Quantitative changes in cytomegalovirus DNAemia and genetic analysis of the UL97 and UL54 genes in AIDS patients receiving cidofovir following ganciclovir therapy

Bowen, EF; Cherrington, Julie M.; Lamy, Patrick D.; Griffiths, Paul; Ma, Jun; Emery, Vincent

doi:10.1002/(sici)1096-9071(199908)58:4<402::aid-jmv13>3.0.co;2-5

Cited by 17 publications

(9 citation statements)

References 17 publications

(26 reference statements)

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“…Vertical bars indicate the positions of mutations that have been associated with drug resistance. Other mutations (at codons 304, 393, 406, 521, 691, 695, 737, 751, 830, 834, 841, 961, and 972) potentially associated with drug resistance have been reported, but the presence in the same isolate of other known UL54 resistance mutations or the lack of phenotypic evaluation have precluded the ability to make an association with drug resistance (23,26,44,49,75,112,116 ated with various drug resistance profiles. Among the most frequent DNA pol mutations associated with drug resistance are V715M, V781I, and L802M, which confer resistance to FOS, and F412C, L501I/F, and P522S, which confer resistance to GCV and CDV.…”

Section: Molecular Mechanisms Of Hcmv Resistance To Current Antiviralmentioning

confidence: 99%

Human Cytomegalovirus Resistance to Antiviral Drugs

Gilbert

Boivin

2005

Antimicrob Agents Chemother

196

176

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Section: Molecular Mechanisms Of Hcmv Resistance To Current Antiviralmentioning

confidence: 99%

Human Cytomegalovirus Resistance to Antiviral Drugs

Gilbert

Boivin

2005

Antimicrob Agents Chemother

196

176

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“…It is likely that the L595S mutation causes a fitness disadvantage to CMV such that once the selective pressure of ganciclovir was removed, the small population of virus carrying wild-type UL97 (evident in the sequencing performed around 870 days) rebounded. This phenomenon has been previously documented in patients with CMV retinitis when therapy was shifted from ganciclovir to cidofovir (26,28).…”

Section: Discussionmentioning

confidence: 99%

Rapid Detection of Human Cytomegalovirus UL97 and UL54 Mutations Directly from Patient Samples

et al. 2013

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cHuman cytomegalovirus (CMV) is a significant contributor to morbidity and mortality in immunocompromised patients, particularly in the transplant setting. The availability of anti-CMV drugs has improved treatment, but drug resistance is an emerging problem. Here, we describe an improved, rapid, sequencing-based assay for the two genes in CMV where drug resistance occurs, the UL97 and UL54 genes. This assay is performed in 96-well format with a single master mix and provides clinical results within 2 days. It sequences codons 440 to 645 in the UL97 gene and codons 255 to 1028 in the UL54 gene with a limit of detection of 240 IU/ml. With this assay, we tested 43 specimens that had previously been tested for UL97 drug resistance and identified 3 with UL54 mutations. One of these patients had no concurrent UL97 mutation, pointing toward the need for an assay that facilitates dual UL97/UL54 gene testing for complete resistance profiling. Human cytomegalovirus (CMV) causes morbidity and mortality in immunocompromised patients, including transplant and HIV-infected patients (1). The first-line drug therapy for CMV infection is ganciclovir (GCV) or its prodrug valganciclovir (VGCV). GCV or VGCV must be activated by phosphorylation before they act on human CMV. This phosphorylation is carried out by the viral kinase UL97, and activated GCV subsequently inhibits the viral DNA polymerase UL54. Clinically, GCV resistance usually arises first from a UL97 mutation resulting in decreased accumulation of the activated drug. Subsequent UL54 mutations can confer high levels of GCV resistance and various degrees of cross-resistance to the second-line drugs cidofovir (CDV) and foscarnet (FOS) (2).Our group previously published a rapid PCR-and sequencingbased detection method for UL97 mutations conferring ganciclovir resistance (3). This test, currently used to detect mutations directly from clinical specimens, results in the sequence for UL97 gene codons 440 to 645. This region covers the known drug resistance mutation sites in the UL97 gene. However, because UL54 is the target of all currently marketed anti-CMV drugs, a detection method for UL54 mutations is also needed. Polymerase mutations are more likely to emerge after prolonged GCV treatment and typically add to the level of resistance conferred by UL97 mutations or introduce cross-resistance to CDV or FOS (4).Despite its predicted utility in treatment management, clinical tests for UL54 drug resistance mutations have been slower to develop for a number of reasons. First, the coding sequence of UL54 is almost twice as long as that of UL97. In addition, the baseline sequences are more variable and the number and variety of resistance mutations are greater in the UL54 gene than in the UL97 gene. Polymerase genotypic testing therefore requires more-extensive sequencing, typically covering codons 300 to 1,000. To meet the clinical need for complete CMV drug resistance profiles, we adapted our previous UL97 sequencing method (3) to develop a single assay that amplifies six region...

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“…However, emergence of drugresistant CMV mutants has been observed for CDV-and GCV-treated AIDS patients (5). The molecular basis of such de novo resistance is often described as mutations in the UL54 DNA polymerase gene (3,29,35). Combinatorial therapy using such antiviral agents, not necessarily administered simultaneously, may have desirable synergistic effects in vivo without potential problems associated with the development of drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Ganciclovir and Cidofovir Treatment of Cytomegalovirus-Induced Myocarditis in Mice

Lenzo

Shellam

Lawson

2001

Antimicrob Agents Chemother

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The cardiovascular disease myocarditis is characterized by inflammation and necrosis of cardiac muscle. This disease has been associated with various viral etiologies, including cytomegalovirus (CMV). Murine CMV (MCMV) infection of adult BALB/c mice produces a disease with acute and chronic phases similar to that found in humans. In our murine model, we have investigated the therapeutic efficacy of antiviral drug administration on myocarditis. Two drugs commonly used for CMV treatment, ganciclovir and cidofovir, were subjected to trials, with both drugs showing potent antiviral activity against MCMV both in vitro and in vivo. The acute phase of myocarditis was significantly reduced when antiviral therapy commenced 24 h postinfection. Such treatment also reduced the severity of the chronic phase of myocarditis. In contrast, antiviral treatment commencing after the acute phase had no effect on chronic myocarditis. Reinfection of mice with MCMV caused exacerbation of myocardial inflammation. Such an increase in severity of myocarditis could be prevented with either ganciclovir or cidofovir treatment, but the preexisting inflammation and necrosis of the myocardium persisted. These data highlight possible therapeutic uses of antiviral drugs in viral myocarditis as well as further elucidating the pathogenic nature of the disease.

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Quantitative changes in cytomegalovirus DNAemia and genetic analysis of the UL97 and UL54 genes in AIDS patients receiving cidofovir following ganciclovir therapy

Cited by 17 publications

References 17 publications

Human Cytomegalovirus Resistance to Antiviral Drugs

Human Cytomegalovirus Resistance to Antiviral Drugs

Rapid Detection of Human Cytomegalovirus UL97 and UL54 Mutations Directly from Patient Samples

Ganciclovir and Cidofovir Treatment of Cytomegalovirus-Induced Myocarditis in Mice

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