Hyperimmune globulin enriched for CMV (CMV-IGIV) is an immunoglobulin G (IgG) containing a standardized number of antibodies to cytomegalovirus. It may be used for the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas, and heart. Alone or in combination with an antiviral agent, it has been shown to: * Reduce the risk of CMV-related disease and death in some of the highest-risk transplant recipients * Provide a measurable long-term survival benefit * Produce minimal treatment-related side effects and adverse events. Ganciclovir (Cytovene) treatment is used for people with depressed immunity who have either sight-related or life-threatening illnesses. Valganciclovir (Valcyte) is an antiviral drug that is also effective and is given orally: it is a pro-drug that gets converted into ganciclovir in the body, but is much better absorbed orally than the latter. The therapeutic effectiveness is frequently compromised by the emergence of drug-resistant virus isolates. A variety of amino acid changes in the UL97 protein kinase and the viral DNA polymerase have been reported to cause drug resistance. Foscarnet or cidofovir are only given to people with CMV resistant to ganciclovir, because foscarnet has notable nephrotoxicity, resulting in increased or decreased Ca2+ or PO43−, and decreased Mg2+ levels. Letermovir has been approved by the European Medicines Agency and the FDA for treatment and prophylaxis of HCMV infection. Drug resistance 400x400px All three currently licensed anti-HCMV drugs target the viral DNA polymerase, pUL54. Ganciclovir (GCV) acts as nucleoside analogue. Its antiviral activity requires phosphorylation by the HCMV protein kinase, pUL97. The second drug, Cidofovir (CDV), is a nucleotide analogue, which is already phosphorylated and thus active. Finally, Foscarnet (FOS) has a different mode of action. It directly inhibits polymerase function by blocking the pyrophosphate binding site of pUL54 (note: investigational drug letermovir acts through a mechanism that involves viral terminase). Two HCMV proteins are implicated in antiviral resistance against these three drugs: pUL97 and pUL54. Specific mutations in pUL97 can cause reduced phosphorylation activity of this viral protein kinase. Thus, fewer monophosphorylated – and thus active – GCV can be synthesized, leading to antiviral resistance against GCV. About 90% of all GCV resistances are caused by such mutations in UL97. Mutations in pUL54 may have different effects leading to antiviral drug resistance: A. They can lead to decreased affinity to antiviral compounds. This resistance mechanism concerns GCV, CDV and FOS and may lead to multidrug resistance. B. Some mutations in pUL54 can increase the polymerase's exonuclease activity. This causes enhanced recognition of incorporated GCV and CDV. As a result, these dNTP analogues are excised more efficiently. Major risk factors for HCMV drug resistance are the residual capacity of the host's immune system to control viral replication and the overall amount and duration of viral replication. HCMV antiviral drug resistance can be detected by phenotypic or by genotypic drug resistance testing. Phenotypic resistance testing involves cultivation of the virus in cell culture and testing its susceptibility using different antiviral drug concentrations in order to determine EC50 values. In contrast, genotypic resistance testing means the detection of resistance associated mutations in UL97 and UL54 by sequencing. Genotypic resistance testing is becoming the method of choice because it is faster, but requires previous phenotypic characterisation of each newly found mutation. This can be performed via a web-based search tool that links a person's HCMV sequence to a database containing all published UL97 and UL54 mutations and corresponding antiviral drug susceptibility phenotypes.
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