Pharmacokinetic and Pharmacodynamic Assessment of Oral Valganciclovir in the Treatment of Symptomatic Congenital Cytomegalovirus Disease

Since murine cytomegalovirus (MCMV) was first described in 1954, it has been used to model human cytomegalovirus (HCMV) diseases. MCMV is a natural pathogen of mice that is present in wild mice populations and has been associated with diseases such as myocarditis. The species-specific nature of HCMV restricts most research to cell culture-based studies or to the investigation of non-invasive clinical samples, which may not be ideal for the study of disseminated disease. Initial MCMV research used a salivary gland-propagated virus administered via different routes of inoculation into a variety of mouse strains. This revealed that the genetic background of the laboratory mice affected the severity of disease and altered the extent of subsequent pathology. The advent of genetically modified mice and viruses has allowed new aspects of disease to be modeled and the opportunistic nature of HCMV infection to be confirmed. This review describes the different ways that MCMV has been used to model HCMV diseases and explores the continuing difficulty faced by researchers attempting to model HCMV congenital cytomegalovirus disease using the mouse model.

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Incidence of UL97 Resistance Mutations in Infants with Congenital Cytomegalovirus Disease Receiving 6 Months of Oral Valganciclovir Therapy

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx162.058 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S23-S23 ◽

Cited By ~ 1

Author(s):

Scott H James ◽

Ra’Shun L Conner ◽

David W Kimberlin ◽

Richard Whitley ◽

Mark N Prichard

Keyword(s):

Antiviral Therapy ◽

Antiviral Resistance ◽

Sequence Variants ◽

Resistance Mutations ◽

Phase 3 ◽

Congenital Cytomegalovirus ◽

Study Population ◽

Oral Valganciclovir ◽

Cmv Disease ◽

Ul97 Gene

Abstract Background A recently completed Phase 3 randomized, controlled, double-blind, multicenter study of infants with symptomatic congenital cytomegalovirus (CMV) disease receiving 6 months of oral valganciclovir (VGCV) therapy represents the largest such population in which to evaluate treatment-emergent antiviral resistance. The most common mechanism of CMV antiviral resistance occurs through mutations in the CMV UL97 gene that confer resistance to ganciclovir (GCV). Genotypic resistance analyses were performed on infants receiving 6 months of VGCV to assess the incidence of antiviral resistance due to UL97 sequence variants. Methods Resistance analyses were performed by conventional DNA sequencing of the UL97 gene at multiple time points. Following CMV DNA extraction from frozen whole blood specimens, the UL97 gene was amplified with a double nested polymerase chain reaction method and sequenced to identify polymorphisms and mutations that might confer GCV resistance. Results Forty-six infants with symptomatic CMV disease who received a 6-month course of VGCV underwent resistance analysis to identify UL97 sequence variants. In addition to a range of natural polymorphisms known to have no effect on antiviral susceptibility, 2 subjects developed UL97 mutations known to confer resistance to GCV (A594V and G598S detected in one subject; E596G detected in another), yielding an incidence of 4%. Each of these resistance mutations occurred in specimens collected after at least 4 months of antiviral therapy. As evaluated in the original Phase 3 trial, neither of these infants showed an improvement in hearing outcome. Conclusion The development of treatment-emergent UL97 resistance mutations was determined in a controlled study population of infants with congenital CMV disease receiving 6 months of VGCV. This targeted resistance analysis demonstrated an incidence approaching the total incidence of antiviral resistance for CMV disease in some immunocompromised populations, such as solid-organ transplant recipients. Further studies within this study population are warranted to elucidate the risk of emerging antiviral resistance and to assess clinical impact as well as the potential need for combination antiviral therapy. Disclosures All authors: No reported disclosures.

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