Resistance of Human Cytomegalovirus to Antiviral Drugs

Abstract

SUMMARY Resistance of cytomegalovirus (CMV) to antiviral agents is a well-recognized phenomenon that has been observed in the laboratory and in the clinical setting. Infections caused by antiviral-resistant CMV have been found exclusively among immunocompromised individuals, including patients with AIDS, bone marrow and solid-organ transplant recipients, and patients with hematologic malignancies, and in individuals with primary immunodeficiencies. The majority of these infections have been described to occur in patients with AIDS receiving prolonged antiviral therapy for CMV end-organ disease. Antiviral agents currently licensed for the treatment of CMV infections include ganciclovir, foscarnet, and cidofovir. Resistance of CMV to ganciclovir is related to mutations in the UL97 region of the viral genome and/or mutations in the viral DNA polymerase. Resistance to foscarnet and cidofovir is associated with mutations in the viral DNA polymerase. Antiviral susceptibility of CMV strains containing DNA polymerase mutations is dependent on the region of the DNA polymerase where the mutations are located. Some DNA polymerase mutant viruses are cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition that specific UL97 and UL54 mutations are associated with resistance to antiviral agents has led to the development of molecular methods for detection of mutant viruses. This article reviews the mechanisms of resistance of CMV to antiviral agents, the laboratory methods for detection of resistant CMV, and the clinical aspects of infections caused by antiviral-resistant CMV.

Ganciclovir for Cytomegalovirus: a Call for Indefinite Prophylaxis in Lung Transplantation

“…However, in the setting of prolonged ganciclovir use, GCV-resistant CMV has been observed in solid-organ transplantation. 17 Bhorade et al 18 detected an incidence of GCV-resistant CMV disease of up to 6%, higher than previously reported in solid-organ transplantation. Although concerns over ganciclovir resistance have arisen in part due to the low bioavailability of oral drug formulations, 19 one report suggested that GCV prophylaxis does not select for resistant isolates of CMV.…”

A Single-center Experience With Ganciclovir-resistant Cytomegalovirus in Lung Transplant Recipients: Treatment and Outcome

“…This may reflect the decreased efficacy of ganciclovir in comparison to foscarnet due to the presence of the UL54 gene in these patients, which is associated with increased levels of ganciclovir resistance. 11,17 Another potential mechanism could be related to lack of prior immunologic memory to CMV in these patients, which appears necessary to efficiently clear CMV infection. 18,19 The development of higher levels of ganciclovir resistance due to UL54 mutations in this sub-group could also be attributed to longer periods of prophylaxis in mismatch patients.…”

“…11,12 Reported risk factors for development of ganciclovir resistance include being a seronegative recipient of a seropositive organ (D ϩ /R Ϫ ), prolonged exposure to oral ganciclovir and intense immunosuppression. 12,13,16 Despite multiple reports of ganciclovir-resistant CMV disease in solid-organ transplant recipients, optimal treatment regimens are unknown.…”

The emergence of cytomegalovirus resistance to ganciclovir therapy in kidney transplant recipients

“…Resistance to GCV is associated with mutations in one or both of the CMV DNA polymerase (UL54) and viral phosphotransferase (UL97). The majority of GCV resistance strains have mutations in the UL97 gene [10]. The UL97 mediates the initial phosphorylation of GCV which is needed for its antiviral action [11].…”

“…Deletions of the UL97 gene result in a drastic reduction in its efficiency by inhibiting CMV replication. Mutations in the viral DNA polymerase gene (UL54) can also increase GCV resistance and cross-resistance to other drugs [10].…”