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Cytomegalovirus Drug Resistance Mutations

The three most commonly used medications for treatment of cytomegalovirus (CMV) infections are ganciclovir, foscarnet and cidofovir. Ganciclovir is a guanosine analogue that inhibits CMV DNA polymerase. In order to become active it must first be phosphorylated by a CMV enzyme called phosphotransferase. Phosphorylated ganciclovir is a competitive substrate for DNA polymerase and inhibits viral growth by slowing CMV DNA replication.

Foscarnet is a direct competitive inhibitor of DNA polymerase. Unlike ganciclovir, it does not need to be phosphorylated in order to inhibit CMV DNA polymerase. Cidofovir is a monophosphorylated cytosine analogue which, like ganciclovir, is further phosphorylated intracellularly to form a compound that impedes DNA polymerase activity

Ganciclovir is most commonly used to treat CMV infections. During viral replication in the presence of ganciclovir, CMV may develop mutations that confer drug resistance. Prevalence of CMV resistance ranges between 0 and 15% among patients receiving solid organ transplants. Risk factors for developing ganciclovir resistance include transplantation of a seropositive organ into a CMV seronegative recipient, degree of immunosuppression, magnitude of CMV viremia, and prolonged exposure to anti-CMV medication.

CMV phosphotransferase is encoded by the CMV gene UL97. Point mutations or deletions in this gene interfere with phosphorylation of ganciclovir and lead to drug resistance. Mutations in the UL97 gene account for >90% of cases of ganciclovir-resistance.

Prolonged exposure to ganciclovir can give rise to additional mutations in the UL54 gene, which codes for CMV DNA polymerase. Mutations in the UL54 gene are associated with a higher level resistance to ganciclovir and cross-resistance to foscarnet and cidofovir since these agents also target CMV DNA polymerase. Triple-drug resistance is associated with mutations in UL54 gene.

Testing for mutations in CMV UL97 and UL54 genes is indicated for patients who are no longer responding to treatment. Some experts recommend sequential testing of UL97 first, followed by UL54. CMV UL54 and UL97 genes are amplified by PCR and then sequenced to detect mutations conferring anti-viral resistance.

Specimen requirement is a purple top tube of blood (EDTA), 1 mL of CSF or 1 mL of bronchoalveolar lavage.

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