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Background (Val)ganciclovir resistance mutations in CMV UL97 (UL97-GCV-R) complicate anti-CMV therapy in recipients of solid organ and hematopoietic stem cell transplants, but comprehensive data on prevalence, emergence, and outcome are scarce. Methods Using next-generation sequencing (NGS; Illumina MiSeq platform), we analyzed UL97-GCV-R in patients with available plasma samples and refractory CMV replication/DNAemia (n = 87) containing viral loads ≥910 IU/mL. Twenty-one patients with CMV DNAemia resolving under antiviral therapy were analyzed as controls. Detected mutations were considered induced and of potential clinical significance if they increased by ≥10% compared with the first detected frequency or if they had a maximum frequency ≥25%. Results Nineteen of 87 (21.8%) with refractory CMV replication had ≥1 UL97-GCV-R detected by NGS, in comparison to 0/21 of the controls (P = .02). One-third of the recipients had 2 or more induced UL97-GCV-R mutations. The most frequently induced mutations affected codons 595 (42% [8/19]), 594 (32% [6/19]), and 603 (32% [6/19]). C592G was present in all episodes of both cases and controls at frequencies Conclusions UL97-GCV-R is common among transplant patients with refractory CMV replication. Early testing by NGS allows for identification of major mutations at codons 595, 594, and 603 and excludes a major role of C592G in ganciclovir resistance. Large prospective studies on UL97-GCV-R are warranted.

Objective. To identify mutations in UL97 gene associated with antiviral drug resistance in recipients of allogeneic hematopoietic stem cells transplants (allo-HSCT). Materials and Methods. A total of 9 HCMV DNA samples were studied. These samples were received from the blood of 8 allo-HSCT recipients who were infected with HCMV and undergoing treatment at NMRC of Hematology (Russia) over the period of 2016 to 2017. Sanger sequencing was used to find mutations. The sequenced part of the virus DNA was analyzed using nucleotide BLAST and Genome compiler. Mutations were identified using MRA program which compared the obtained nucleotide sequence with the reference sequence of UL97 gene from Merlin strain. Results. Rate of detection of viruses with mutations that may lead to drug resistance is relatively high – 3 of 8 patients. The following mutations were identified: C592G, C607F and C603W. The obtained data shows that the presence and characteristics of mutations affect the viral load and the time when HCMV DNA is identified in blood. Conclusions. Obtained data show that presence of mutations impacts the course infection, leading to higher viral load and longer persistence of viral DNA in blood samples. Identified mutations had different resistance factor, which also impacted on the pattern of infection.

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after solid organ transplantation. There has been a significant shift in disease epidemiology with the introduction of antiviral prophylaxis, with CMV disease occurring later and clinical presentations more atypical. We describe two cases of very late-onset CMV disease where first disease occurred 15 and 18 years post-renal transplantation, with both cases complicated by antiviral drug resistance. We subsequently review the published cases and literature of very late-onset CMV disease (onset > 10 years post-solid organ transplantation) as an increasingly recognized phenomenon which is emerging as an important aspect in improving long-term patient outcomes in the current era of renal transplantation.

Aim: Ganciclovir (GCV) is used as an antiviral drug for the treatment of human cytomegalovirus infection. The aim of this study was to demonstrate GCV-resistant human cytomegalovirus in congenitally infected neonates. Patients & methods: DNA of CMV positive newborn samples was extracted and UL97 and UL54 genes were amplified by PCR and real-time PCR. Sequencing of UL97 and UL54 genes were performed and analyzed. Results: UL97 GCV resistance mutation C603W was detected in one newborn. D605E was the most common polymorphism in UL97 observed in 7/13 (53.8%) of samples. N685S, A688V, A885T and N898D were four known common UL54 polymorphisms. Conclusion: The rate of GCV resistance in congenital CMV is low. Common polymorphisms in UL97 and UL54 genes are also reported as new mutations.

Cytomegalovirus (CMV) infection is a common complication following kidney transplantation resulting in significant morbidity, graft loss, and occasional mortality. Patients at high risk of CMV disease are CMV-seronegative recipients (R-) who receive an organ from CMV-seropositive donor (D+) and those receiving an intensive T-cell depleting induction immunosuppression. The diagnosis is based on the detection of viral replication by pp65 antigenemia or CMV DNAemia. Current preventive strategies in kidney transplant recipients include universal prophylaxis for 3–6 months after kidney transplantation or pre-emptive therapy with valganciclovir or intravenous ganciclovir. Established disease should be treated using either intravenous ganciclovir or oral valganciclovir until CMV replication can no longer be detected. Ganciclovir-resistance CMV, which consists of a lack of clinical or virological response to prolonged therapy due to viral gene mutations, is an emerging clinical challenge. In this review, we highlight the most relevant topics on CMV and kidney transplantation based on current evidence and guidelines.

Background Ganciclovir-resistant (ganR) cytomegalovirus (CMV) is an emerging and important problem in solid organ transplant (SOT) recipients. Only through direct comparison of ganR- and ganciclovir-sensitive (ganS) CMV infection can risk factors and outcomes attributable specifically to ganciclovir resistance appropriately be determined. Methods We performed a retrospective, case-control (1:3) study of SOT recipients with genotypically confirmed ganR-CMV (n = 37) and ganS-CMV infection (n = 109), matched by donor/recipient CMV serostatus, year and organ transplanted, and clinical manifestation. We used χ2 (categorical) and Mann-Whitney (continuous) tests to determine predisposing factors and morbidity attributable to resistance, and Kaplan-Meier plots to analyze survival differences. Results The rate of ganR-CMV was 1% (37/3467) overall and 4.1% (32/777) among CMV donor-positive, recipient-negative patients, and was stable over the study period. GanR-CMV was associated with increased prior exposure to ganciclovir (median, 153 vs 91 days, P < .001). Eighteen percent (3/17) of lung transplant recipients with ganR-CMV had received

Buyukdogan, Murat/0000-0001-7948-0235; Aki, Sahika Zeynep/0000-0002-3068-5085; acar, muradiye/0000-0003-4357-5229; hancer, veysel sabri/0000-0003-2994-1077 WOS:000416975700007 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.

Cytomegalovirus (CMV) infection is an important cause of morbidity in renal transplant recipients, due to both direct and indirect effects of the virus on the graft and patient [1]. Ganciclovir (GCV) remains the most common first-line therapy, but its low oral bioavailability was identified as a risk factor for the emergence of resistant strains [1], and intravenous (IV) administration is inconvenient for use in prophylactic or pre-emptive therapy. Valganciclovir (VGCV) is a prodrug of GCV with a much higher oral bioavailability, which makes it very useful for prophylaxis and pre-emptive therapy, as well as for treatment in selected patients [2–4]. Although initially associated with a negligible risk of drug resistance [5], subsequent papers identified patients with GCV-resistant CMV infection after VGCV prophylaxis and treatment [6, 7]. Patients with drug-resistant CMV strains often have more tissue-invasive disease and unfavourable clinical outcomes [8, 9], but there is some heterogeneity, and reports of asymptomatic infection, particularly in non-lung transplant recipients, suggest that some mutations are less pathogenic than others [10]. The therapeutic approach is a challenge and must balance the severity of the infection against the risks of drug toxicity and reduction of immunosuppression. We report two cases of GCV-resistant CMV from our unit: the first is a case of invasive CMV disease in a low-risk renal transplant recipient while on therapy with VGCV, and the second is a high-risk patient who developed GCV-resistant CMV infection while on VGCV prophylaxis.

Human cytomegalovirus (CMV) infection is a major issue in solid organ transplant recipients. Although development of prophylaxis and preemptive procedures have presented significantly improved consequences in CMV infection, increasing incidence of antiviral resistance has raised virologists' concern.The present study focused on kidney transplant recipients with high quantities of CMV load after antiviral therapy. We collected 5 mL blood from each of 58 patients. DNA extraction was performed with the use of the QIAamp DNA Mini kit (Qiagen), in accordance with the manufacturer's instructions.Our population study was 38% female and 62% male. CMV DNA was observed in 50 specimens (86%) with the range of 1.9 × 10(3) to 11 × 10(7) copies/mL serum. All of these patients had received ganciclovir for3 months. Sequencing showed 18 mutations in 10 patients. Among these, 16 mutations were associated with Ul97 and the rest with Ul54 gene. Forty CMV-positive patients did not show any mutations.The consequences of long-term ganciclovir resistance could not be determined.

publisher: Elsevier articletitle: Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient journaltitle: Antiviral Research articlelink: http://dx.doi.org/10.1016/j.antiviral.2016.05.020 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved. ispartof: Antiviral Research vol:132 pages:149-153 ispartof: location:Netherlands status: published

Longer wait times for deceased donor kidney transplant have prompted newer initiatives to expedite the process. Reuse of a previously transplanted kidney might be appropriate in certain circumstances. However, one must also consider the unique issues that may arise after such transplants. We describe our experience in one such case where the donor kidney had lesions of focal and segmental glomerulosclerosis and signs of alloreactivity (positive C4d staining) prior to transplantation and the recipient developed ganciclovir-resistant cytomegalovirus (CMV) infection, which was perhaps transmitted from the donor. Despite the challenges, the allograft function remained stable 5 years after reuse.

Cytomegalovirus (CMV) infection is latent in the majority of adult humans. The reactivation of CMV causes pneumonia and gastrointestinal disease in severely immunosuppressed patients, who consequently suffer very high mortality due to CMV central nervous system disease. We report here a case involving a 28-year-old female patient with mycosis fungoides who underwent umbilical cord blood transplantation three times and developed CMV ventriculoencephalitis. The patient's CMV viremia was successfully preempted with ganciclovir (GCV) as indicated by undetectable CMV antigenemia, but despite this successful treatment, the patient developed CMV ventriculoencephalitis. Foscarnet (FCV) therapy led to a temporary recovery, after which CMV ventriculoencephalitis recurred and the patient died after receiving combination GCV and FCV therapy. Autopsy samples revealed CMV ventriculoencephalitis, as indicated by numerous inclusion-bearing cells (Owl's eye). It is likely that this patient harbored a GCV-resistant CMV strain; however, it was not possible to obtain nucleic acids suitable for use in assessing this possibility.

Based on data from the European and US multicenter study in liver transplant recipients, an oral preparation of ganciclovir has recently received FDA approval as prophylaxis for cytomegalovirus (CMV) in solid-organ transplant recipients (1). Oral ganciclovir, administered for three months, was ef® cacious as prophylaxis for CMV disease, both in seropositive recipients and seronegative recipients of seropositive donor allografts (1). Because of the ease of administration and relatively benign toxicity pro® le of oral ganciclovir, widespread use for prolonged durations is not only likely but is already occurring at many transplant centers. However, a major concern with the utilization of prophylaxis for all patients is the potential for emergence of ganciclovir resistance.

Cytomegalovirus retinitis successfully treated with ganciclovir implant in a patient with blood ganciclovir resistance and ocular ganciclovir sensitivity

SummaryWe report the case of a young female lung transplant recipient with difficult-to-treat cytomegalovirus (CMV) disease. While treatment with intravenous (IV) ganciclovir failed due to antiviral drug resistance, a trial with foscarnet resulted in severe side effects. In addition, the patient received IV CMV-specific immune globulins as adjunctive therapy and leflunomide as experimental therapy. In this context, CMV-specific immune monitoring was performed and was successfully implemented in management decisions. The patient was screened for acquisition of an adaptive immune response, and antiviral prophylaxis and therapy was tailored according to results. This report highlights the impact of CMV-specific immune monitoring on individualized therapy for appropriate prophylaxis and management of CMV infection and diseases.