Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis

Boivin, Guy; Goyette, Nathalie; Farhan, Mahdi; Ives, Jane; Elston, Robert C.

doi:10.1016/j.jcv.2011.12.019

Cited by 47 publications

(40 citation statements)

References 14 publications

(13 reference statements)

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“…These are now the furthest-upstream UL97 mutations known to confer definite GCV resistance with relatively preserved growth competence. Current diagnostic genotyping, including methods used in randomized valganciclovir clinical trials, seldom covers UL97 codons below positions 360 to 400 (11,30,33), thus leaving the above-described mutations undetected if present. Expanded UL97 sequencing of specimens from subjects receiving prolonged antiviral therapy is advisable.…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus UL97 Kinase Catalytic Domain Mutations That Confer Multidrug Resistance

Chou

Ercolani

Marousek

et al. 2013

Antimicrob Agents Chemother

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cHuman cytomegalovirus UL97 kinase mutations that commonly confer ganciclovir resistance cluster in different parts of the gene than those conferring resistance to maribavir, an experimental UL97 kinase inhibitor. The drug resistance, growth, and autophosphorylation phenotypes of several unusual UL97 mutations in the kinase catalytic domain were characterized. Mutations V466G and P521L, described in clinical specimens from ganciclovir-treated subjects, conferred a UL97 kinase knockout phenotype with no autophosphorylation, a severe growth defect, and high-level ganciclovir, cyclopropavir, and maribavir resistance, similar to mutations at the catalytic lysine residue K355. Mutations F342S and V356G, observed after propagation under cyclopropavir in vitro, showed much less growth attenuation and moderate-to high-level resistance to all three drugs while maintaining UL97 autophosphorylation competence and normal cytopathic effect in cell culture, a novel phenotype. F342S is located in the ATP-binding P-loop and is homologous to a c-Abl kinase mutation conferring resistance to imatinib. UL97 mutants with relatively preserved growth fitness and multidrug resistance are of greater concern in antiviral therapy than the severely growth-impaired UL97 knockout mutants. Current diagnostic genotyping assays are unlikely to detect F342S and V356G, and the frequency of their appearance in clinical specimens remains undefined.

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Section: Discussionmentioning

confidence: 99%

Cytomegalovirus UL97 Kinase Catalytic Domain Mutations That Confer Multidrug Resistance

Chou

Ercolani

Marousek

et al. 2013

Antimicrob Agents Chemother

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“…Ganciclovir resistance occurs mainly in the D+/R-subset where the usual incidence of resistance after viremia is 5% to 12% and is higher in lung transplant recipients (187Y190). Presentations of drug-resistant CMV infection range from asymptomatic (e.g., when drug resistance is monitored during antiviral prophylaxis clinical trials (191)) to severe or fatal end-organ disease (192). During CMV prophylaxis, the incidence of ganciclovir resistance is low, in the 0% to 3% range, and did not appear to be increased when the prophylaxis duration was increased from 100 to 200 days in D+/R-kidney recipients (191).…”

Section: Antiviral Drug Resistance Risk Factors Frequency and Clinimentioning

confidence: 99%

Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation

et al. 2013

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Cytomegalovirus (CMV) continues to be one of the most common infections after solid-organ transplantation, resulting in significant morbidity, graft loss, and adverse outcomes. Management of CMV varies considerably among transplant centers but has been become more standardized by publication of consensus guidelines by the Infectious Diseases Section of The Transplantation Society. An international panel of experts was reconvened in October 2012 to revise and expand evidence and expert opinion-based consensus guidelines on CMV management, including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues. The following report summarizes the recommendations.

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“…Thereafter, the drug-resistant virus predominates and becomes detected persistently in the blood. The incidence of ganciclovir-resistant CMV infection in SOT recipients remains low, at less than 1% (205,206). However, ganciclovir resistance should be suspected when (i) the viral load persists, plateaus, or rises during treatment; (ii) the patient is highly immunocompromised from use of lymphocyte-depleting agents; (iii) the patient is a high-risk CMV Dϩ/RϪ SOT recipient; and (iv) there is a history of prolonged antiviral exposure, through either antiviral prophylaxis, preemptive therapy, or antiviral treatment (3).…”

Section: Relapse and Resistancementioning

confidence: 99%

Clinical Utility of Viral Load in Management of Cytomegalovirus Infection after Solid Organ Transplantation

2013

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SUMMARY The negative impact of cytomegalovirus (CMV) infection on transplant outcomes warrants efforts toward improving its prevention, diagnosis, and treatment. During the last 2 decades, significant breakthroughs in diagnostic virology have facilitated remarkable improvements in CMV disease management. During this period, CMV nucleic acid amplification testing (NAT) evolved to become one of the most commonly performed tests in clinical virology laboratories. NAT provides a means for rapid and sensitive diagnosis of CMV infection in transplant recipients. Viral quantification also introduced several principles of CMV disease management. Specifically, viral load has been utilized (i) for prognostication of CMV disease, (ii) to guide preemptive therapy, (iii) to assess the efficacy of antiviral treatment, (iv) to guide the duration of treatment, and (v) to indicate the risk of clinical relapse or antiviral drug resistance. However, there remain important limitations that require further optimization, including the interassay variability in viral load reporting, which has limited the generation of standardized viral load thresholds for various clinical indications. The recent introduction of an international reference standard should advance the major goal of uniform viral load reporting and interpretation. However, it has also become apparent that other aspects of NAT should be standardized, including sample selection, nucleic acid extraction, amplification, detection, and calibration, among others. This review article synthesizes the vast amount of information on CMV NAT and provides a timely review of the clinical utility of viral load testing in the management of CMV in solid organ transplant recipients. Current limitations are highlighted, and avenues for further research are suggested to optimize the clinical application of NAT in the management of CMV after transplantation.

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Incidence of cytomegalovirus UL97 and UL54 amino acid substitutions detected after 100 or 200 days of valganciclovir prophylaxis

Cited by 47 publications

References 14 publications

Cytomegalovirus UL97 Kinase Catalytic Domain Mutations That Confer Multidrug Resistance

Cytomegalovirus UL97 Kinase Catalytic Domain Mutations That Confer Multidrug Resistance

Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation

Clinical Utility of Viral Load in Management of Cytomegalovirus Infection after Solid Organ Transplantation

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