Approach to drug-resistant cytomegalovirus in transplant recipients

Abstract

Purpose of review updated information on diagnosis of CMV drug resistance, treatments for drug-resistant infection and potential uses of experimental antiviral compounds. Recent findings For established CMV antivirals, uncommon viral UL97 kinase and UL54 DNA polymerase drug resistance mutations are sporadically described that expand an extensive existing database. Some novel mutations reported from treated patients have no drug resistant phenotype and may be genotyping artifacts. Next generation sequencing technology may enable earlier detection of emerging resistance mutations in treated patients. Management options for drug-resistant infection include optimization of host defenses, antiviral dose escalation, substitutions or combinations of standard or experimental antivirals. Maribavir and letermovir have antiviral targets distinct from the classic DNA polymerase. UL97 mutations elicited by ganciclovir and maribavir are different, although a single p-loop mutation can confer significant cross-resistance. High-grade resistance mutations in the UL56 terminase gene are readily selected in vitro under letermovir and await clinical correlation. Summary Technical advancements can enhance the accurate and timely genotypic detection of drug resistance. Antivirals undergoing clinical trial offer the prospect of new viral targets and drug combinations, but unresolved issues exist with regard to their therapeutic potential for drug-resistant CMV and their genetic barriers to resistance.

How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients

“…69 Rare in vitro mutations have been described, but their clinical relevance is yet to be determined. 71,72 Because C592G UL97 mutation confers low-level resistance to ganciclovir (Table 1), when managing CMV resistance for case 1, we could have increased the ganciclovir dose up to double the standard induction dose, with successful outcomes in some reported cases ( Figure 5). 73,74 However, in our patient with CMV disease, switching empirically to foscarnet was thought to be more appropriate.…”

Cytomegalovirus (CMV) Encephalitis in HIV Patients

“…Resistanceassociated mutations have been identified in the UL97 kinase gene and the UL54 DNA polymerase gene [31][32][33][34][35][36]. Resistance is characterized by an increase in drug concentration required to reduce the viral growth by 50% [33,34]. Viral UL97 kinase gene mutations confer ganciclovir resistance, but viral UL54 DNA polymerase gene mutations can confer resistance to any of the standard anti-CMV antiviral agents (ganciclovir, foscarnet, and cidofovir) [34,35].…”

“…The decline in reported resistance has been attributed to better control of CMV replication with ART. Resistanceassociated mutations have been identified in the UL97 kinase gene and the UL54 DNA polymerase gene [31][32][33][34][35][36]. Resistance is characterized by an increase in drug concentration required to reduce the viral growth by 50% [33,34].…”

“…Cidofovir can also be considered in patients where ganciclovir resistance is only due to a UL97 mutation [33]. In patients with a UL54 mutation, high grade foscarnet resistance is rare but may confer low-grade ganciclovir with or without cidofovir cross resistance [34,40]. In patients with confirmed resistance to all standard anti-CMV or in those who are not clinically improving, other agents that have been used in the transplant population include: artesunate, maribavir, and leflunomide [41][42][43].…”

“…Resistance is characterized by an increase in drug concentration required to reduce the viral growth by 50% [33,34]. Viral UL97 kinase gene mutations confer ganciclovir resistance, but viral UL54 DNA polymerase gene mutations can confer resistance to any of the standard anti-CMV antiviral agents (ganciclovir, foscarnet, and cidofovir) [34,35]. Resistance is unusual in the first six weeks of therapy, but should be suspected when persistent or increasing CMV viral loads are reported or progression of disease occurs after several weeks of appropriate anti-CMV therapy [33,[36][37][38].…”