Diversity of antiviral‐resistant human cytomegalovirus in heart and lung transplant recipients

Abstract

Immunocompromised transplant recipients are at high risk for human cytomegalovirus (CMV)-related infection and disease. Antiviral prophylaxis and treatment have reduced CMV morbidity and mortality, but at times promote development of antiviral-resistant CMV strains that can significantly contribute to adverse clinical outcomes in transplant recipients. We have investigated CMV genotypes in transplant recipients (bone marrow, stem cell, kidney, heart, lung, and liver) receiving antiviral prophylaxis or preemptive therapy or treatment, to determine the viral characteristics and clinical impact of antiviral-resistant CMV in these different groups. Antiviral-resistant CMV strains were detected by polymerase chain reaction sequencing of the CMV protein kinase (UL97) and viral DNA polymerase (UL54) genes from clinical specimens. A trend toward more frequent detection of multidrug resistance and co-circulation of multiple resistant strains was seen in heart and lung transplant recipients compared with other transplantation types. A greater diversity and number of UL97 and UL54 mutations were observed in heart and lung transplant recipients; whereas antiviral-resistant CMV infections in other transplant recipients were predominantly the result of a single mutant genotype. Furthermore, 43% (6/14) of CMV-positive heart and lung transplant recipients were infected with CMV strains containing UL54 mutations conferring multidrug resistance compared with only 6% (1/18) of CMV-positive recipients of other transplanted organs or stem cells. Emergence of CMV strains containing previously unrecognized UL54 mutations (F412S and D485N) also occurred in 1 lung and 1 heart transplant recipient. The development of these mutations under antiviral selective pressure, and clinical outcome of infection suggests these mutations are likely to confer antiviral resistance. Emergence of CMV antiviral resistance remains a significant issue in immunocompromised patients treated with antiviral agents, and emphasizes the relevance of regular antiviral resistance testing when designing optimal patient-management strategies.

Rapid Detection of Human Cytomegalovirus UL97 and UL54 Mutations Directly from Patient Samples

“…Cases of patients with dual UL97 and UL54 mutations are particularly prevalent in lung transplant recipients. A recent 39-patient study showed that lung transplant recipients accounted for 57% of patients with dual UL97 and UL54 mutations, even though that transplant procedure accounted for only 22% of CMV-positive patients (27). Several cases of multidrug-resistant, dual UL97/UL54 mutant CMV viruses have been reported in solid organ and stem cell transplant recipients (21,24,25).…”

“…If a drug-resistant variant is identified in the UL97 gene, subsequent UL54 gene sequencing is recommended (19). Many cases of resistance have been documented, both as case reports (6,(20)(21)(22)(23)(24)(25)(26) and cohort studies (5,15,27). Most of these cases report resistance arising from canonical UL97 ganciclovir resistance mutations.…”

Viral factors influencing the outcome of human cytomegalovirus infection in liver transplant recipients

“…[2][3][4]16,17,19,26 Antiviral resistant CMV strains also continue to emerge in 2-10% of treated solid organ transplant recipients. 7,[27][28][29][30][31] We undertook a five-year randomised study examining the efficacy of valGCV prophylaxis and preemptive therapy for prevention of CMV infection and disease following OLT at a tertiary referral hospital in Melbourne, Australia. We examined the importance of viral load, CMV genotype, antiviral resistance, herpesvirus co-infections, and host factors such as pre-transplant serostatus.…”

Antiviral treatment of cytomegalovirus infection: an update

“…Until now, fast genotyping of the viral polymerase requires 5 --7 working days, but owing to several limitations it is not yet established for the routine diagnostic setting. However, despite suspected symptoms and/or signs of HCMV disease by clinicians, HCMV DNA could not be detected in~20% of patients [1,3,12]. This often-observed discrepancy of treatment failure due to suspected viral resistance, but lacking of resistance mutations in genotypic assays or even viral DNA or pp65 antigenaemia, points to the requirement for well-directed diagnostic tools and better defined clinical symptoms of HCMV-associated disease.…”

“…In conclusion, more studies are required on the dynamic of virus populations under drug pressure. Clinicians have to face the decision as to whether risking a re-exposure to the antiviral compound in relapses is reasonable or whether an evolution of HCMV-resistant virus in long-term patients should be feared [12,13].…”