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Human cytomegalovirus (CMV) infection is the most prevalent infection affecting organ transplant recipients, and it is a cause of morbidity and mortality in patients undergoing kidney transplantation. The introduction of ganciclovir (GCV) for both prophylaxis and treatment has vastly improved patient outcomes. GCV resistance can be caused by mutations in the UL97 phosphotransferase gene or the UL54 polymerase gene. It occurs in 1 to 2% of kidney transplant recipients with CMV infection or disease. Antiviral resistance should be considered when increased viral loads and disease progression are observed despite the administration of adequate antiviral therapy. The degree of resistance varies depending on the type of mutation present. We report a patient with resistance to GCV due to a UL97 del597-599 mutation who, despite typically requiring an 8-fold increase in GCV dose, showed a significant decrease in viral load with just a double dose increase. However, the patient’s overall clinical course remained complicated. Due to severe leukopenia, maribavir had to be started, with a good response. Nevertheless, he ultimately died due to indirect CMV-related complications. This case also highlights the complexity of transplant patients, who present multiple challenges ranging from infections to therapy management.

Infection with cytomegalovirus (CMV) with resistance to ganciclovir (GCV) is a therapeutic challenge in kidney transplant patients, because standard treatment options are nephrotoxic. We report the case of a kidney transplant recipient with GCV-resistant CMV disease, in whom letermovir, a novel inhibitor of CMV packaging, was administered off-label and prevented a relapse of disease once the CMV load was decreased by cidofovir. Furthermore, we observed significant drug interactions between letermovir and tacrolimus.

Therapeutic management of cytomegalovirus (CMV) disease in hematopoietic stem cell transplantation patients can become a challenge because of the emergence of anti-CMV drug resistance. This case report presents a patient with clinical ganciclovir resistance due to a new mutation: histidine-to-asparagine change at residue 393 of UL97. This mutation, which is located in the nonfunctional region of the UL97 gene, is very unusual. Having more information about the mutations leading to drug resistance in CMV is important for both improved clinical management and development of new diagnostic tests and drugs. [ABSTRACT FROM AUTHOR]

Abstract: Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity, including sensorineural hearing loss (SNHL), in newborns. Antiviral therapy with ganciclovir (GCV) and its oral prodrug, valganciclovir (VAL-GCV) are increasingly being administered to infected infants, toward the goal of improving neurodevelopmental and auditory outcomes. In this case report, we describe a symptomatic congenitally infected infant treated with VAL-GCV in whom GCV resistance was suspected, based on a 50-fold increase in viral load after 6 weeks of oral therapy. Analyses of CMV sequences from both blood and urine demonstrated populations of viruses with M460V and L595F mutations in the UL97 phosphotransferase gene. In contrast, analysis of viral DNA retrieved from the newborn dried blood spot demonstrated wild-type UL97 sequences. DNAemia resolved after the discontinuation of VAL-GCV. Long-term VAL-GCV therapy in congenitally infected infants can select for resistant viral variants, and anticipatory virological monitoring may be warranted. [Copyright &y& Elsevier]

Background Cytomegalovirus ( CMV) infection may cause serious disease after hematopoietic cell transplantation ( HCT) and solid organ transplantation ( SOT), but few reports describe ganciclovir ( GCV) resistance in pediatric patients. Objectives This study was performed to describe the clinical impact of CMV infection with UL97 mutation in pediatric transplant recipients. Methods Quantitative surveillance data for CMV infection in pediatric patients between October 2001 and February 2007 at the University of Washington were analyzed. Testing for UL97 mutation was performed in selected patients with prolonged CMV viremia despite therapy. Data associated with the detection of UL97 mutations were reviewed. Results CMV was detected in 89 pediatric transplant recipients. Among these, 39 had undergone HCT and 50 SOT (12 heart, 22 kidney, 15 liver, and 1 bilateral lung transplants). CMV with at least one UL97 sequence variation was detected in 5 patients: 4 HCT recipients (4/39, 10%) and 1 heart transplant recipient (1/50, 2%). All 5 pediatric patients were CMV seropositive before transplantation. Underlying conditions included chronic myelogenous leukemia, primary immunodeficiency disorders, and hypoplastic left heart syndrome. One known GCV drug-resistant mutation was detected in 2 HCT recipients (A594V). Three strain variants with mutations considered to have no significant impact on UL97 function (H469Y, N510S, and D605E) were detected. Two of these 5 patients died, 1 because of uncontrolled CMV infection and 1 with other complications. Conclusions UL97 drug-resistant mutations occur in pediatric transplant recipients with CMV viremia and can cause serious disease. Screening for mutations conferring resistance to CMV antivirals should be considered for patients with persistent viremia during therapy and the sequences of UL97 mutations evaluated. [ABSTRACT FROM AUTHOR]

We report a case of recurrent cytomegalovirus (CMV) retinitis in an HIV-negative patient with CD4+ T lymphocytopenia. Case report. A 41-year-old HIV-negative woman with a history of systemic lupus erythematosus, idiopathic thrombocytopenic purpura requiring splenectomy, and diabetes presented with primary CMV infection, high-grade viremia, CMV pneumonia followed by CMV retinitis (CMVR) and a CD4+ T lymphocyte (CD4) count of 12 cells/mm3 after therapy with rituximab, prednisone, and methotrexate. Persistent CMV viremia led to genotypic analysis of the circulating virus, which revealed UL97 and UL54 mutations known to be associated with resistance to ganciclovir (GCV) and cidofovir. CMV clearance from the bloodstream followed systemic antiviral therapy and recovery of CD4 cell count. However, CMVR recurred multiple times despite GCV implants, systemic valganciclovir, intravitreal GCV injections, and persistent CD4 counts greater than 100 cells/mm3. Recurrent episodes of CMVR responded to multiple high dose intravitreal GCV injections (5000–6000 micrograms) and recovery of CD4 cell counts to greater than 200 cells/mm3. This case demonstrates that recurrent CMVR occurs in HIV-negative patients at CD4 cell counts thought to be protective in HIV patients, and suggests that an ineffective local immune response to retinal infection combined with CMV drug resistance may have been important factors leading to recurrent disease in this patient. Treatment producing high local concentrations of GCV may be effective therapy for CMV retinitis due to GCV-resistant virus. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection is a major complication following solid organ transplantation resulting in significant morbidity and mortality. The guidelines published in 2004 have recommendations for therapy; however, the frequency of resistant CMV infection is increasing and therapy is not clearly defined. There are a few alternatives to ganciclovir such as foscarnet, cidofovir, and leflunomide; however, their use is limited by adverse effects. This report summarizes the successful use of high-dose ganciclovir for the treatment of a resistant CMV caused by UL97 mutation. [ABSTRACT FROM AUTHOR]

A 20-year-old patient, who received a bone marrow transplant in order to treat metachromatic leukodystrophy (MLD), succumbed to cytomegalovirus (CMV) encephalitis. After CMV viremia developed, the patient received ganciclovir, but he was switched to foscarnet when ganciclovir resistance was suspected. Foscarnet was discontinued because of concern about its potential central nervous system toxicity. Autopsy samples of brain and cerebrospinal fluid contained CMV DNA with a UL97 mutation (M460V) known to confer ganciclovir resistance. No foscarnet resistance mutations were found. [ABSTRACT FROM AUTHOR]

Infection with cytomegalovirus (CMV) with resistance to ganciclovir (GCV) is a therapeutic challenge in kidney transplant patients, because standard treatment options are nephrotoxic. We report the case of a kidney transplant recipient with GCV-resistant CMV disease, in whom letermovir, a novel inhibitor of CMV packaging, was administered off-label and prevented a relapse of disease once the CMV load was decreased by cidofovir. Furthermore, we observed significant drug interactions between letermovir and tacrolimus., Learning Points: Cytomegalovirus (CMV) disease with resistance to ganciclovir (GCV) is difficult to manage in transplant patients.Letermovir may become a new option for treatment and prophylaxis of GCV-resistant CMV infection, but assessment of treatment response is difficult.Letermovir may lead to drug interactions via CYP3A4., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2020.)

Letermovir was approved by the Food and Drug Administration (FDA) in November 2017 for use in adult cytomegalovirus (CMV)‐seropositive allogeneic stem cell transplant (SCT) recipients for primary prophylaxis of CMV infection and disease. We report off‐label use of letermovir for secondary prophylaxis of genotype‐confirmed ganciclovir‐resistant cytomegalovirus (CMV) syndrome (UL 97 mutation [C603W]) in a heart transplant recipient initially treated with intravenous cidofovir followed by foscarnet, both discontinued due to unacceptable toxicities. [ABSTRACT FROM AUTHOR]