marked attenuation of viral DNA replication (12,13,15). Although mutations conferring GCV resistance have been mapped to both genes, mutations in the UL97 gene appear to be detected during antiviral therapy much more frequently than DNA polymerase gene mutations (7,9,17,31). The occurrence of these resistance mutations has prompted efforts to develop genotypic methods for rapid antiviral susceptibility testing.The standard phenotypic method for detection of drug resistance has been the plaque reduction assay, which requires lengthy viral propagation to obtain sufficient infectivity for performance of the assay (22). The slow growth of cell-associated clinical isolates limits the value of this assay for therapeutic decisions. In addition, the assay is inherently subjective in the differentiation of true drug-resistant plaques from foci of drug-sensitive infectivity that slowly resolve in the presence of drug. Additional phenotypic assays which are more objective and which require less time to determine...

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“…The facts, that specific mutations in the UL97 and UL54 genes are associated with antiviral drug resistance, have led to the development of genetic methods. These are based on PCR amplification of the specific region of the genome followed by restriction enzyme analysis or direct sequencing of the amplification product/products (Alain et al, 1997;Lurain et al, 2002;Mendez et al, 1999b;Wolf et al, 1995). An obvious advantage of these assays is the possibility to use clinical specimens directly, rather than virus isolates, which significantly shortens the time required for performance of the test.…”

Section: Laboratory Diagnosis Of Hcmvmentioning

confidence: 99%

Drug Resistance due to Mutation in UL 97 and Certain Other Specific Genes in Cytomegalovirus Strains: An Overview

Kumar¹

2013

IOSR-JPBS

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Failure of Ganciclovir Treatment Associated With Selection of a Ganciclovir-Resistant Cytomegalovirus Strain in a Lung Transplant Recipient

Cited by 60 publications

References 9 publications

New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

Sequencing of Cytomegalovirus UL97 Gene for Genotypic Antiviral Resistance Testing

Drug Resistance due to Mutation in UL 97 and Certain Other Specific Genes in Cytomegalovirus Strains: An Overview

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